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University M icrofilm s International 300 N. Zeeb Road Ann Arbor, Ml 48106 8518937
Fiscus, David Michael
THE CHEMISTRY OF 3-DIAZO-3H-1.2.4-TRIAZOLE AND 3H-1,2,4-TRIAZOL-3- YLIDENE
The Ohio State University Ph.D. 1985
University Microfilms
International300 N. Zeeb Road, Ann Arbor, MI 48106
Copyright 1985 by Fiscus, David Michael All Rights Reserved The Chemistry of 3-Diazo-3H-1,2,4-triazole and 311-1,2,U-Triazol-3-ylidene
Dissertation
Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University
By
David Michael Fiscus, B.S., M.A.
***««
The Ohio State University
1985
Reading Committee: Approved By
Dr. D. Hart
Dr. H. Shechter
Dr. J. Swenton Adviser
Department of Chemistry © 1985
DAVID MICHAEL FISCUS
All Rights Reserved To Mr. and Mrs. Don Fiscus
ii ACKNOWLEDGEMENTS
Many people have contributed to my education, the preparation of this manuscript and personality development over the term of this graduate program. My thanks and recognition to their efforts follows:
Dr. H. Shechter for allowing me to work in his laboratories and for providing the educational experiences resulting from this work; the taxpayers of Ohio and The National Institutes of Health for their financial support; the faculty and staff in the Chemistry Department at
The Ohio State University from 1979 to present, particularly Dr. J.
Hine, Dr. M. Platz, and Dr. V.A. Yagello for their instruction as well as Ms. B. Cassidy and Ms. P. Fonda for their secretarial assistance; Dr
T. Engler, Dr. J. Glinka, Dr. D. Hart, Dr. S. Hoshino, and Dr. C.B. Rao for their advice and instructions in laboratory work; Mrs. J.E. Merritt
(Chemical Abstracts Service) for her help in nomenclature, Ms. D. Tyler and Ms. B. Bennett for their role in preparing the final manuscript; Ms
K. Willardson, Mr. B. Griffin, Mr. T. Schaefer, and Mr. J. Strode for their friendships; and the members of this reading committee for their participation in the final stages of this thesis. VITA
March 23, 1954 Born - Columbus, Ohio
May 1977 B.S., The University of Alaska, Fairbanks, Alaska
May 1979 M.A., The University of Alaska, Fairbanks, Alaska TABLE OF CONTENTS
Page
Dedication...... ii
Acknowledgements...... iii
Vita...... iv
List of Tables...... viii
Statement of Problem...... 1
I. Introduction...... 2
II. Results and Discussion...... 34
Formation and Characterization of 3-Diazo-3H.-1,2,4-triazole...... 34
Cycloaddition Chemistry...... 40
Reactions with Alcohols...... 44
Preliminary Reactions with Aromatics...... 45
Synthesis of Authentic Samples...... 65
Substituted-N-s_-triazol-4-ylbenzamidines...... 65
3-(Substituted)- 1H-1,2,4-triazoles...... 66
Reactions with Aromatics...... 71
Electron-rich Aromatics...... 74
Electron-poor Aromatics...... 79
Competition Experiments...... 97
ESR Study...... 113 Kinetic Deuterium Isotope Study...... 113
Mechanism...... 118
III. Experimental...... 146
General Comments...... 146
Materials...... 147
Commercial Chemicals...... 147
General Synthesis of Reagent Chemicals...... 148
Detailed Syntheses of Reagent Chemicals...... 149
Amidine Synthesis...... 151
Acylthiosemicarbazide Synthesis...... 163
Triazole-thione Synthesis...... 164
Triazole Synthesis...... 168
Preparation of 3-Diazonium-1H.-1,2,4-triazole...... 183
Preparation of 3-Diazo-3H.-1,2,4-triazole...... 184
Isolation of 3-Diazo-3]1-1,2,4-triazole...... 184
Explosive Behavior of 3-Diazo-3H.-1,2,4-triazole... .184
IR Spectrum of 3-Diazo-3J3-1,2,4-triazole...... 185
ESR Spectrum...... 186
Cycloaddition Chemistry...... 187
Reactions of 3-Diazo-1P[-1,2,4-triazole with Alcohols...... 191
Thermolysis of 3-Diazo-3H.-1,2,4-triazole in Benzenoid Solvents...... 193
Photolysis of 3-Diazo-3H-1,2,4-triazole in Benzenoid Solvents...... 210
Competition Reactions of 3-Diazo-3JH-1,2,4- triazole in Benzenoid Solvents...... 215
vi Kinetic Deuterium Isotope Study...... 223
Reactions of 3-Diazo-3H.-1,2,^-triazole with Benzenoid/WaterEmulsions ...... 22^
IV. Appendixes
Appendix I...... 227
Appendix II...... 237
Appendix III...... 255
V. List of References...... 259
vii LIST OF TABLES
Table Page
1. Reactions of 3-Diazo-5-phenyl-3H-1,2,4-triazole with Substituted Benzenes...... 11
2. Thermal Reactivities of 3-Diazo-5-phenyl-3H-1,2,4-triazole with Substituted Benzenes Relative to Benzotrifluoride...... 11
3. Results of Reactions of Diazotetrachlorocyclopentadiene with Benzene...... 20
4. Products from Reactions of 3-Diazo-2,5-diphenylpyrrole with Monosubstituted Benzenes...... 23
5. Products from Reactions of 3-.t.-Butyl-5-diazopyrazole with Monosubstituted Benzenes...... 24
6 . Products from Reactions of 4-Diazoimidazole with Monosubstituted Benzenes...... 24
7. Products from Reactions of 2-Diazoimidazole with Monosubstituted Benzenes...... 26
8. Summary of Information Concerning Extraction of 3-Diazo-3H.-1 ,2,4-triazole from Aqueous Solutions...... 39
9. Yields of Aldehydes or Ketones Produced in the Reactions of 3-Diazo-3H.-1,2,4-triazole with Various Alcohols...... 44
10. Summary of the Slopes and Intercepts of GLC Calibration Curves Used in the Competitive Experiments...... 54
11. Slopes and Intercepts of the GLC Calibration Curves Used to Analyze the Products from the Reactions of _1_ with Chlorobenzene and Bromobenzene...... 55
12. Summary of the Extinction Coefficients of 3-(Substituted Phenyl)-TH-1,2,4-triazoles in Ethyl Acetate at 254 nm...... 58
viii 13. Summary of the Actual and the Observed Mole Ratios and Percentages of the Isomers in Standard Samples of 3-(o^ and j)-Tolyl)-111-1,2,4-triazoles as Determined by HPLC Analysis...... 62
14. Summary of the Solutions of 3-(o^ and j)-Chlorophenyl)- 1JH— 1,2,4-triazoles Used in Establishing the Accuracy of the HPLC Method of Analysis...... 62
15. Summary of the Actual and the Observed Values of the Mole Ratios and the Percentages of the Isomers in a Standard Sample of 3-(o- and j3 -Chlorophenyl)-111-1,2,4-triazoles as Determined by HPLC Analysis...... 63
16. Summary of the Data for Chromatography of the Product from Thermolysis of _1_ in Chlorobenzene...... 63
17. Summary of the Results of the HPLC and GLC Analyses of the Product from Thermolysis in Chlorobenzene...... 64
18. Summary of the Preparation and Properties of the Substituted- N-S-4H-1,2,4-triazol-4-ylbenzamidines Synthesized...... 67
19. Summary of the Preparation and Properties of the 3-(Substituted Phenyl)-1H-1,2,4-triazoles Synthesized...... 69
20. Summary of the Properties of the 3-(Substituted Phenyl)- 1H-1,2,4-triazoles Isolated from Thermolyses of 3-Diazo- 311-1,2,4-triazole in Benzonitrile and in Methyl Benzoate...... 71
21. Products (Mole Percent) from 3-Diazo-3H.-1,2,4-triazole and Substituted Benzenes, as Determined by HPLC Analysis...... 73
22. Phenylations of Monosubstituted Benzenes with Benzoyl Peroxide at 90°C...... 92
23. Reactions of 3,5-Dichloro-1,4-diazooxide with Monosubstituted Benzenes...... 93
24. Nitrations of Monosubstituted Benzenes with Nitric Acid in Sulfuric Acid...... 93
25. Nitrations of Monosubstituted Benzenes using Different Nitrating Agents...... 94
26. Nitrations of Monosubstituted Benzenes with Nitronium Tetrafluoroborate in Tetramethylene Sulfone...... 95
ix 27. Halogenations of Monosubstituted Benzenes with Different Halogenating Agents...... 96
28. Molar Reactivities of 3-Diazo-3H.-1,2,4-triazole with Cyclohexane and Monosubstituted Benzenes Relative to Benzene at 80°C...... 98
29. Reactivities of Carbenes with Monosubstituted Benzenes Relative to Benzene...... 105
30. Relative Reactivities of Electrophiles in Aromatic Substitutions of Monosubstituted Benzenes...... 106
31. Relative Reactivities of para-Substituted Phenyl Radicals Toward Monosubstituted Benzenes...... 107
32. Estimation of the Percentages of 3-(Substituted Phenyl)- 1H-1,2,11-triazoles Formed in Mixed-Solvent Experiments...... 108
33. Summary of the Partial-Rate Factors of Monosubstituted Benzenes Used in the Mixed-Solvent Experiments...... 109
3*1. Partial-Rate Factors of 2-Azolylidenes and Electrophilic Reagents for Monosubstituted Benzenes Used in the Mixed-Solvent Experiments...... 110
35. Equilibrium Constants for Formation of Silver Nitrate Complexes with Substituted Benzenes...... 112
36. Stabilization Energies of Substituted 1,3-Cyclohexadienes..... 131
x Statement of Problem
The present study is an investigation of the chemistry of 3-diazo-3H-
1,2,^-triazole (_1_) and 3H-1,2,4-triazol-3-ylidene (2^, the carbene derived from 3-diazo-3_H-1,2,4-triazole (J_).
N2 h ~ * < ( /N y a \ N'” I
The principal objective of this research is to study the thermolytic, photolytic and cycloaddition reactions of 3-diazo-3H,-1,2,4-triazole (_1_) with various substrates.
1 INTRODUCTION
In 1898 J. Thiele and W. Manchot initiated study of 3-diazo-3H_-
1 ? 1 ^^-triazoles by diazotizing 3-amino- 1H-1,2,4-triazole ’ (_3.) to
produce 3-diazo-3H.-1 , 2,11-triazole (_1_).
n_ ^ NH2 I) HN02
2)B (1) H 3
They stated that, upon treatment with a solution of nitrous and
hydrochloric acids, the aminotriazoles:
...wie bei den aromatischen Basen entstehen durch salpetrige Saure Diazoverbindungen, welche aber in einigen Punktensich von den gewohnlichen aromatischen Diazoverbindungen unterscheiden. Sie sind zwar noch kuppelungsfahig, gehen aber,.•.ausserst leicht in die Isoform uber; offenbar lieght hier ein gemeinsames Charakteristicum der Diazoazole vor, welches duch den negativen Charakter der Azolringe verursacht ist.*
3-Diazo-3H.-1,2,^-triazoles show a breadth of physical properties. 3-
Diazo-3.H-1,2 ,H-triazole-5-carboxylate (jja) precipitates as a white solid which explodes on slow heating between 120-123 °C and seems to be
*...as in the case of aromatic amines form diazonium compounds in nitrous acid, which are different from the usual aromatic diazonium compounds in only one way. They are indeed still capable of coupling, but change...easily into the other form [i.e., the diazocompound]. Obviously, here exists a common characteristic of diazoazoles, which is produced through the negative character of the azole ring. 3
capriciously shock-sensitive. Ethyl 3-diazo-3jh-1,2,4-triazole-5- o carboxylate-1 (5b) and 3-diazo-5-phenyl-3_H-1,2,4-triazole (^cO behave
similarly; they precipitate out of solution and are also shock-sensi
tive. In contrast with the properties of diazotriazoles 5a-5c are
N_/ NH? 2 l)HN02nuMo N-'C' N2 R-V N (2) A 4 5
4a CO2 H 5a
4b CO?C2H5 5b
4c Ph 5c
4d CH3 5d
4e C2 H5 5e
4f n-Pr 5f
4g i-Pr 5g
4h i-Bu 5h
those of simple 5-alkyl-3-diazo-3H-1,2,4-triazoles 5d-5h and 3-diazo-3H_-
1,2,4-triazole (_1_). 3 - D i a z o - 5 - m e t h y l - ^ (5d_), -ethyl-^’^’^ (5e),
- p r o p y l - ^ ( 5f)f -isopropyl-^’®’^ (5g), and -isobutyl-®3Ji- 1,2,4- triazoles (5h) and 3-diazo-3H-1,2,4-triazole^(J_) are water soluble compounds which lose diazo-nitrogen even when their solutions are carefully refrigerated.
Although diazotriazoles show a great variety of physical properties, their chemistry is similar. They all behave as electrophiles, frequently adding electron-rich reagents with retention of diazo-nitrogen (Eq
3) . 10’ 11
No N=N-Nu , Rn N N (3 ) 5 H
Thus, coupling with activated aromatics gives azo compounds, some of
which cyclize to [ 1,2 ,4]triazolo[5,1-c] [ 1,2 ,^triazines, ^ a process
which is structure- and frequently solvent-dependent. For example,
c:o 2h
,N=N-\\ A o H OH (4)
OH
OH
H
N ,N-dimethylaniline, phenol, salicylic acid, ^ ' 3 and a-naphthol^ * 5 couple with 3 -diazo-3ii-1,2 ,^-triazole (_1_) to give azo compounds which do 1 O 1 1 V\ not cyclize (Eq 4) whereas j)-cresol (Eq 5), _|3-naphthol » » 1_, R = OH, Eq 6) and 2-aminonaphthalene^’ (]_, R = NH2 , Eq 6) yield
azo compounds which ring-close under proper conditions.
1H-1,2,^-Triazole-S-azo-C2'-hydroxy-5'-methylbenzene) (_6 , Eq 5)
cyclizes in refluxing ethylene glycol whereas 1H-1,2,H-triazole-3-azo-
1 '-(2'-naphthol) {]_, R =0H, Eq 7) undergoes ring closure under the less
stressful conditions of boiling methanol or glacial acetic acid.
R R
(6 )
7
In methanol, 7_ (R = OH, Eq 7) converts to naphtho[2,1-eJ][1, 2,l4]tri-
azolo[5,1-c][1 ,2,4]triazine (8), whereas in methanol spiked with con
centrated sulfuric acid, a mixture of _8 and naphtho[2 ,1-e_][ 1,2 ,U] —
triazolo[3j^-c^][1,2,1<]triazine (9.) is obtained (Eq 7).
R r = N N=N- \- / ( s ' !}~$ (7) VN 'N' U- A IJ s ^ )
3-Diazo-3H-1,2,4-triazole (_1_) undergoes intermolecular condensations with a variety of active methylene compounds in alcohol-water mixtures to yield hydrazones.^ Some 8-diketones and 8-ketoesters couple with _1_ while others couple and cyclize. Thus, acetyl acetone and _1_ give a 7:1 mixture (60°/fc yield) of 3-( 1H-1,2,1l-triazol-3-ylhydrazono)pentane-2,1l-dione (10) and 7-methyl-
[1,2,*l]triazolo[5,1-£][1,2,*J]triazine-6-acetate (11) (Eq 8, R, R' = CH^).1^
H R x i. 0 0 \ > 0 N—4* R - ^ R „_yN_N=C „ .. (Tj; -* N-i >0 — . 0 (8, N V
I H .0 II
Benzoyl acetone and dibenzoylmethane condense with _1_ to give 1-
phenyl-2-(1H-1,2, *4-triazol-3-ylhydrazono)butane-1,3-dione (10, R = CH^,
R' = Ph, 78%) and 1,3-diphenyl-2-( 1H-1,2,*l-triazol-3-ylhydrazono)- propane-1,3-dione (10, R = R' = Ph, 35%) without ring closure to the 1 O corresponding triazolotriazines. J On the other hand, ethyl aceto- acetate reacts with J_ to yield ethyl 7-methyl[1,2,*l]triazolo[5,1-
£][1,2,4]triazine—6—carboxylate (11, R = CH^, R' = OEt) whereas ethyl- benzoylacetate gives ethyl 2-benzoyl-2-(1H-1, 2,*l-triazol-3-ylhydra- zono)acetate (_10, R = Ph, R' = OEt, 70%) and no triazolotriazine.
Condensation of diethyl malonate with _1_ results in a *1:1 mixture
(70%) of diethyl 1f1-1,2,*l-triazol-3-ylhydrazonomalonate (10, R= R' =
OEt) and ethyl 7-hydroxy[1,2,*l]triazolo[5, 1-£][1 ,2,*l]triazine-6-carboxy late (11, R = OH, R 1 = OEt) whereas malonitrile forms 1H-1,2,*l-triazol
3-ylhydrazonomalononitrile (12, R' = R = CN) which cyclizes to 7-amino-6-cyano[ 1,2,4]triazolo[5,1-c_] [ 1,2,4]triazine (_1_3, R = NHp, R 1
= CN, Eq 9) on attempted recrystallization from ethanol.^3,14
Even more interesting is reaction of _1_ with ethyl eyanoacetate to
give ethyl 1H-1,2,4-triazol-3-ylhydrazonocyanoacetate (12, R = C02 ET, R 1
= CN) which cyclizes in acid to ethyl 7-amino[1,2,4]triazolo[5,1-
_c][1,2,i1]triazine-6-carboxylate (_1_3, R = NH2 , R' = C02 Et) and in base to
6-cyano-7-hydroxy[1,2,4]triazolo[5,1-c_][1,2,4]triazine (13, R = OH, R f =
CN, Eq 9) . 111
Cycloaddition of 3-diazo-1H-1,2,4-triazoles occurs with electron-
rich multiple bonds. Thus 3-diazo-5-phenyl-1j^-1,2,4-triazole (5c)
condenses with cyclohexanone enamines: [l-(N-morpholinyl)-, 1-(N-piper
idenyl)-, l-(N-pyrrolidenyl)-, and 1-(N,N-diethylamino)cyclohexene] to
yield adducts which eliminate to 2 -phenyl[1,2 ,4]triazolo[5,1-c]cyclo-
hexa[e_][ 1,2,4]triazine (14, Eq 10).1^
NR2 R Ph Ph R~N n ^ n n .V N- ^ ‘ (10) ' f ~ A ;n - h n r 2 Ph N ;N N5 5c I4 nsj
With vinyl ethers ^c^ behaves similarly.^ Ethyl vinyl ether
condenses with 5c_ to give 2 -phenyl[ 1,2 ,4]triazolo[5,1-c][ 1,2,4]tri- azine^ (15, Eq 11) while 1-ethoxy-2-methylpropene yields 6,7-dihydro-7- ethoxy-6 ,6-dimethyl[1,2,4]triazolo[5,1-c][1,2,4]triazine^ (16, Eq 12). 8
Ph C2H50C2H3 f ' (11) 'N' Nr N-^y ‘ 15
P h ^ n ""N Ph (ch3)2c = c h o c2h5 /V5c C2H50Y^NNf N (CH3)^'N:;N (12 ) 16 rj
Electron-rich triple bonds behave similarly to electron-rich double bonds. Thus, 1-ethoxypropyne and 5c^ form 7-ethoxy-6-methyl-2-phenyl-
[ 1,2,)4]triazolo[5,1-c_] [ 1,2,4]triazine^ (17, Eg 13) and N-methyl-N- Pb
N—^ CH3C=COC2 H5 C2H5<^>Y ,N'^ f
P h ^ - N ’ c h X nJN <’3)
5c 3 |7
Ph Nc=\
N-p*2 CH^CECNCH^Ph CH^rN (PO ON ------• X 'N N C H , N' i T8 phenylpropynamine condenses with _1_ to produce N-methyl-N-phenyl-7-amino-
6-methyl[ 1,2,4]triazolo[5,1-c^][ 1,2,4]triazine^ (18, Eq 11!).
Behaving as electron-rich multiple bonds, the cumulenes: phenyliso- cyanate and phenyl isothiocyanate react with J5c_ to form 2,6-diphenyl [ 1,2,4] triazolo[5,1-d_] [ 1,2,3,5] tetrazin-7-one^ (19» X = 0,
Eq 15) and 2,6-diphenyl[1,2,4]triazolo[5,1-d_] [1,2,3,5]tetrazin-7-thione
(19, X = S, Eq 15), Ph Ncr< N2 ' N N—^ PhNCX < r 1 P h ^ N (15) Ph N 19
In addition to their behavior as electrophiles, 3-diazo-1H-1,2,H-
triazoles decompose thermally or photolytically with loss of diazo- nitrogen to produce intermediates which (1) add nucleophiles, (2 ) undergo oxidation-reduction with primary and secondary alcohols and (3 ) react with aromatic and heteroaromatic compounds.
In aqueous solution and in aqueous hydrogen halides diazotriazoles form hydroxytriazoles and halotriazoles. For example, 3-diazo-1JH-1,2,U— triazole-5-carboxylic acid (JO decomposes in water to 3 -hydroxy- 1.H-
1 ^H-triazole-U-carboxylic acid (20, Eq l6).^J^a In the presence
OH N - f h 2o H O g C - ^ N A * ___ 20
h o 2 c < ^ n Cl (16) HCI 5a -COc VN A 2 I of hydrochloric acid, J^ undergoes displacement of nitrogen by chloride ion and decarboxylation to 3-chloro-1F[-1,2,4-triazole (21, Eq 16)."*’^ In general, _1_ and its 5-alkyl derivatives are decomposed by hydrogen halides to the corresponding 3 -halo- 1J1- 1,2 ,H-triazoles. »^,3,6,14 10
The behavior of 3-diazo-1H_-1,2,4-triazoles (_1_ and JO in water is
different than in primary and secondary alcohols. 3-Diazo-3JJ-1,2 ,14—
triazole-5-carboxylic acid (JO and 3-diazo-5-phenyl-3H.-1,2,!l-triazole
(5c) are converted to 1_H— 1 ^^-triazole-S-carboxylic acid^’^a (22, R=
C02 H) and 3-phenyl-111-1,2,4-triazole1^ (22, R =Ph), respectively, by
heating with primary and secondary alcohols. The alcohols are oxidized
to their corresponding aldehydes and ketones. The mechanisms for these
oxidation-reduction reactions are not clear but the overall chemistry is
illustrated in Equation 17. It is again noted that strong nucleophiles
in alcohol/water solvents usually undergo coupling with nitrogen
retention rather than oxidation-reduction.
^OCHRe RpCHOH /NrN N-'t' 2 N-^< N-tv M i N "r" CO*" J l ' N (17> H H 5 22
In their pioneering 1898 article, Thiele and Manchot reported thermolysis of 3-diazo-3JJ-1,2,U-triazole-5-carboxylic acid (5a) in benzene and isolation of 3-phenyl-1H-1,2,4-triazole as the only capture A product. The mechanism by which 3-phenyl-1H-1,2,4-triazole (5c) is formed was not explained and the reaction was not examined further. In
1980 Glinka reported that 5c_ reacts with nitrogen expulsion and 1 5 insertion into the C-H bonds of alkanes and aromatics. In a study of its carbenic intermediate and its reaction mechanisms, 5c was thermolyzed and photolyzed in various substituted aromatic solvents.
The substitution patterns were found to depend on the 11
Table 1
Reactions of 3-Diazo- ■5-phenyl-3H- 1,2,4-•triazole (5c) with Substituted Benzenes
Isomer Percentages Thermolysis Photolysis
Substituent 0^ in £ o_ m_ £
OCH3 42 58 50 50
ch(ch3 ) 3 51 49 50 50
ch3 67 33 53 47
Cl 9 91 34 66
Br 55 45 30 70
cf3 100 100
CN 100 100
no2 100 100
electronic character of the aromatic substituent. Electron-donor groups
lead mainly to ortho- and para-substitution whereas strong electron- withdrawing groups cause meta-substitution (Table 1). Also found was
that _5c reacts preferentially (Table 2) with electron-rich benzenes
Table 2
Thermal Reactivities of 3-Diazo-5-phenyl-3.H.-1 >2,4-triazole (5c) with Substituted Benzenes Relative to Benzotrifluoride
Substituent Relative Reactivity
OCH3 3-^2
ch3 2.17
Cl 1.00 (such as anisole and toluene) in competition with relatively electron- poor benzenes (such as halobenzenes, nitrobenzene and benzonitrile). A further interesting feature of the mechanistic process is that hexa- fluorobenzene reacts with ring expansion to give 2 -phenyl-1J,5,6,7,8,9- hexafluoro[ 1,2,lJ]triazolo[5,1-aJazocine (J23, Eq 18).
F
(18)
F F 5c 23
Aromatic substitution by 5c_ can be explained by an overall elec- trophilic process summarized in Eq 19. Important features of the sub stitution process are initial addition to a benzene, forming unstable norcaradienes (24_), which collapse heterolytically to dipolar inter mediates 25_, which undergo hydrogen rearrangement to 26 .
Z
5c 24 25 26
Formation of _23 is also understandable on the basis of initial formation of 3-phenyl-1,2,l1-triazaspiro[l1.6]undeca-1,3,6,8,10-pentaene (.27) which rearranges electrophilically and sigmatropically to its requisite 2 -
phenyl[1, 2,4]triazolo[5,1-jc]azocine (23, Eq 20).
In addition to C-H insertion _5c effects substitution of the halo gens of halobenzenes (Eq 21), yields nitrosobenzene when generated in nitrobenzene (Eq 23) and forms ylides (29 and 3*0 with halobenzenes and with pyridine (Eq 21 and 2*4). These products can be accounted for by one common theme: coordination of 5-phenyl-3_H-1,2,4-triazol-3-ylidene
(28) with lone pair electrons of the substituents to give ylides (27) of different stabilities. In halobenzenes 2J3 effects substitution to give
1,3-diphenyl-5-halo-1J1-1,2,4-triazoles (30, Eq 21). The halogen
Ph
(21 )
Ph 28 29 30 substitution appear to involve coordination of carbene 2^ with a lone pair of electrons on the halogen to give intermediate ylides (29) which subsequently rearrange by phenyl migration. The tendency of the halo- benzene to coordinate with 2B_ seems to increase with the polarizability and the size of the halogen. Thus, the halogen-substitution product
Increases from 1% for chlorobenzene to l40/> for bromobenzene and to *17% for iodobenzene. It is of further interest that 28 reacts with 14
iodobenzene by dephenylation to give 3-iodo-5-phenvl-1H-1,2,4-triazole
(31, 10%, Eq 22). The fate of the phenyl group in this reaction is
unknown.
In nitrobenzene 5c_ reacts to give a 77% yield of nitrosobenzene (Eq
23). The oxygen-abstraction reaction occurs by coordination of carbene
28 with an oxygen of the nitro group to give ylide 32_ which subsequently collapses to nitrosobenzene and 3-phenyl-3H-1,2,4-triazol-3-one (33).
3-Phenyl-3j1-1,2,4-triazol-3-one is unstable and fragments to benzo- nitrile (84%), carbon monoxide and nitrogen.
0.® 0;N-Ph PhN02 N - ^ ° phCN (23) Ph hT Ph N -PhNO ph -C0.N2 28 32 33 r v rsj
In pyridine, 28_ coordinates with the lone electron pair of the nitrogen of the solvent to give a stable ylide (34, Eq 24) in about 15% yield.
n - Y c 5h 5n N /
p h V ------P h ^ N (2,) 28 34
3-Diazo-3H.-1,2,4-triazoles (_1_ and _5) are of interest because they are heterocyclic diazocompounds. More specifically, 3-diazo-3H.-1,2,4- triazoles (_1_ and 5.) are members of one of six possible azole systems.
The other parent azoles are 2-diazo-2H-pyrrole (35), 15
3-diazo-3H.-pyrrole (,36), 3-diazo-3H.-pyrazole ^ (37), 4-diazo-4H-
pyrazole2^ (38), 2-diazo-2H-imidazole^ (39), 4-diazo-4H-imidazole2^
(40), 4-diazo-4H-1, 2 ,3 -triazole^ (41) and diazo-^H-tetrazole^ (42).
Of these 35. and 3§_ ha.ve yet to be prepared.
Diazoazoles 35-42 are analogs of 1-diazo-1H,-cyclopentadiene^ (43) and are frequently referred to as diazoazacyclopentadienes and as 4N + 2 heterocyclic diazo compounds. The p-orbital and the pl-electrons of of the C=N units in such diazo compounds are part of planar 4n + 2 pi- electron systems and thus ,43. and the varied diazoazoles 35-42 have aro matic character. As might be expected, the chemistry of diazocyclo- pentadiene and of diazoazoles is similar. That is ,38, 39,, j£0, and 41, and derivatives of 35, 36 and j^3 capture electron-rich reagents with retention or loss of diazo-nitrogen and form structurally similar ylidenes on photolysis and thermolysis.
35 36 37 rv rv
No
No ro N-N & 38 39 40 /V
n2 No A 2 SW-I N-N ☆ 6 41 42 43 rv 3H-pyrrole2^’^® (44), 3-tert-butyl-5-diazo-5H-pyrazole^ (45), 4-diazo- 4H-imidazole^® (40), 2-diazo-2H-imidazole^^ (39) and 2-diazo-4,5- dicyano-2H-imidazole^ (.46.) with benzene and substituted benzenes will be summarized. 44 45 46 rs-/ rs*j On photolysis or thermolysis at room temperature 1-diazo~1jl- cyclopentadiene (43) reacts with benzene to give spironorcaradiene 47 (Eq 25).^ Also, on the basis of the exothermic reaction of adduct 47 with maleic anhydride to give 49^ in 85% yield, it has been presumed that and JJf) are in equilibrium (Eq 26 ).^ 17 Surprisingly the product from j£3 and hexafluorobenzene (Eq 27) is 6,7,8,9,10,11-hexafluoro spiro[ll.6]undeca-1,3*6,8,10-pentaene (50) rather than 6,7,8,9,10,11-hexafluoro spiro[2,H-cyclopentadiene-1,7'- norcaradiene] (51, Eq 27).^ (27) 51 The differences in the equilibrium positions between spiro[2,1t- cyclopentadi.ene-1,7'-norcaradienes] and spiro[4.6]undeca-1,3,6,8,10- pentaenes are revealing. The free energy of activation for conversion of into has been calculated to be 7-11 kcal/mole.^ This value is in agreement with the activation energy for isomerization of norcara- diene to cycloheptatriene (11 kcal/mole).^ The free energy of ^7 has also been calculated to be 10-13 kcal/mole less than for The free energy difference is somewhat higher than the 4 kcal/mole difference n O measured for norcaradiene and cycloheptatriene.-' In refluxing benzene kl_ isoraerizes to 1j1-cyclopentacyclooctene (52, Eq 2 8 ).3** Presumably, spiroC^^Jundeca-l,3,6,8,10-pentaene (48) under goes 1,5-sigmatropic rearrangement to J52. Under similar conditions 6,7,8,9,10,11-hexafluoro spiro[4.6]undeca-1,3,6,8,10-pentaene (51) rearranges to 6,7,8,9,10,11-hexafluoro-IH^cyclopentacyclooctene.^ The activation energies for 1,5-rearrangements of spiro[4,4]nona- 1,3-diene (53, Eq 29) and spiro[4,5]deca-1,3-diene (54, Eq 30) are 36 and 47 kcal/mole, respectively.^ The activation energies therefore required for the rearrangements of _47 to 52_ and 5J_ to 6,7,8,9,10,11- hexafluoro-11[-cyclopentacyclooctene are about 45 kcal/mole. o o — ■ e O 53 54 Further chemistry of _47 is its acid catalyzed conversion to phenyl- cyclopentadiene (55, Eq 3 1 ) The isomerization reveals an important rearrangement outlet for norcaradienes. \ — / \JJ (31) 55 Derivatives of 1-diazo-1F[-cyclopentadiene (47) yield different products when reacted with benzenoids than does. For example, 2-diazo-1,3-diphenyl-2H-cyclopentadiene (56) and benzene give 4fr-1,2,3-triphenyl-1JH-cyclopentadiene (57) and 1 ,lJ-diphenyl-5fr-benzo- cycloheptene (58, Eq 32).^ Ph 59 60 Further, h-diazo-1,2,3-triphenyl-4H-cyclopentadiene (59) and benzene h p yield 1,2,3-triphenyl-1H-cyclopentacyclooctene (60, Eq 33). The thermal stabilities of the substituted spiro[2,H-cyclopenta- diene-1,7'-norcaradienes] (62) formed by photolyses of diazotetrachloro- oyclopentadiene (5j_) in benzene, trifluoromethylbenzene and jn-hexa- liq fluorodimethylbenzene have been studied. J The percentages of the spiro[4.6]undeca-1,3,6,8,10-pentaenes (63) from _6j2 decrease as the benzene becomes more electron deficient (Eq 31» Table 3)- 20 Table 3 Results of Reactions of 6± with Benzenes Yield (%) % 62 in G (kcal/mole) RR’ 62 + 63 mixture 62 + 63 64 H H 30 19 26 c f 3 H 40 28 27 c f 3 c f 3 45 66 28.5 Further, mixtures of _6l_ and _63 thermally rearrange to substituted 1-phenyl-2,3,4,5-tetrachloro-2j1-cyclopentadienes (6*1, Eq 35). The free energies of several such rearrangements are shown in Table 3. R (35) Cl R R Cl H Cl 63 62 64 The isomerizations of Equation 35 are similar to thermal rearrange ments of bicyclo[4.1.0]heptanes to benzenes; the latter processes occur at higher temperature (100 °C). The activation energies for conversion of spiro[2,4-cyclopentadiene-1,7'-norcaradienes] j62 to _64_ are indeed smaller than that for rearrangement of 7,7-dicyanonorcaradiene (65, R = CN, R' = H) and 7,7-dimethylnorcaradiene (65, R = CH^, R' = H) to dicyanobenzyl (66, R = CN, R' = H) and cumene (66, R = CH-^, R' = H) (31.5 and 40 kcal/mole, respectively) (Eq 3 6 ) . ^ ’^-’ The lower activation energies for aromatization of spiro-[2,4-cyclopentadiene- 1,7'-norcaradienes] 62_ in comparison to 7,7-disubstituted norcaradienes 65 are probably consequences of greater stabilization of the 21 zwitterionic or the diradical intermediates generated from 5%_ than of those generated from 65. Further, mixtures of 1-, 2- and 3-methyl-7,7-dicyanonorcaradienes (65, R = CN, R' =CH^) thermolyze to a-, in- and jv-tolylmalononitriles (66, R = CN, R 1 = CH^) at 55-100 °C. ^ The composite rate constants for aromatization of the methyl-7,7-dicyanonorcaradienes (65, R = CN, R' = CH^, 3.5 x 10“5 mole/sec) are 16 times that for 7,7-dicyanonorcaradiene (65, R = CN,R' = H, 2.17 x 10“^ mole/sec). Considering that the activation energies for aromatization of 7,7-dicyanonorcaradienes (65, R = CN, R 1 = H) are about 31.5 kcal/mole, those for aromatization of methyl-7,7-dicyanonorcaradienes 65_ (R = CN, R' = CH^) have to be about 29 kcal/mole. The above results indicate electron-donating substituents at the C-1 to C-6 positions of a norcaradiene promote aromatization while electron-withdrawing substituents at these positions have the reverse effect, i.e., retard aromatization. Additional information regarding the factors which stabilize norcaradienes comes from Hoffman.1^ Thus the interaction of the HOMO of the Walsh orbitals in the cyclopropyl ring of norcaradienes with the LUMO of vicinal double bonds at the Cy position causes (1) electron transfer from the cyclopropane ring to the TT-system, (2) an increase in the strength of the C-pCg bond due to delocalization of the antibonding 22 Ci—Cg orbital, and (3) a decrease in the bond strengths at C^-Cj and Cg-Cy. Further, these effects should increase with the acceptor strength of the ir-ligand, i.e., with a lowering in the energy of the unoccupied tt-MO of the ligand. Diazoazoles show behavior with benzene and substituted benzenes similar to that of substituted diazocyclopentadienes. The diversity in the chemistry of diazoazoles with monosubstituted benzenes originates from the number and positions of the nitrogens in the diazoazole rings. For example, 3-diazo-2,5-diphenylpyrrole (4U) reacts thermally and photolytically with benzenes to give products resulting from ring expansion and aromatic substitution (Eq 37).^ Ph ' n - h n 2 Ph Ph Ph (37) 44 Ph Ph-^?~$-Ph N rt 68 The processes are determined by the nature of the benzenic substituent, the reaction environment and the initation method. Thus hydrogen substitution occurs in the thermal and photolytic reactions of with benzenes bearing electron-donor groups (such as anisole and toluene, Table 4) to yield 3-(substituted phenyl)-2,5-diphenyl-1fl-pyrroles (Eq 37). Ring expansion predominates, however, in the reactions of UU with benzene and with benzenes bearing electron-withdrawing groups (N02 and CN) to give substituted 2H-1,3-diphenylcycloocta[c]pyrroles (67, Eq 37, 23 and Table 4). Further, photosensitization of _44 by thioxanthene-9-one in benzene results in formation of 2,3,5-triphenyl-1H-pyrrole (68) rather than 1,3-diphenyl-2H-cycloocta[cJ) pyrrole (67). Table 4 Products from Reactions of 3-Diazo-2,5-diphenyl-3H- pyrrole (_44) with Monosubstituted Benzenes Yield (%) of Product Substituted C-H Substituted Ring- Benzene Condition ortho meta para expanded Anisole A/hv — — 50 -- Toluene A/hv 10 10 10 -- Benzonitrile A/hv __ __ _ '16-47 — —— 35-36 Nitrobenzene A — 19 — 23 As does 3-diazo-2,5-diphenyl-32[-pyrrole (_44_), 3-tert-butyl-5-diazo- 5_H-pyrazole (U5) reacts with substituted benzenes to give products arising from hydrogen substitution and ring expansion (Eq _38, Table 29 5). The substituent directs the position of substitution and 45 controls the paths to substitution and ring expansion. Substituents on benzene which are electron-donating by induction and/or resonance direct substitution by 3-tert-butyl-5H-pyrazole-5-ylidene for ortho- and 24 Table 5 Products from Reactions of 3-tert-Butyl-5-diazopyrazole (45) with Monosubstituted Benzenes Relative Yield (%) of Product Substituted Reactivity C-H Substituted Ring- Benzene kX/kH ortho meta ..para expanded Anisole 1.2 51 -- 39 t Toluene 62 -- 30 t Chlorobenzene 0.6 56 -- 29 10 Benzonitrile 0.4 51 20 13 16 Nitrobenzene t 12 30 40 Table 6 Products from Reactions of 4-Diazo-4fr-imidazole (40) with Monosubstituted Benzenes Product Percentages (%) Substituted Reaction C-H Substituted Benzene Condition ortho meta para Anisole 77 33 hU 50 25 _t-Butylbenzene 68 31 hU 68 32 Chlorobenzene 13 87 hU 0.5 35 Trifluoromethyl- benzene 12 88 ho 16 84 Benzonitrile 45 55 ho 49 51 Nitrobenzene 68 32 hO 61 27 11 25 para-hydrogen. Substituents which are electron-withdrawing by resonance (1) lead to substitution mainly at the ortho- and meta-positions and (2) enhance azocine formation at the expense of hydrogen substitution. Unlike 3-tert-butyl-5-diazo-5H-pyrazole, M-diazo-MH-imidazole (J40) reacts with benzenes to give products from hydrogen substitution and none from ring expansion (Table 6).3® 4H-Imidazol-M-ylidene substitutes the ortho- and the para-positions of benzenes containing inductive and/or resonance electron-donor groups. Electron-withdrawing substi tuents with the exception of the nitro group, cause meta substitution to predominate. The nitro group directs substitution primarily in the ortho-position; meta-substitution is also significant. Monosubstituted benzenes undergo C-H substitution in reactions with 2-diazo-2H-imidazole (39).^ The substitution patterns are similar to those for M-diazo-MH-imidazole (MO) but the ratios of isomers are different except for the reactions with benzonitrile (Compare Tables 6 and 7). A further difference is that 39_ reacts with substituents with the exception of the nitro group, causing meta substitution to predominate. The nitro group directs substitution primarily in the ortho-position; meta-substitution is also significant. Monosubstituted benzenes undergo C-H substitution in reactions with 2-diazo-2H-imidazole (39).^ The substitution patterns are similar to those for M-diazo-MH-imidazole (MO) but the ratios of isomers are different except for the reactions with benzonitrile (Compare Tables 6 and 7). A further difference is that _39_ reacts with all halobenzenes except fluorobenzene to give 2-halo-1-phenyl-1H-imidazoles, 2-halo-5- phenyl-111-imidazoles and 5-halo-2-phenyl-1jl-imidzoles along with 26 Table 7 Products from Reactions of 2- Diazo-2j4--imidazole (39) with Monosub- stituted Benzenes Yield (%) of Product Substituted Reaction C-H Substituted Reaction with Benzene Conditions ortho meta para Substituent Anisole hv) 25 -- 24 — Toluene hv> 30 4 23 — Cumene hU 31 -- 26 — Fluorobenzene hU 114 -- 29 — Chlorobenzene hU 37 23 14 Bromobenzene hU 18 -- 19 23 Iodobenzene hU 14 17 38 Benzonitrile hU 15 13 1 15 Nitrobenzene A/hv) 3 5 — >50 Methyl Benzoate A/hU — 25 3 — Trifluoromethyl benzene A/hO 7 60 16 2-(o-, m- and jD-bromophenyl)-111-imidazoles. The mechanisms proposed for formation of 2-halo-1-phenyl-1jl-imidazoles and 2-halo-5-phenyl-1j1- imidazoles are similar to that for 1,3-diphenyl-5-halo-12l-1,2,4- triazoles (30) from 3-diazo-5-phenyl-3H-1,2,4-triazole and halobenzenes (Eq 22). 5-Halo-2-phenyl-1H-imidazoles could be formed by a mechanism similar to the one for ipso substitution in aromatic nitrations. Thermolysis of 39_ in benzonitrile, followed by work-up, results in virtually equal quantities of m- and jD-cyanophenyl)-1H-imidazoles as well as some N-benzoyl-2-amino-1H-imidazole. Further, _3<8 and 27 nitrobenzene yield nitrosobenzene as a major product along with 2-(o_- and m-nitrophenyl)-111-imidazoles. The mechanisms for conversion of nitrobenzene to nitrosobenzene by J5c_ and 39_ are apparently similar (Eq ' 23). Ring substituents in diazoazoles also effect the behavior of azoly- lidenes with benzenes. For example, 4,5-dicyano-2-diazo-2H-imidazole (46) reacts with halobenzenes to give C-H substitution products along with those resulting from initial attack on halogen.^ Thus effects ipso substitution to give 4 ,5-dicyano-2-halo-1-phenyl-1H-imidazoles (71). These reactions appear to involve coordination of 4,5-dicyano-2H- imidazol-2-ylidene (69) with the halogen to give ylides 70_ which subse quently rearrange by phenyl migration. The abilities of halobenzenes to coordinate with 69, and the stabilities of ylides 70_ seem to increase with the polarizability and the size of the halogen. NC/ ^ N, PhZ NC^N © NC?TNv NC V - - _ NC%ZPh — NCY Z (39) Ph 69 70 71 4,5-Dicyano-2-fluoro- and 4,5-dicyano-2-chloro-1-phenyl-IH-imid- azoles are produced in 23% and 21% yields. The yields of 2-bromo-4,5- dicyano-1-phenyl-111-imidazole (7_1_, X= Cl) and 4,5-dicyano-2-iodo-1- phenyl-1H-imidazole (71, X = I) are somewhat lower. Further, ylide J0_ (X = F) was not observed in the reactions of 4J5 with fluorobenzene. A 26% yield of ylide 70^ (X = Cl) was produced from Jl6^ and chlorobenzene. Ylide 70 (X = Br) is formed in greater than 26% yield from bromobenzene 28 whereas J0_ (X = I) is the only product produced in the reaction with iodobenzene. As will be presented later, the reactions of 3-diazo-3H_-1, 2,1!- triazole (_1_) with various substrates are of interest with respect to overall synthesis as summarized in Scheme I_. That is, _1_ may be useful N 2 N = \ R-CEC-R ^ •S-N ------* I 72 N-\ ^ H5Z N f* Ni N*K V — y j / \ Ph-Z t H 73 74 75 Scheme I for preparing 6- and 7-substituted[ 1 ^^ItriazoloCS, 1-c][ 1 ,2,H]tri- azines^® (72), 3-(substituted phenyl)-1H-1,2,^-triazoles^^ (73), substituted 1F[-cyclohepta[5,6-d_][ 1,2,lJ]triazines-^ (7*0 and [ 1,2,H ]triazolo[5,1-aJazocines^ (75) (Scheme I). In order to evaluate practical approaches for preparing 72^ to ^75 current routes to their synthesis will now be discussed. As mentioned previously, triazolotriazines have been synthesized from _1_ and active methylene compounds (Eq 8 and Eq 9)- The synthetic methodology has been limited however to preparations of J2_ with carbonyl functionality at positions C-6 and C-7. Triazolotriazines 12_ without carbonyl groups at those positions can be prepared conceptually by extending triazines ]6_ from their 3-positions to hydrazinotriazines 77. and then triazolotriazines J8_ which can be isomerized by rearrangements of the Dimroth-^ type to desired triazolotriazines (72, Scheme II). This route to J2 suffers, however, from the necessity of preparing initial 76_ and tedious chromatographic separation of the isomeric triazolotriazines (78_ and 79) • 76 77 78 79 i 72 Scheme II 1,2,4-Triazines are frequently prepared by construction of (Method 1) bonds 1,6 and 4,5 as in 80_ and (Method 2) bonds 2,3 as in 81. 4 4 80 81 Method 1 is commonly used and takes the form of condensing 1,2-dicar bonyl compounds with semicarbazide^, thiosemicarbazide^^, aminoguani- dines^ or anamidrazone-^ (Methods 1a, 1b and 1c) as in Eq 40. 30 R X • ° NH2CNHNH2 R 'Y ^ 'k '.X ^ ;0 X = NH,0,S „ J ^ N n (40) R R N 'H The orientations in the condensations frequently can not be controlled and thus this method is not usually used with unsymmetric 1,2-diketones. Method 2 involves reaction of 1,2-bisacylhydrazones with ammonia (82, Method 2a, Eq 41) or dehydration of ot-acylamidohydrazones^® (83, Method 2b, Eq 42). 0 R ^ n n h c r Nh3 r Y ^ NY r * r ^N N H C R 0 " ^ n«'N (41) q R N 82 0 Rv^NHCR' R r' (42) r -^NNHR' R ^ N ' 83 H Methods 1d, 2a and 2b place alkyl or aryl groups at position 3 of the triazine ring. Hence they can not be used for synthesis of [1,2,4]— triazolo[5,1-c][1,2,4]triazines (72) and have limited applicability for preparing cyclohepta[5,6-d_][1_H-1,2,4]triazines (74). The most efficient method for preparing 3-substituted-1,2,4-tri- azoles (73) involves formation of bond 4,5 of the ring from a preformed skeleton (84).^9 31 4 3 N—\ A n 'n I 84 The necessary intermediates are usually prepared by (1) acylations of semicarbazide,^° thiosemicarbazide, ^ aminiguanidine^ or their derivatives^ (Eq 43), 0 9 X RCCI (43) n h 2 c n h n h 2 RCNHNHCNH2 X =N H ,0 , S 0 KNCX 0 X (44) RCNHNHCNH2 RCNHNH2 X = 0,S (2) condensation of acyl hydrazines with potassium cyanate or thiocyan- a t e ^ (Eq 44), (3) reactions of acylisothiocyanates with hydrazine^ (Eq 45), and (4) formation of N-s-triazol-4-ylamidines^ (85, Eq 46). n h 2 n h 2 0 X (45) RCNCS RCNHCNHNH2 / ^ N ' 2 ' ^ N RCN ------* RC (46) NH; 8 5 32 Methods 1-4 proceed via intermediates which under alkaline conditions or on heating between 185-220 °C cyclize to triazoles bearing mercapto, hydroxyl or amine groups which must then be removed (Eq 4 7 ).64a,66 Additionally, preparation of 5-aryl-1,2,4-UI-triazoles by closure of acyl semicarbazides or acyl aminoguanidines take place in less than 50% ,N= t X [0] N-» R N'N'H X = NH2,0H,SH r ^ N ' N <1|7) A yields and thiadiazoles are formed competitively with 1,2,4-triazoles (Eq 48) in closure of acyl thiosemicarbazides. However 3-aryl-1j1-1,2,4- triazoles have been obtained from substituted-N-^-triazol-4-ylben- zamidines in 65% yield (Eq 49)*88 9 S s - ^ n h 2 (1,8) RCNHNHCNHo ------, ~\\ ^ V N R N /==M //NN\=s-N N—\ (49) RC N ------» v 'NH2p R- N H Additionally, other ring systems can be transformed into 3-substi- tuted-1Jl-1,2,4-triazoles. The tricyclic compound ^-triazolo[3,4-a_]- phthalazine (86) undergoes N-N bond cleavage in the presence of base to give 3-(2-cyanophenyl)-1H-1,2,4-triazole (87) in 40% yield (Eq 50). s^Triazolo-CS,1-a_]isoquiniline (88) is oxidized by permanganate to 3-(2- carboxyphenyl)-1H-1,2,4-triazole (89, Eq 51).88 Beyond yielding additional information on the properties of internally stabilized carbenes, it was hoped that (1) a comparison of the behavior of J_ with other diazoazoles would be instructive; (2) the reactivity of _1_ and 2^ with various substrates might be of value in developing shorter and new routes to ]2_, _73, and J4_, as well as 75; (3) a better understanding of the mechanisms by which azolylidenes react with benzenoids would result; and (4) differences or similarities in the behavior of _1_ and the other diazoazoles would indicate special properties of each of the azolylidenes. Re3ult3 and Discussion The present study is an investigation of the chemistry of 3-diazo- 3H.-1,2,4-triazole (_1_) and 3H.— 1,2,H-triazol-3-ylidene ^2), the carbene generated from _1_ on photolysis or thermolysis. Of the 3-diazo-3H-1,2,^- triazoles known, _1_ was chosen for study because it is the parent of the family and offers minimal complications with respect to spin multipli 2 city of its carbene, because of the work of J. Glinka on 3-diazo-5- phenyl- 1H-1,2,U-triazole (5c), ^ and because its precursor, 3-amino- 1H- 1,2,!)-triazole(_3), is commercially available. Formation and Characterization of 1 3-Diazo-3H-1, 2,*t-triazole (_1_) is generated from _3 as shown in Equation 36. Diazotization of _3 is effected with sodium nitrite and nitric or tetrafluoroboric acids at 0 °C to give pale yellow solutions 0 O n _ ^ n h 2 NqNO; n _ ^ N2 A NqQH C'N> h n o 3 (52) 3 90 3^ 35 of 1H-1,2, ^-triazole^-diazonium salts (90: A = NO^- , BFjj-). The nitrate and tetrafluoroborate salts (90) are much more stable than the CO corresponding chloride, bromide, or sulfates. Diazonium salts (90) cannot be extracted into organic solvents such as methylene chloride, benzene, toluene, chlorobenzene, and anisole. Evidence for this conclusion is that such extracts of the acidic diazotized solutions do not produce coupling products when treated with electron-rich aromatic compounds such as N,N-dimethylaniline and B-naphthol. However, the pale yellow aqueous solutions of 1H-1,2,4-triazole-B- diazonium salts (90) convert to pale yellow aqueous solutions of 3-diazo-3ji-1,2,1t-triazole (_1_) on neutralization with sodium bicarbo nate. Further, when the acidic and neutral aqueous solutions are treated with base (NaOH) to pH = 8-12 they turn red in color. The red color may be caused by 1H-1,2,11-triazole-3-diazonium hydroxides: ,0-H N = N N~\( (f N A or more likely, due to the acidity of the triazole nucleus and the pH of the solutions, their mono- or disodium salts: /O-H % N a ® m - / =N n=n/ Attempts were made to isolate and characterize _1_. Methylene chloride extracts of the neutral and basic aqueous solutions described above were concentrated at 0 °C in vacuo to small volumes (<5ml) of slightly orange solutions. The infrared spectra of these concentrates were predominated by a large peak at 2200 cm“ ^, indicating that a diazo compound was present. Of further importance is that there were no spectral bands for OH and/or NH groups. Hence, 1H-1 ,2,4-triazole-3- diazonium hydroxides were absent from these concentrates. Additionally, the mono- and disodium salts of 1H-1,2,4-triazole-3-diazonium hydroxides were absent from these concentrates. Additionally, the mono- and disodium salts of 1H-1,2,4-triazole-3-diazonium hydroxides would be highly ionic and thus would be unextractable from water into methylene chloride. These methylene chloride concentrates gave a single yellow band when chromatographed over silica gel using ehtyl acetate as the developing solvent. Attempts to ioslate the yellow material by TLC failed because the band exploded when touched with a spatula producing a small white cloud of silica gel. It is emphasized that the time which elapsed between removing the plate from the developing chamber and touching the band was less than 1 min and that the TLC plate was still wet. Hence, throughout this work _1_ and concentrated solutions of _1_ have been considered to be contact explosives and were handled with great care. Methylene chloride extracts of aqueous solutions of 3-diazo-3H- 1,2,4-triazole (_1_) react rapidly with electron-rich aromatic compounds at 0 °C. Upon addition of N,N-dimethylaniline to methylene chloride solutions of _1_, a red color, indicative of coupling, forms instantly. 37 Workup of the reaction mixture yields the bright red, solid product, 1H— 1,2,4-triazolo-3-azo-1 *-[4'-N,N-dimethylaniline] (91, Eq 53). In a similar experiments, _1_ couples with J3-naphthol to yield 1H-1,2,4- triazolo-3-azo-1'[2'-naphthol] (92, Eq 54). The structures of 9J_ and 92_ 1 11 d are confirmed by comparison with literature information. ’ To determine the amount of _1_ extracted into methylene chloride, the above methylene chloride extracts were concentrated in_ vacuo to dry white solids. The solids from diazotized solutions neutralized with sodium bicarbonate at 0 °C indicate that _1_ had been obtained in 63% to 65% yields. The solids from extraction of diazotized solutions at pH = 9-11 reveal that _1_ had been isolated in less than 20% efficiency. Presumably, reduction in the efficiency in the amount of _1_ isolated is from conversion of _1_ to the insoluble mono- and/or disodium salts of the diazo hydroxides (see page 35). The exact structure of the isolated white solid is unknown. It may be monomeric or aggregated _1_. However, in this dissertation _1_ will be represented throughout as a monomer. To minimize any complications in the chemistry of _1_ caused by aggregation or otherwise, _1_ was extracted directly into the solvent in which it was to be reacted. Further, _1_ was usually extracted from basic aqueous solutions of pH = 9-11. This method of isolation was chosen in order to limit possible acid-catalyzed reactions of _1_ and/or _2 with various substrates, even though the pH range 9-11 diminishes the amount of _1_ which can be extracted into organic solvents in comparison to the amount which can be extracted from neutral solutions. Because of the isolation procedure chosen it was necessary to determine the amounts of _1_ extracted into various solvents. The amounts of _1_ thus obtained were determined from the volumes of gas evolved from decomposition of _1_ i-n the various solutions. For example, a methylene chloride solution (200 ml) of _1_ was stored at room temperature overnight while the gases evolved were collected. Simultaneously, an equal volume of methylene choride at 0 °C was allowed to stand at room temperature while the vapors evolved were collected.* The difference in the volumes of gases (40 ml) was attributed to nitrogen evolution by decomposition of _1_. Application of the ideal gas law to this difference in volumes indicates that about 1.6 mmole of _1_ was extracted into methylene chloride (200 ml). Similarly, the amounts of 3-diazo-3H-1,2,4-triazole (_1_) extracted into other solvents were determined by application of the ideal gas law *To assure complete decomposition of _1_, solutions of _1_ in solvents with boiling points below 120 °C were allowed to stand overnight at room temperature, while those having boiling points above 120 °C were heated at 80 °C for 1 hr. The solutions of _1_ heated at 80 °C evolved most (90%) of the gases within 20 min, and those left standing at room temperature within 2 hr. 39 to the differences in the volumes of gases evolved by solutions* of _1_ and of corresponding blank solutions. The volumes of gases evolved, the mmoles of _1_ extracted into different solvents, and the molarities of the solutions obtained are shown in Table 8. This method thus yielded _1_ i-n 7- 13 % efficiency. Table 8 Summary of Information Concerning Extraction of 3-Diazo-3H-1,2,4- triazole (_1_) from Aqueous Solutions* Solution Gas Produced Molarity Solvent ml mmoles Methylene Chloride 40 1.6 0.008 Benzene 40 1.6 0.008 Cyclohexane 40 1.6 0.008 Anisole 25 0.8 0.004 Chlorobenzene 25 0.8 0.004 Benzonitrile 30 1.0 0.005 Methyl Benzoate 30 1.0 0.005 Nitrobenzene 35 1.2 0.006 *See the footnote on the previous page In summary, _1_ can be generated from 3-amino-■111-1,2,4-triazole (_3), it can be extracted from aqueous solutions to give approximately 10-i* M organic solutions; and, most importantly, its chemistry can be success fully and safely explored. More specifically, methylene chloride solu tions of _1_ can be used to explore cycloadditions of _1_ with (1) olefins and acetylenes in which the unsaturated centers bear strong electron- donor groups and (2) cumulene systems. Solutions of _1_ in benzenoid solvents can be used to study the thermolytic and photolytic reactions *See the footnote on the previous page. 140 of _1_ with aromatic compounds, the results of which will be described in detail later in this thesis. Cycloaddition Chemistry of J_ In order to characterize _1_ further, methylene chloride extracts of aqueous _1_ pH = 9 were reacted with activated unsaturates. Study was first made of _1_ with (1) cyclohexenes in which the double bond contains electron-donor groups and (2) 1-ethoxypropyne. N-Pyrrolidino-1-cyclo- hexene (93, Z = N(CH2 )n, the enamine from cyclohexanone and pyrrolidine) reacts with _1_ at 0 °C by overall cycloaddition and elimination of pyrrolidine to give a product assigned as [1,2,4]triazol[5,1-_c]cyclo- hexa[e_] [ 1,2,l4]triazine (95, Eq 55), rather than [ 1, 2,44]triazol[^4,5- £]cyelohexa[eJ[1,2,i4]triazine (96, Eq 56). The probable overall reactions, excluding mechanistic details, are illustrated in Equations 55 and 56. Choice of _95 rather than 96_ as the structure of the product is understandable on the basis of (1) mechanistic principles which (55) (56) 96 will be described; (2 ) the precedents of other such cycloaddition- elimination reactions; and (3) the fact that N-2 is more electron-rich than N-i» in _1_-69 Of further interest are the facts that N-morpholino-1-cyclohexene (93> Z = N(CH2 )2 0 )j N-piperidino-1-cyclohexene (93, Z = and 1-ethoxycyclohexene (93, Z = OC2 H5 ) all undergo cycloaddition- eliraination with _1_ to give 95. The yield of 95_ was best from N-piper- idino-1-cyclohexene and _1_ although no effort was made to optimize the reaction conditions. It is noted that adducts 96_ were not formed in the above experiments. Eliminations of jjM are presumably favorable because of the heteroaromaticity in 95. At least four possible mechanisms account for formation of 95. One of the mechanisms is a three step process involving coupling to 97_ (Eq 57), which closes to a 9a,9b-dihydro-9a-substituted [1, 2,il]triazolo- (57) 97 98 [5,1-cJcyclohexateH 1 ^jMltriazine (9 8), elimination of which gives 95. An obvious alternative is concerted H + 2 cycloaddition of J3 and _93, to yield 98, with subsequent conversion to 95. A third possibility (Eq 58) involves 3 + 2 concerted cycloaddition of _1_ and _93. to give spiro intermediate j)£ which undergoes 1,5-rearrange ment to 98 with elimination to 95. This mechanism receives some support from the results of reactions of various diazoazoles with electron-rich olefins at low temperature as studied by Padwa, et al. ^ A further alternative (Eq 59) involves 1 + 2 cycloaddition of _1_ and 93 to produce aziridine 100 which then rearranges through _99, to 98, and finally gives 95_. Such a mechanistic possibility had been suggested by 70 Padwa' and receives support from recent observations by Rao in this laboratory. Of note is the fact that all of the mechanisms proposed V'NJMt " V'NM 99 <59) I 100 make use of greater electron demand at N-2 rather than N-4 in the tri- azole ring. Ege, et al., has reported that _1_ and ynamines undergo net H + 2 cycloaddition to yield triazolotriazines J_8 (Eq 14).1^ Attention had been presently directed to the behavior of 1_ with 1-ethoxypropyne. In deed reaction occurs smoothly at 0 °C in methylene chloride to yield an adduct assigned as 7-ethoxy-6-methyl[1,2,4]triazolo[5,1-c_]C1,2,4]- triazine (101, Eq 60). As with 1 and enamines there are many N—^ CH^C^COCgH^ unresolved questions with respect to the reaction mechanism in the overall cycloaddition of _1_ and 1-ethoxypropyne. In this laboratory phenyl isocyanate has been previously observed to react with 3-diazo-5-phenyl-3H.-1, 2,lJ-triazole (5c) at 0 °C to form 3,7-diphenyl-1 ^H-triazoloCS, 1-d_][ 1,2,3,*1]tetrazine-7-one (J_9, Eq 15).^ Phenyl isocyanate has been presently found to add _1_ to yield 6-phenyl [ 1,2,4]triazolo[5,1-e] [ 1,2,3 ,J4]tetrazine-7-one (102, Eq 61), N^=\ N? .! N N~ i PhNCO VN Ph'^N^ (61) I I02 assignment of which is based on the products IR and NMR spectra. There is much yet to be done mechanistically and synthetically with such systems. An important question is whether phenyl isocyanate is behaving as an electron-rich or an electron-poor reagent with _1_. If indeed the isocyanate functions as a nucleophile with _1_, the mechanistic possibilities for cycloaddition are similar to those with enamines and transition states or intermediates such as 103 - 105 may be involved in the present reaction. However, if the isocyanate is as an electrophile, the mechanism for cycloaddition would involve capture of the triazolide moiety of 1 by the carbon of the isocyanate functionality. The 44 transition state for the reaction would involve a structure such as 10*4 and 105. Reactions of with Alcohols Heterocyclic diazo compounds such as 5c_ and oxidize alcohols to aldehydes and ketones. Hence, the reactions of _1_ with methanol, ethanol, 2-propanol, and cyclohexanol at 0 °C were studied. Rapid de gassing occurred when aqueous solutions of J_ (pH = 9) were added to the alcohols. The product aldehydes and ketones were identified and their quantities estimated by precipitation as 2,4-dinitro-phenylhydrazones. The results of these experiments are summarized in Table 9. No attempts were made to optimize or perfect each oxidation- reduction system. The mechanism by which J_ effects oxidation of Table 9 Yields of Aldehyde or Ketone Produced in the Reactions of 3-Diazo-3H- 1,2,4-triazole with Various Alcohols. Isolated Yield of 2,4-DNP Derivative alcohol mmoles percent methanol 1.2 10 ethanol 7.0 60 2-propanol 7.0 60 cyclohexanol 4.8 40 45 alcohols is not clear but the process may be envisioned overall as in Equation 62. o c h r 2 2 RoCHOH fv Methanol reacts vigorously— almost violently— with _1_ and it is difficult to control the reaction and accurately determine the yield of formaldehyde produced. Ethanol and 2-propanol are oxidized rapidly to acetaldehyde and acetone in yields greater than 6 0 % . Cyclohexanol does not dissolve totally in the aqueous reagent, yet the heterogeneous reaction gives cyclohexanone in greater than 40% efficiency. Investigation of the behavior of with benzene and benzene derivatives was then initiated. Preliminary Study of the Reactions of _1_ with Aromatics As has been summarized in the introduction, azolylidenes may react with benzene and its derivatives to give products resulting from substitution, ring expansion and reaction with the aromatic substi tuents. In the present investigation the behavior of _1_ with benzene and substituted benzenes was determined in efforts to obtain substituted and, particularly, ring-expanded products of structures 73., 74_ and 75, as described previously in Scheme I. The study was initiated by extracting a freshly prepared aqueous solution of _1_ with benzene and refluxing the combined extracts for 1 hr. Work-up of the solution gave 3-phenyl-1 FI-1,2, U-triazole (106, Eq 63).6J4a,65 structure of 106 was assigned upon comparison (mp, MS, IR and NMR) with a sample synthesized by a literature procedure to be described later. N' (63) A I06 The study was extended to thermolysis of _1_ in toluene, performed and worked-up as in the previous experiment with benzene. A mixture of 3-(tolyl)-1Fb-1,2,U-triazoles was obtained. GLC analysis of the product revealed two major components, while HPLC analysis revealed three components; two major and one minor. The mixture could be marginally separated by TLC and satisfactorily by MPLC to give 3-(o-tolyl)-1F[- 1,2,lJ-triazole and 3-(_£-tolyl)-1jl-1,2,U-triazole. The minor isomer could not be isolated but was shown to be 3-(rn-tolyl)-1jF-1,2,H-triazole. Identifications of the isolated products were made by comparing their physical properties (mp, MS, IR and NMR) to those of authentic samples. This experiment is discussed in greater detail in the section titled "Reactions of J_ with Aromatics". Similarly, thermolysis and photolysis of in other substituted benzenes resulted in complex mixtures of 3-(substituted phenyl)-1Fl- 1,2,4-triazoles from which the major isomers could be isolated. The 47 identities of most of the isolated products could be established by spectroscopic methods. However, in some cases, the splitting patterns in the aromatic regions of the NMR spectra and unaccountable bands in the 600-800 cm” IR regions left the structures open to question. The above results were extremely disappointing with regard to syn thesis of 74_ and 7^5_ (Scheme I) from _1_ and aromatics. Further, the tedious chromatographic separations of the product mixtures and the existence of other methodology (Eq 41 - 51) limit the use of reactions of _1_with benzenes for preparing 3-(substituted phenyl)-1H^1,2,4-tri- azoles. The above disappointments, coupled with the inadequate theory for explaining aromatic substitution by azolylidenes, refined the objective of this study to establishing the mechanisms by which _1_ reacts with benzenoids. Methods for establishing reaction mechanisms have been reviewed.^ At this point it is sufficient to say that studies such as the present one usually follow the course: (1) characterizing the reagents and intermediates involved in the reactions, (2) definition of the reaction sequences, and (3) identifying the rate-determining steps of the various reactions. The first stage is to determine the general character of the process, i.e., whether the reaction involves attack by an electrophile, a nucleophile, a radical-like reagent or some other process.^ In aromatic C-H substitution reactions this is usually accomplished by determining the effects substituents have on (1) directing the sub stitution processes, i.e., determining the ratios or percentages of the ortho-, meta- and para-isomers produced and (2) activating or deactivating the substitution processes relative to a standard substance, usually benzene, i.e., the relative molar reactivities of the substrates. The second stage involves comparison of the quantitative information obtained to that of known r e a c t i o n s . T h e similarity in reactivity patterns usually identifies the type of reagent involved and indicates the mechanism by which the reaction occurs. As outlined previously, 3-diazo-3H-1,2,4-triazole (JO reacts with benzenes upon loss of diazo-nitrogen on thermolysis and photolysis. The rate-determining step for substitution is assumed to be decomposition of _1_ with formation of 3H-1,2,^-triazol-3-ylidene (2); 2_ then reacts rapidly with its environment."^ In principle ylidene 2_ can behave as a carbene with a pair of p electrons occupying the sp orbital (107) or the ^-orbital (108) of the carbenic carbon or as a diradical in the singlet state (109) or triplet state (110): I07 I08 I09 IIO r v /"v/ rs/ Thermal decomposition of _1_ should give initially a singlet carbene which can be approximated as 108. The nature of ylidene _2 can be anticipated from its resonance forms. For 107 - 110, 108 might be the carbene of lowest energy, since the pair of electrons in the ^-orbital of its carbenic center is expected to be extensively delocalized over the ring as represented by the following canonical forms: These canonical forms make extensive uses of the electronegativity of the nitrogen atoms and can be summarized as hybrid 111. III Hybrid 111 indicates that its carbenic electrons are delocalized in a planar cyclic Hn + 2 electronic array. A further effect in 2_ is that the lone-pair electrons of the a- and B-nitrogens can delocalize into O the sp orbital of its carbenic center. The through-space interactions of the electrons from the a-nitrogens are revealed as: © Through-space interactions thus delocalize positive charge and stabilize 111 as a singlet. Also, since the nitrogens contribute electron density p to the empty sp orbital the carbene from J_ might have some radical character. In this study, characterization of 2_ and delineation of the mechanisms by which 2_ reacts with benzenes were accomplished by decom posing _1_ in substituted benzenes and in solutions of mixed benzenes. For example, substitution of hydrogen in benzene and the substitution pattern from _1_ and toluene indicate that 2 is a radical-like or an electrophilic reagent. Further discussion of characterization of the 50 substituting reagent from _1_ will be delayed until the analytical methods employed in this study have been described and the results of reactions of _1_ with monosubstituted benzenes have been presented. Since reaction of 3-diazo-3H-1,2,^-triazole (_1_) with a monosubsti tuted benzene yields a mixture of at least three isomers and the simi larity in the properties of these isomers causes their quantitative determination to be difficult, a major consideration in this study is choice of an accurate method for analysis of the products. The methods employed in the present study are discussed in the following paragraphs. In order to determine product compositions accurately, a technique capable of routine high-resolution separation and quantification of mixtures of isomers is required. Of the analytical techniques available only two are practical: HPLC analysis employing a UV detector and GLC analysis employing a FID detector. The HPLC method is more satisfactory for analyzing the products from reactions of 1 with substituted benzenes since, as mentioned previously, 3-(substituted phenyl)-1ji-1^j^-tria- zoles completely separate by HPLC, whereas 3-(m.- and ^-substituted phenyl)-1H-1,2,4-triazoles do not separate by GLC. Conversely, GLC is more appropriate for analyzing the mixtures from the competition experiments since the method effects separation of 3-phenyl-1H-1,2,4- triazole from 3-(o.-substituted phenyl)-1H-1,2,4-triazoles and mixtures of 3-(rn- and ^-substituted phenyl)-TH-1,2,4-triazoles, whereas HPLC does not separate 3-phenyl-1H-1 ,2,4-triazole from mixtures of isomeric 3-(substituted phenyl)-1IL-1,2,4-triazoles. There are three methods for determining chromatographically the amounts of the isomers in a mixture: external-standard, 51 7ll internal-standard and peak-normalization.1 They all require that the chromatographic peak area corresponding to a compound be linearly related to the concentration of that compound in the solution being analyzed. In the external-standard method, the quantity of a compound in a solution is determined by correlating the chromatographic peak areas of the compound with "similar" areas obtained on analysis of solutions having known concentrations of the compound— provided, of course, that the analyses are performed under similar conditions. This is usually done from a graph of quantities of the compound analyzed versus the chromatographic peak areas corresponding to the compound. This method suffers from the defects that one has (1) to accurately make up solutions of known concentrations, (2) to reproducably inject the samples into the chromatographic instrument, and (3) to accurately measure the areas under the peaks in the chromatograms. These problems produce a 15 to 20% error in the amount of any 3-(substituted phenyl)- 1H-1,2,4-triazole in the product from J_ and a substituted benzene.^ This large error is undesirable in the present study and thus the analytical method was not used. A better method of analysis employs an internal standard. In this method a known quantity of a compound which gives a separate peak is added to a sample containing the compound of unknown concentration. Internal-standard calibrations are constructed by chromato graphing appropriate volumes of calibration mixtures con taining the compound(s) of interest with a constant concen tration of the internal-standard compound. [The]... peak areas of the compounds are determined, and the compound to internal-standard...peak-area ratios are plotted versus the concentration of the compound of interest. If calibration 52 mixtures have been prepared properly, this calibration plot is linear and intercepts the origin. a This method compensates for experimental variations leading to differences in peak sizes, including sample-size fluctuations, and increases accuracy as compared with the external standard method. The internal-standard method produces less than a 10% error in the amounts of any isomer and hence in the mole ratios relative to the standard. In theory the internal-standard method is appropriate for the present study. In practice however this method was undesirable. It requires finding a compound having response factors and retention times similar to that of the 3-(substituted phenyl)-111-1,2,^-triazoles while still being completely resolved from them to serve as an internal- standard. Also, standard solutions and calibration curves for all isomers produced in this study must be prepared and the reproducibility and accuracy of the curves verified prior to analysis of the reaction products. The time consumed in finding compounds to serve as appropriate internal standards and in preparing the standard solutions and curves would have been enormous. A third method of analysis was found which provides the same accuracy in less time. A more pleasing analytical method involves a variation of the internal-standard method in which one of the isomers from the reactions of _1_ with a substituted benzene is used as the internal standard. This alleviates the necessity of finding an auxiliary compound to serve as the internal standard and reduces the number of standard samples and curves required to perform the study. This method requires construction of calibration curves by plotting the compound to internal-standard 53 peak-area ratios versus the ratios of the concentrations of the compound to internal-standard. This method of analysis was employed in the competitive experiments using 3-phenyl-1H-1,2,4-triazole as the internal standard. Calibration curves were constructed as follows: (1) suitable solutions containing mixtures of pure 3-(substituted phenyl )-1I[-1,2,4-triazoles and 3-phenyl- 11I-1,2,4-triazole were chromatographed in a GC equipped with a FID; (2) the peak areas in the chromatograms corresponding to the compounds in the mixtures were measured; and (3) the response factors from the plots of the ratios of the moles of 3-(substituted phenyl)-1II-1,2,4-triazole to 3-phenyl-1jI-1,2,4-triazole versus the ratios of the areas of the peaks of 3-(substituted phenyl)-1H-1,2,4-triazole to 3-phenyl-1tl-1,2,4- triazole were determined by least-squares methods (Appendix 1). The slopes and intercepts of these curves are summarized in Table 10. The calibration curves were then used to establish the moles of 3-(substituted phenyl)-TH-1,2,4-triazole produced per mole of 3-phenyl- 1H-1,2,4-triazole. For example, the peak-area ratios of 3-(o-tolyl)-1II- 1.2.4-triazole (PAo_) and the mixture of 3-(m.- and j3-tolyl)-1II-1 ,2,4- triazoles (PAjo) are 0.49 and 0.33, respectively. Use of the information in Table 10 for 3-(o_-tolyl)-1H-1,2,4-triazole and 3-(j3- tolyl)-1H-1,2,4-triazole gives the moles of 3-(o-tolyl)-1jI-1,2,4- triazole (MIto) and 3-(ja-tolyl)-IH-l ,2,4-triazole (MRjd) to 3-phenyl-1H- 1.2.4-triazole to be 0.47 and 0.30, respectively, to 1.00. That is, PA£ = 1.11MRO -0.03 (64) which on rearrangement gives: MIto = (PAo. + 0.03)/1 • 11 =0.47 (65) 54 Table 10 Summary of the Slopes and Intercepts of the GLC Calibration Curves Used in the Competitive Experiments. Substituent Isomer Slope Intercept Methoxy ortho 1.39 -0.19 meta 1.00 -0.11 para 0.52 0.00 Methyl ortho 1.11 -0.03 meta 0.81 0.00 para 1.24 . -0.04 Trifluoromethyl ortho 1.18 0.03 meta 0.85 0.03 para 1.18 0.06 Chloro ortho 1.93 -0.24 meta 0.61 0.21 para 1.28 0.24 Similarly, MR£ =(PA£ + 0.04)/1.24 = 0.30 (66) The mole ratio of 3-(o-tolyl)-IH-l,2,4-triazole to 3-(.£-tolyl)-1H-1,2,4- triazole is thus 1.6 and the product is 61% 3-(o_-tolyl)-1H-1,2,4-tri azole and 39% 3-(j>-tolyl)-1H-1,2,4-triazole. Due to the time required to construct the standard curves, as made evident in preparing the curves to analyze the mixtures from five competitive experiments, the above modified internal-standard method was not desirable for analyzing the products from the many single solvent experiments. Hence only two such curves were prepared: those for 3-(chlorophenyl)-1H-1,2,4-triazoles and 3-(bromophenyl)-1I1-1,2,4-tri- azoles. The slope and intercepts of the curves are given in Table 11. 55 Table 11 Slopes and Intercepts of the GLC Calibration Curves Used to Analyze the Products from the Reactions of _1_ with Chlorobenzene and Bromobenzene. Substituent Isomer Slope Intercept Chloro ortho/para 0.85 -0.02 Bromo ortho/para 0.81 0.10 The information in Table 11 will be used later to demonstrate that HPLC and GLC analyses give comparable results. Tables 10 and 11 require the following comments. The slopes and intercepts in Table 10 are to be used with Equation 67. PA(I)/PA(Phenyl) = S(I)x[M(I)/M(Phenyl)] + 1(1) (67) where PA(I) and PA(Phenyl) are the areas under the curves in the chromatograms corresponding to a 3-(substituted phenyl)-1H-1,2,4-tri- azole and 3-phenyl- 1H-1,2,iJ-triazole, respectively; M(I) and M(Phenyl) are the moles of the 3-(substituted phenyl)-1H[-1,2,iJ-triazole and 3-phenyl-1H-1,2,H-triazole, respectively, in the solution being analyzed; S(I) is the slope of the curve and 1(1) is the intercept of the curve. The slopes and intercepts in Table 11 are to be used with Equation 68: PA(o)/PA(jo) = Sx[M(o)/M(j3)] + I (68) where PA(o) and PA(j)) are the areas in the chromatograms corresponding to the ortho- and para-isomers of the 3-(substituted phenyl)-1H-1,2,H- triazoles respectively; M(o) and M(g) are the moles of the ortho- and para-isomers of the 3-(substituted phenyl)-111-1,2, ^-triazoles, 56 respectively, in the solution being analyzed; S and I are the slopes and intercepts of the curves. Because of the effort required to construct the calibration curves for the internal-standard method, a less time-consuming method of analysis providing the same accuracy was desirable. Such an analytical method— and the most pleasing one for this study— is that of peak- normalization. In the peak-normalization method the area under every peak in a chromatogram is measured and the percent area of each component as based on the sum of the peak areas is reported as the percentage of that component in the mixture. This method requires that the detector responds essentially equivalently to each compound being analyzed. In a mathematical sense, not only must all the areas under the peaks be linearly related to the concentrations of the components, the slopes and intercepts of the calibration curves for the compounds as determined by the external-standard method must be the same or virtually the same. A variation of the peak-normalization method is to determine the percentages of the components in a mixture from the sum of the peak areas, as adjusted for differences in the detector response to each component in the sample. This approach requires determination of detec tor response for each component in the sample. These detector-response correction factors are then used to adjust the areas under the peaks in a chromatogram to compensate for differences in the detectors response to each component in the sample. Finally, the percent area for each component as based on the sum of the adjusted peak areas is determined and represents the percentages of the components in the mixture. 57 The reader will recognize that the above variation of the peak- normalization method and the peak-normalization method, when the detector responds equivalently to each compound in the mixture, are versions of the internal-standard method and the errors in the values determined for the mole ratios and percentages are the same as in the internal-standard method. Hence, both the peak-normalization method and the variation of the peak-normalization method are appropriate for this study. The detector-response correction factors for the UV-detector system in the HPLC analyses are the UV-extinction coefficients of the 3-(substituted phenyl)-1H-1,2,4-triazoles being analyzed. The extinction coefficients of the 3-(substituted phenyl)-1H-1,2,4- triazoles as determined in ethyl acetate at 254 nm are summarized in Table 12. To show the accuracy of the HPLC analytical method a solution containing known concentrations of 3-(o- and j3-tolyl)-1Il-1 ,2,4-triazoles was chromatographed and the observed mole ratio [MR(obs)] determined from the extinction coefficients in Table 12 was compared to the actual molar ratio [MR(actual)]. This was accomplished by chromatographing a solution containing 11.0 mg of 3-(o_-tolyl)-1H-1,2,4-triazole and 10.4 mg of 3-(j>_-tolyl)- 1H-1,2,4-triazole. Analysis of the chromatogram gave area percentages corresponding to 32% 3-(o-tolyl)-1H-1,2,4-triazole and 68% 3-(g-tolyl)-1H-1,2,4-triazole. The observed mole ratio and the percentage of each isomer in the mixture can be determined as follows. 58 Table 12 Summary of the Extinction Coefficients of 3-(Substituted phenyl)-1H- 1,2,4-triazoles in Ethyl Acetate at 254 nm • Isomer Substituent ortho meta para OCHo 11953 7119 12167 CHo 4768 7414 12538 F ^ 7880 8152 10285 Cl 7194 8955 17891 Br 5019 12271 16044 CFo 2088 8348 9464 CN 9915 1750 10851 n o 2 4183 15200 1684 From Beers' Law the peak area CPA(I)] in a chromatogram correspond ing to component _I is related to the molarity [M(I)] of component I_ in the solution being chromatographed by PA(I) = e (I)xM(I)x B(I) + I (69) where e(I) is the extinction coefficient of compound I_ and B(I) is the total volume of the solvent containing component _I_ that passes through the UV-detector cell and gives rise to the peak in the chromatogram. Rearrangement of Equation 64 gives the molarity of component _I as: M(i) = PA(I)/[e(I)B(I)] + I' (70) Hence, the relative molarities of any two components (I and J) in the solution, since B(I) and B(J) are the same, is: M(I) - PA(I) e (J) TIt M(J) PA(J)e (I) + 1 (71) 59 where "I" is the intercept of the plot and represents the error in the mole ratio. Equation 67 represents a plot of the ratio of the concentrations of two components of a mixture versus the ratio of the areas under the peaks in the chromatogram corresponding to the two components, i.e., a calibration curve for the internal-standard method of analysis. It is important to note that the error in such plots is from 1% to 10% and is usually less than 5% of the slope of the plot.7** The extinction coefficients for 3-(o- and j)-tolyl)-1H-1,2,4-tri- azoles in Table 12 and the percentage of the total peak area each peak composes of the total peak areas mentioned above, give the observed molar ratio of 3-(.o-tolyl)-1F1-1 ,2,4-triazole to 3-(j3-tolyl)-1H^1,2,it— triazole as: M(o) _ 32 12538 _ (?2) •mfrz w iw + IM M(o)/M(g_) = (0.47) (2.62) + I" (73) Assuming a very large error for the molar ratio, I = 5%, gives the mole ratio of: M(o_)/M(jd) = (0.47 x 2.62) + (0.05 x 2.62) = 1 .23 + 0.13 (74) This result implies that there is less than a 10% error in the mole ratio• VMP M(oVM(j>) is the observed molar ratio [MR(observed) ], the molarity of 3- (£-tolyl)-1B1-1,2,4-triazole can be determined relative to the molarity of 3-(j>-tolyl)-1J1-1,2,4-triazole: 60 M(o_) = MR (observed )M(^) (76) The error in the molarity of 3-(o-tolyl)-1H-1,2,4-triazole is determined by taking the total differential of M(o): ^M(o) = ^-E-^MR (observed) + ^ (observe d)Vj^^) (77) Inserting Equation 75 into Equation 77 and rearranging the resultant equation gives: VM(o) = MR(observed)[0.08M(jO + VM(£)] (78) By defining M(^) and v (^) to be 1 and zero, respectively, the error in the mole ratio becomes the error in the molarity of 3-(.o-tolyl )-1H.- 1,2,^-triazole. The percentage of each isomer in the mixture is determined as follows: M(T) = M(o) + M(jd) (79) where the error in the total molarity is equal to the error in the molarity of 3-(o-tolyl )-1F[-1,2,^-triazole, as can be seen by differ entiating Equation 79. %(0) = %(T) <80) The fraction of the mixture that is of 3-(o-tolyl)-1H-1,2,4-triazole [F(o_)] is: F(o) = M(o)/M(T) (81' with the error: VF(o) = VM(o )/M(T) - M(o )Vm (t )/[M(T)]2 (32) Inserting Equation 80 into Equation 82 and rearranging the resultant equation gives: VF(o) = v m (o )[1/M(T) " M(o )/{M(T)} ] (83) Evaluating Equation 83 leads to: F(o) = 0.63 + 0.02 (81*) The fraction of the mixture which is 3-(jKtolyl)-1H.-1,2,4-triazole is 0.37. To evaluate the accuracy of the observed mole ratio and the observed percentages, the actual mole ratio and the actual percentages must be determined. The actual mole ratio is equal to the ratio of the weights of the 3-(tolyl)-111-1,2,4-triazoles used to make up the sample: MR(actual) = 11.0/10.4 = 1.06 (g5) and the error in MR(actual) tVMR(actual)^ determined by differenti ating Equation 86: MR(actual) = M(o-actual)/M(j>-actual) (&&) where M(o-actual) and M(jD-actual) are the actual moles of the 3-(o_- and jD-tolyl)-111-1,2,4-triazoles in the mixture. That is, vMR(actual) = ^ g ( o ) ^ ^ S ) “ 3 where g(o_) and g(j>) are the grams of the ortho- and para-isomers weighed out, respectively, and Vg(0 ) and vg(j>) are the errors in weighing the compounds, respectively, which are 0.0001 g. Hence the error in MR(actual) is: VMR(actual) =Vg(o)/g(^ = 0.0001/0.0110 = 0.009 (88) The percentage of the mixture that corresponds to 3-(o-tolyl)-111-1,2,4- triazole [PC(o_)l is: PC(o) = [11.0 g /(11.0 + 10.4 g)]100 = 51% (89) and that which corresponds to 3-(jD-tolyl)-111-1,2,4-triazole [PC(]3)] is PC(jd) = [10.4 g /(11.0 + 10.4 g))100 = 49% (90) The error in these percentages is: (91) VPC(o) = ^ ( 0 ) ^ ^ ~ g(o)Vg(T)/g(T)2)100 where g(t) = g(o_) + g (£_) and Vg(T) = 2Vg(o) ^92) Solving Equation 91 gives the value of 0.01% to VpC(0). Similarly, the error in the percentage of the para-isomer in the composed mixture is 62 Table 13 Summary of the Actual and the Observed Mole Ratios and Percentages of the Isomers in a Standard Sample of 3-(.o- and j3-Tolyl)-1H-1,2,4- triazoles as Determined by HPLC Analysis. Percentages Molar Ratios ortho para Actual 1.06 +0.01 51 + 0.01 49 + 0.02 Observed 1.23 +0.13 55 + 2 45 0.02%. Table 13 summarizes the observed and the actual values for the mole ratios and the percentages of each isomer in the sample. Two additional examples used to establish the accuracy of the HPLC ■method involve mixtures of 3-(.o- and j)-chlorophenyl)-1H_-1,2,4-triazoles. Descriptions of each solution and the area percentages of their chroma tographic peaks are presented in Table 14. The results of the analyses are contained in Table 15. The information in Tables 14 and 15 shows that the HPLC method reproduces the percentages of the isomers in a sample within 5% of the actual value. Having established the accuracy of the HPLC analytical method, it is important to evaluate the accuracy of the GLC method of analysis and to compare the results of analysis of a given sample by both methods. Table 14 Summary of the Solutions of 3-(£- and £-Chlorophenyl)-1ff-1,2,4-triazoles Used in Establishing the Accuracy of the HPLC Method of Analysis. Weight, mg Peak Area Percentages Solution ortho para ortho para 1 20.9 10.0 43 57 2 5.2 10.0 15 85 63 Table 15 Summary of the Actual and the Observed Values of the Mole Ratios and the Percentages of the Isomers in a Standard Sample of 3-(o.- and j3-Chlorophenyl)-1H-1,2,4-triazoles as Determined by HPLC analysis. ortho/para Percentages Mole Ratios ortho para Actual 2.09 + 0.01 68 + 0.01 32 + 0.02 Observed 1.87 +0.12 65+2 35 Actual 0.52 + 0.01 34 + 0.01 66 + 0.02 Observed 0.44 +0.12 31+2 69 The products from reaction of _1_ with chlorobenzene were then analysed by both the HPLC and the GLC methods. The areas under the peaks in the the HPLC and the GLC chromatograms corresponding to the 3-(chlorophenyl)-1H-1,2,4-triazoles are summarized in Table 16. The procedure for determining the results of HPLC analysis has been described earlier. From Equations 72, 80 and 82 and the data in Tables 12 and 16 the 3-(chlorophenyl)-1P[-1,2,4-triazoles can be calculated to be 47% + 1% ortho, 13% + 1% meta and 40% para. The GLC analytic Table 16 Summary of the Data for Chromatography of the Product from Thermolysis of _1_ in Chlorobenzene Peak Area Percentages Isomer______GLC______HPLC ortho 55 32 meta 7 45 para 61 64 method has also been summarized previously. Utilizing Equations 68, 80 and 82, the data in Tables 11 and 16, and assuming that the peak area for the mixture of the meta- and para-isomers is totally that of the para-isomer, indicates the chlorophenyl isomers to be 59% + 1% ortho and 41% + 1% para. The results of the two methods of analysis are presented in Table 17. The results in Table 17 require certain elaboration. It is first noted that the assumption made above makes the percentage of the ortho- isomer artifically large. As can be seen by comparing the slopes for the calibration curves of the meta- and para-isomers given in Table 17, the FID detector is 1.5 times more sensitive to the para- than to the meta-isomer. Thus, if (1) a calibration curve similar to those reported in Table 17 involving ortho- and para-isomers was created using the meta-isomer as the internal standard, and (2) the calibration curve was used to interpret the GLC data in Table 17, the percentages of the ortho-isomer would then decrease. Taking these conclusions into consideration, it can be argued that the percentage of the ortho isomer in the above product is less than 59%. Table 17 Summary of the Results of the HPLC and GLC Analyses of the Product from Thermolysis of _1_ in Chlorobenzene Peak Area Percentages Isomer GLC HPLC ortho 59 + 1 51 +1 meta 9 +1 41 + 1 para 40 65 The results in Table 17 also reveal that one method of analysis fixes the percentage of the ortho-isomer within 10% of that by the second method. A similar comment can be made regarding the values for the percentages of the meta- and para-isomers. Considering the approxi mations made in the two methods of analysis, a 10% error is not alarming, nor is it to be interpreted to mean that the two analytical methods give different results. Further— taking into consideration that the reasons for using gas chromatography for analysis are (1) to deter mine the relative reactivities of different benzenoids and (2) to show that certain experiments in mixed solvents are not truly competitive— a 10% error in the percentages of the ortho-, meta- and para-isomers is unimportant. Having discussed the analytical methods used in this study, the methods of preparation and the physical properties of the authentic samples used in this study will now be summarized. Synthesis of Authentic Samples of Substituted-N-£^-triazol-4-yl-benz- amidines Of the methods available for synthesizing 3-(substituted phenyl)-1j1- 1,2,4-triazoles (Eq 43 - 4 9 ) , ^ ’^ conversions of substituted benzo- nitriles to the corresponding 3-(substituted phenyl)-1H-1,2,4-triazoles via substituted-M^s-triazol-4-ylbenzamidines (85, R=Ph, Eq 46 and 49) were found to be the most applicable, ^ as follows. 4-Amino-1E-1,2,4-triazole^ and a substituted benzonitrile (1 equiv) were condensed in ethanol to give the corresponding 66 substituted-N-s^triazol-4-ylbenzamidine (Eq 46). The structures of the substituted-N-£wtriazol-4-yl benzamidines are based on their chemical origins and their MS, IR, and NMR spectra. The MS have the proper mole cular ions for the condensation products of 4-amino-4j1-1 ,2,4-triazole and the corresponding benzonitriles, and degradation patterns character istic of compounds containing a triazole nucleus"^ and benzenoid rings. The IR spectra reveal the presence of NH, C=N and C=C groups. All the NMR spectra show absorptions for compounds containing triazole rings and aromatic nuclei. Additionally, the NMR spectra of the alkyl-substi tuted benzamidines contain proper absorption patterns for the side chains. For a partial summary of the preparation and properties of the substituted-N-s^triazol-4-ylbenzamidines synthesized, see Table 18. (Substituted Phenyl)-1J3-1,2,4-triazoles The substituted-N-s^triazol-4-ylbenzamidines were converted into 3-(substituted phenyl)-1H-1,2,4-triazoles (106, 112-132) by ethyl chloroformate (1 equiv) in nitromethane (Eq 49). The structures of the 3-(substituted phenyl)-1_H-1,2,4-triazoles are assigned on the basis of their chemical origins and their MS, IR, and NMR spectra. The MS of each product show the proper molecular ion for a 3-(substituted phenyl)- 1j1-1,2,4-triazole and a degradation pattern for a compound containing a triazole nucleus*^ and a benzenoid ring. The IR spectra indicate the presence of NH, C=N and C=C groups. All the NMR spectra have absorp tions for compounds containing triazole rings and aromatic nuclei. Addi tionally, the NMR spectra of the alkyl-substituted triazoles show 67 Table 18 Summary of the Preparation and Properties of the Substituted-N-s- triazol-4-ylbenzamidines Synthesized* MS, Mol. Ion R Percent Mp,°C calcd; Isomer yield obs(lita ) obs (inten) H 187.08578 48 244-245(262) 188.0890( 17.87) OCHoD 217.09634 o 33 242-243 217.0991( 6.33) m 35 237-238 217.0974( 5.68) R 52 246-247 217-0989( 28.49) CH, 201.10143 o^ 49 232-233 201.1006(11.26) rn 37 247-248 201.1096( 8.91) R 54 274-275(278) 201.1034( 14.62) C(CHo)o 243.14838 D o_ 22 212-214 243. 1559( 3.49) rn 46 221-222 243.1525( 36.49) R 24 293-294 243.1470(100.00) F 205.07635 o^ 48 217-218 205.0756( 78.16) m_ 67 229-230 205.0772( 21.04) R 48 254-255 205.0790( 34.50) Cl 221.0468 o_ 46 231-232 221.0571( 27.82) rn 66 253-254 221.0492( 70.42) R 45 270-271(277) 221.0458( 19.21) Cl M++2 o_ 223-0487( 10.91) rn 223.0472( 24.60) R 223.0440( 6.98) Br 264.99625 o_ 56 244-245 264.9965( 6.40) m 62 261-263 264.9953( 9.62) R 36 246-249 264.9951( 3.2 ) Br M++2 o_ 266.9972( 5.90) rn 266.9941( 9.14) R 266.9956( 2.5 ) 68 Table 18 continued MS, Mol. Ion R Percent Mp, °C calcd; Nu Isomer yield obs (lit) obs(inten) c f 3 255.07315 o *»3 233-235 255.0777( 14.50) m 67 204-205 255.0767( 15.66) JD 39 276-277 255.0701( 52.32) #The literature references for the compounds can be found in the Experimental Section. proper absorption patterns for the side chains. Table 19 is a partial summary of the preparation and properties of the various 3-aryl- 1H_- 1,2,4-triazoles prepared by the method of von Becker, et al., unless 65 otherwise stated. Several 3-(substituted phenyl)-1JI-1,2,4-triazoles-3-(nitrophenyl)-, 3-(cyanophenyl)-, and 3-(methoxycarbonylphenyl)-1fr-1,2,4-triazoles (133— 140)— and 3-(cyclohexyl)-1j1-1,2,4-triazole could not be prepared by the above method. The nitrophenyl triazoles (133 - 135) and 3-(cyclohexyl)- 1H-1,2,4-triazole were obtained by dehydration of the corresponding benzoyl thiosemicarbazides to give A^-5-substituted-2,4-dihydro-1,2,4- triazole-3-thiones from which sulfur was removed by oxidation (Eq 43 and 47).^ 3-(o-Cyanophenyl)-1H-1,2,4-triazole(138) was prepared by the novel ring dehydration summarized previously (Eq 50).^7 a partial summary of the preparation and properties of these 3-(substituted phenyl) — 1_H — 1,2,4-triazoles are also included in Table 19. 69 Table 19 Summary of the Preparation and Properties of the 3-(Substituted phenyl)- 1 H_-1,2, 4-triazoles Synthesized MS, Mol. Ion R Percent Mp, °C calcd Nua Isomer yield obs (lit ) obs(inten) 106 _H 145.06399 56 115-117(117) 145.0630(100.00) 0CH,c D 175.07445 112 R 86 174-175(186) 175.0751( 9.12) 113 m 98 182-183 175.0725(100.00) H i £ 98 169-170 175.0728(100.00) CH3° 159.07964 115 R 93 171-172(172) 159.0786(100.00) 116 m 98 67-68 ( 67) 159.0774(100.00) 117 77 135-136 159.0786(100.00) c (c h 3)3 201.12659 118 R 98 oil 201.1251( 22.24) 119 m 98 oil 201.1274( 19.94) 120 o_ 98 oil 201.1244( 6.84) F 163.05456 121 R 98 118-119 163.0586(100.00) 122 m 95 115-116 163.0543(100.00) 123 o_ 98 118-119 163.0536(100.00) Cl° 179.02501 124 R 95 193-194(194) 179.0277(100.00) 125 m 67 152-154 179.0271(100.00) 126 o_ 95 152-154 179.0254(100.00) Cl M++2 0^ 181.0209(28.83) m 181.0242( 28.83) R 181.0258(32.82) Br 222.97446 127 R 92 116-117 222.9781(100.00) 128 m 98 173-174 222.9733(100.00) 129 £ 50 173-174 222.9767(100.00) Br M++2 o^ 224.9733( 97.88) rn 224.9736( 96.50) R 224.9748( 90.23) 70 Table 19 continued MS,Mol. Ion • R Percent Mp, °Ccalcd 9 Nua Isomer yield obs (litb) obs(inten) CF^ 213.05136 130 R 98 175-176 213.0480(100.00) 131 m 98 76-77 213.0543( 65.00) 132 o^ 98 159-161 213.0501(100.00) n o 2g »d 135 R 57 216-217(222) 134 m 47 210-211(213) 136 o^ 10 170-171(167) CNc »e 170.02501 87 o^ 34 189-190(193) 170.0591(13.68) Cyclohexyltriazoleb 151.11075 50 oil 151 -1113( 13.73) a) These numbers are the numbers of the compounds as they appear in the equations of the text. b)The literature references are available by con sulting the Experimental Section, c) The aromatic region of the H FT- NMR of these compounds are presented in Appendix 2. d) Synthesized according to the procedure of Cipens, et al. e) Synthesized according to the procedure of von Becker, et al. Authentic samples of 3-(m- and j3-cyanophenyl)-1H-1,2,4-triazoles and the 3-(methoxycarbonylphenyl)-IH-l,2,4-triazoles were not prepared. However, 3-(m- and j)-cyanophenyl)-1H-1,2,4-triazoles (137 and 138) and 3-(,o- and m-methoxycarbonylphenyl)-1H.-1,2,4-triazoles (139 - 140) were separated from the reaction mixtures produced on thermolysis of 1_ in benzonitrile and methyl benzoate, respectively, and identified by spec troscopic methods. To aid in establishing the structures of 3-(m- and £-cyanophenyl)-1H-1,2,4-triazoles and 3-(o- and m-methoxycarbonyl- phenyl)-1.H-1,2,4-triazoles the FT-NMR of the aromatic regions of the isomeric 3-(tolyl)-IH-l,2,4-triazoles and 3-(methoxy-, chloro-, nitro-, 71 cyano-, and methoxycarbonylphenyl)-1H-1,2,4-triazoles, are summarized in Appendix 2. Finally, a partial summary of the preparation and properties of these 3-(substituted phenyl)-1H-1,2,4-triazoles are presented in Table 20. Table 20 Summary of the Properties of the 3-(Substituted phenyl)-1H-1,2,4- triazoles Isolated from Thermolyses of 3-Diazo-3H-1,2,4-triazole in Benzonitrile and in Methyl Benzoate3 MS, Mol. Ion R Percent Mp, °C calcd; Nub Isomer yield obs obs (inten) CN 170.02501 137 £ 15 164-165 170.0604( 35.19) 138 in 21 93-94 170.0602(100.00) COoCH, 203.02501 139 m 63 158-159 203.0659( 5.00) ■ 140 £ 15 oil 203.0452( 8.02) a) The 1H FT-NMR of the aromatic region of these compounds are presented in Appendix 2. b) These numbers are the numbers of the compounds as they appear in the equations of the text. Reactions of 2 with Aromatics Having prepared the above authentic samples, the thermal and photo- lytic reactions of _1_ with (1) substituted benzenes and (2) mixtures of benzene and various substituted benzenes were studied to determine the behavior of 2^ and to establish the mechanisms by which _2 reacts with benzenoids. The results of these experiments are presented in two parts: "Reactions of J2 with Aromatics" and "Competition Experiments of _2 with Aromatics." In the initial studies, "Reactions of 2_ with 72 Aromatics," the products from _1_ and substituted benzenes were found to be mixtures of isomeric 3-(substituted phenyl)-1tl-1,2,4-triazoles by HPLC analysis. The molar percentages of the isomers produced from _1_ with monosubstituted benzenes are reported in each experiment and are summarized in Table 21. The isomer ratios for the reactions of J_with anisole, toluene and chlorobenzene at 80 °C are summarized in Table 29 along with the results from the competition experiments at the end of the section titled "Competition Experiments of _2 with Aromatics." In several experiments the 3-(substituted phenylJ-IH^I,2,4-triazoles from _1_ and a substituted benzene were separated by MPLC, and the 3-(sub stituted phenyl)-1H-1,2,4-triazoles isolated are reported as percentages of the mixtures. These results can be used to evaluate the preparative aspects of the reactions of _1_ with benzenes. Additionally, the compounds isolated were used to confirm the assignments made by HPLC analysis. The yields of isolated compounds obviously do not correspond to the percentages of the isomers in a reaction product as determined by direct HPLC analysis. The second part of this study is subdivided into "Competition Experiments" and "Kinetic Deuterium Isotope Study." In this part the molar quantities of 3-phenyl-1H-1,2,4-triazole and 3-(substituted phenyl)-111-1,2,4-triazoles formed were determined by GLC methods and are presented in Table 29 at the beginning of the section entitled "Competi tion Experiments of 2_ with Aromatics." Further, since the ratios of the isomeric 3-(substituted phenyl)-111-1,2,4-triazoles from reactions of a substituted benzene with _1_ were found to depend on solvent composition, the ratios of the 3-(^-substituted phenyl)-1H-1,2,4-triazole to the 3-(m_- and ^-substituted phenyl)-1H-1,2,4-triazoles from reactions of _1_ 73 Table 21 Products (Mole Percent) from 3-Diazo-3H.-1,2,4-triazole (_1_) and Substituted Benzenes, as Determined by HPLC Analysis Isomer Percentages, Moles Thermolysis Photolysis 80 °C Reflux3 0 °C ubstituent _o in £ o_ in £ o^ in £ o c h 3 52 8 40 67 11 22 53 10 37 c h 3 57 9 33 68 11 21 59 10 31 c h (c h 3)3 11 33 56 6 39 54 14 35 51 F 55 15 30 60 12 28 Cl 51 9 40 74 8 18 76 8 16 Br — 58— 42 — 63— 37 CN 11 75 14 2 96 2 20 62 18 c f 3 — 84— 16 — 83— 17 c o 2c h 3 33 67 — 39 61 — 53 47 — N02 pH 7b — 100 —— 100 — N02 , pH 9° 72 — 28— 83 — 17— 'd 87 — 13— N02 , pH 11c 88 — 12— 93 — 7— a) Compound (bp, °C): Toluene (111); Anisole (154); Chlorobenzene (132); tert-Butylbenzene (169); Benzonitrile (191); Methyl Benzoate (199); Nitrobenzene (210). b) Solid _1_ was thermolyzed in dry nitrobenzene at 80 °C to give of 3-(m-nitrophenyl)-1H~1,2,4-triazole and nitrosobenzene, in 20% yields each. When 1 was thermolyzed in nitrobenzene at 185 °C nitrosobenzene composed 42% of the product and 134 25%. For experi mental details see Footnote 77 and Appendix III. c) 3-Diazo-3H-1,2,4- triazole (_1_) was extracted directly into the nitrobenzene in which it was thermolyzed. d) There was no difference in the percentages of isomers produced in these experiments when the pH was varied from 9 to 12 . with mixed solvents and the ratios of the isomers from the reactions of with anisole, toluene and trifluoromethylbenzenes are also presented in Table 29. The products from the kinetic deuterium isotope study were analyzed using GC-MS techniques. Reactions of 2_ with Electron-rich Benzenes The first electron-rich benzene reacted with 2_ was anisole. Anisole contains the strong electron-donating methcxy group, i.e., a group which is both -I_ and -J3 in usual electrophilic substitution reactions. Thermolysis of in anisole at 80 °C results in a mixture of three isomers identifiable by HPLC as 3-(_o-methoxyphenyl)-1F1-1,2,4-triazole (114), 3-(m-methoxyphenyl)-1H-1,2,4-triazole(113), and 3-(j)-methoxy- phenyl)-1H-1,2,4-triazole (112) in 52, 8 and 40 molar percentages, respectively (Eq 93). ,0CH3 II2 II3 114 Preparative separation of the products form several thermolyses gives 3-(o^-methoxyphenyl)- 1H-1,2,4-triazole (114) (40%) and 3-(j)-methoxy- phenyl)-1H-1,2,4-triazole (112) (25%)* The structures of 112 and 114 are confirmed by comparison (mp, NMR and MS) with authentic samples. Thermolysis of _1_ in refluxing anisole (154 °C) and HPLC analysis yields 3-(o-methoxyphenyl)-1_H-1,2,4-triazole (114), 75 3-(ni-methoxyphenyl)-1H-1,2,4-triazole (113) and 3-(j>-methoxyphenyl)-1 H- 1.2.4-triazole (112) in 67%, 11% and 22% molar proportions. Addition ally, photolysis of _1_ in anisole at 0 °C gives, by HPLC analysis, a mix ture of 53% 3-(£-methoxyphenyl)-1_H-1,2,4-triazole (114), 10% 3-(rn-meth- oxyphenyl)-1H-1,2,4-triazole (113), and 37% 3-(j)-methoxyphenyl)-1H- 1.2.4-triazole (112). No products are obtained from C-H insertion into the methoxy group, cleavage of the methoxy group, or ring expansion of anisole. Finally, the behavior of 3-diazo-3H.-1,2,4-triazole (_1_) is apparent ly insensitive to the method by which it is prepared and introduced into the anisole in which it is decomposed. When solid _1_, as obtained from concentration of dry (MgSOij) methylene chloride extracts of aqueous _1_ (pH = 7), is thermolyzed in anisole at 80 °°C the reaction products are 50% 3-(j3-methoxyphenyl)-1H-1,2,4-triazole (114) and 50% 3-(in- and £-methoxyphenyl)-1H-1,2,4-triazole (113 and 112), by HPLC analysis.^ The second class of electron-rich benzenes reacted with 2_ bear -_I substituents which allow evaluation of steric effects. The substituents are methyl and tert-butyl groups; their electrical effects are similar while their sizes are different. As mentioned previously, reaction of _1_ with refluxing toluene (110 °C) results in a mixture of 3-(tolyl)-1W- 1.2.4-triazoles. The isomers are identified by HPLC methods as 3-(o- tolyl)-1H-1,2,4-triazole (117), 3-(m-tolyl)-1H-1,2,4-triazole (116), and 3-(jj-tolyl)-1F1-1,2,4-triazole (115) in 68, 11, and 21 percentages, respectively (Eq 94). Thermolysis of _1_ in toluene at 80 °C and HPLC analysis give results similar to those at 110 °C: JM7 (57%), JJ£ (9%), and JM5 (33%). The products from several thermolyses on combination and separation by MPLC, yield 3-(o-tolyl)-1H-1,2,4-triazole (117, 45%), and 3-(£-tolyl)-1JH- 1,2,4-triazole (115, 40%). The structures of 115 and 117 are established by comparison (mp, NMR and MS) with authentic samples. 3-Diazo-3H-1,2,4-triazole (J_) behaves similarly with toluene on thermolysis and photolysis at 0 °C. Decomposition of _1_ in toluene at 0 °C gives a product which, HPLC reveals, contains 56% 117, 13% 116 and 31% 115. Photolysis of _1_ in toluene at 0 °C and HPLC analysis yields 3-(o-tolyl)-1H-1,2,4-triazole (117, 59%), 3-(tn-tolyl)-lFI-1,2,4-triazole (116, 10°/o), and 3-(£-tolyl)-1H-1,2,4-triazole (115, 31%). No products are obtained from C-H insertion into the methyl group or from ring expansion of toluene. The reactions of _1_ with toluene are unaffected by the pH of the aqueous solution from which it is extracted and the presence of water. When solid _1_, as obtained from concentration of methylene chloride extracts of aqueous _1_ (pH = 7), is thermolyzed in toluene at 80 °C the reaction product is 66% 3-(o- and in-tolyl)-1H-1,2,4-triazoles (117 and 116) and 33% 3-(£-tolyl)-1H-1,2,4-triazole (115), by GLC analysis.77 Further, when J_ is extracted into toluene from neutral aqueous solution of _1_ and then decomposed without drying the solution at 80 °C, the pro duct composition is 59% 3-(o-tolyl)-lH-l,2,4-triazole (117), 12% 3-(o- tolyl)-1H-1,2,4-triazole (116) and 34% 3-(£-tolyl)-1H-1,2,4-triazole 77 (115), by HPLC analysis. Finally, when basic aqueous solutions of _1_ are poured into toluene at 80 °C the product consists of 58% 117, 12% 116, and 30% 115, by HPLC analysis. At 80 °C tert-butylbenzene and _1_ yields three isomers identified by HPLC analysis as 3-(o-tert-butylphenyl) - 1H-1,2, 4-triazole (120, 11%), 3-(m-tert-butylphenyl) — 1H—1,2,4-triazole (119, 33%), and 3-(p-tert- butylphenyl)-1H-1,2,4-triazole (118, 56%) (Eq 95). Decomposition of _1_ in refluxing tert-butylbenzene (169 °C) gives results (HPLC analysis) similar to that at 80 °C: 6% 3-(o-tert-butylphenyl)-1H-1,2,4-triazole C(CH3 )3 ^lfc(CH3 >3*95) V ft ft H 118 119 I20 (120), 39% 3-(m-tert-butylphenyl)-1H-1,2,4-triazole( 119), and 5*1% 3-(jo- tert-butylphenyl)-1H-1,2,4-triazole( 118). Study of the photolytic reactions of _1_ with tert-butylbenzene at 0 °C is also of importance. Photolysis of _1_ and HPLC analysis thus yields _120 (14%), JM9 (35%), and VL8 (51%). The photolytic behavior of _1_ an^ tert-butylbenzene at 0 °C is thus similar to that at 80 °C. Neither C-H insertion into the tert-butyl group nor ring expansion of tert-butylbenzene is observed by either method of initiation. Thermal and photochemical reactions of _1_ with benzenes bearing electron-donating groups thus result in substitution of _2 into the C-H bonds of the benzene ring to give 3-(substituted phenyl)-1H-1,2,4-tri azoles. Further, the methoxy and methyl groups behave similarly in that they direct substitution of entering triazolylidene mainly at ortho- and para-positions, behavior typical of free-radical and electrophilic aromatic substitution processes. The ratios of the isomers from reactions of _1_ with electron-rich benzenes do vary with the substituent and the reaction conditions. For example, the methoxy group causes the ratios of ortho- to para-isomers to be greater than 1 for all reaction conditions. The ratio is 1.3 for reactions at 80 °C and increases to about 3.0 at higher temperatures (169 °C). Similarly, the ortho;para ratios of the products from toluene are greater than 1 for all reaction conditions. The ratio is 1.7 for reactions under 80 °C and increases to slightly above 3 at 110 °C. These increases in the ortho;para ratios represent an increase in the selectivity of a reactant as the temperature is increased. Since reagents usually lose selectivity with an increase in temperature, the increase in the ortho;para ratio for these reactions with an increase in temperature is unexpected. Additionally, the increases in the ortho;para ratios to values above 2, the ratio for electrophilic aromatic substitution reactions involving completely indiscriminate reagents, are astonishing. Finally, the reactions of _1_ with tert-butylbenzene indicate that the substitution process is sensitive to steric factors. The results of steric interactions can be seen by comparing the ortho to meta (orthometa) and the para to meta (para;meta) ratios of the isomers produced in the reactions of _1_ with benzenes bearing methyl and tert- butyl groups. The ortho meta ratios for the reactions of _1_ with tert- butylbenzene and toluene at 80 °C are 0.3 and 6, respectively. The 79 paratmeta ratio is about 1.4 for _1_ and tert-butylbenzene and 1.9 for J_ and toluene. The simultaneous decreases in the ortho;meta and para: meta ratios with increases in the sizes of the substituent without major changes in the substituent's electrical effects indicate a substitution processes subject to steric factors. So far in this dissertation, the reactions of _2 with benzenes bearing electron-donating groups have been investigated. To learn more about the substitution processes, _1_ was reacted with benzenes containing electron-withdrawing groups. The results of these experiments are presented in the following section. Reactions of _2 with Electron-poor Benzenes The first class of electron-poor benzenes to be reacted with 2_ bear substituents of mixed electrical effects. Halogens in halobenzenes are +1^ and -jS substituents. Reactions of _1_ with such benzenes might thus shed light on the processes by which reacts with benzenoids. 3-Diazo-3H-1,2,4-triazole (_1_) decomposes thermally and photochemi- cally in fluorobenzene giving products resulting from insertion of _2 into the C-H bonds of the benzene ring. Thermolysis of J_ in fluoroben zene at 80 °C and HPLC analysis yield a mixture which is 55% 3-(o_- fluorophenyl)-1H-1,2,4-triazole (123), 1^5& 3-(m_-fluorophenyl)-1H-1,2,4- triazole (122), and 30% 3-(j>-fluorophenyl)-1H-1,2,4-triazole (121, Eq 96). Photolysis of _1_ in fluorobenzene at 0 °C is similar in that 123 (60%), 122 (12%), and 121 (28%) are produced (HPLC analysis). Neither insertion into the C-F bond nor ring expansion of fluorobenzene occurs in these experiments. The reactions of 3-diazo-3H-1,2,4-triazole (_1_) with chlorobenzene were investigated at 0 °C, 80 °C, and 132 °C (the boiling point of chlorobenzene) and photolytically at 0 0C . ^ The results are summarized as follows. On standing in a refrigerator (12 hr) a chlorobenzene solution of _1_ yields (HPLC analysis) 3-(_o-chlorophenyl)-1H--1,2,4-tri- azole (126, 5*1%), 3-(jra-chlorophenyl)-1ji-1,2,4-triazole (125, 9%), and 3-(j3-chlorophenyl)-1ji-1,2,4-triazole (12H, 37%, Eq 97). Heating _1_ at 80 °C in chlorobenzene yields C-H substitution products which by HPLC analysis are 51% 126, 9% 125, and !)0% 12*1. The mixtures from several thermolyses on combination and separation by MPLC give Cl (97) H H H I24 I25 I26 3-(o^-chlorophenyl)-111-1,2,4-triazole (126) in 28% yield and 3-(j3-chlorophenyl)-12l-1,2,^-triazole (12U) in 32% yield. The structures of 126 and 12U are confirmed by comparison of their mp, IR, NMR and MS with those of authentic samples. On thermolysis at reflux and on photolysis _2 substitutes C-H bonds of chlorobenzene to give mixtures of 3-(chlorophenyl)-1H-1,2,4-triazoles in isomer ratios different from that from thermolysis at 0 °C and at 80 °C. On heating J_ in chlorobenzene at reflux (132 °C) 126 (7*1%), 125 (8%), and 124 (18%) are formed as determined by HPLC analysis. Similarly on photolysis, _1_ reacts with chlorobenzene to give 126 (76%), 125 (8%), and 124 (16%) as determined by HPLC analysis. The results from the experiments at 80 °C show less selectivity than those at 110 °C or by photolysis; the results of the reactions at 110 °C however are similar to those from photolysis. Since in all these experiments the products result from aromatic substitution, it appears that the mechanisms by which _1_ reacts with chlorobenzeneare is similar at various temperatures and on photolysis. The differences in the isomer ratios at different temperatures and on photolysis are presumably the results of minor changes in the reactions process. The mechanisms and the suspected mechanistic changes in reac tions of _1_ and chlorobenzene will be considered in the section titled "Mechanism". Thermolytic and photolytic decompositions of _1_ in bromobenzene result in formation of mixtures of 3-(bromophenyl)-111-1,2,4-triazoles (Eq 98). At 80 °C, _1_ and bromobenzene produce 3-(o-bromophenyl)-1JH- 1,2,4-triazole (129) and 3-(in-bromophenyl)-1j1-1,2,4-triazole (128 ) in 82 58% and 3-(j3-bromophenyl)-111-1 ,2,4-triazole (127) in 42% proportions as determined by HPLC analysis. Photolysis of in bromobenzene at 0 °C gives an isomer ratio of 63% 129 and 128 and 37% 127. Mixtures of ortho and meta isomers 129 and 128 can not be separated by HPLC. However, on the basis of (1) chloro- and bromobenzenes have similar physical properties and are expected to have similar chemical reactivi ties towards 2_, (2) the HPLC percentages of 3-(.o-fluoro- and o-chloro- phenyl)-1H-1,2,4-triazoles are similar to the percentage of the mixture of 3-(.o- and m-bromophenyl)-11^-1,2,4-triazoles, and (3) 3-(m-fluoro- and rn-chlorophenyl)-1H-1,2,4-triazoles compose virtually the same amount of the product mixtures resulting from _1_ and fluoro- and chlorobenzenes— the ratio of 3-(bromophenyl)-1H-1,2,4-triazoles can be interpreted to be 58% 129, 8% 128, and 37% 127 for photolysis at 0 °C and 48% ortho, 1C% meta, and 42% para for thermolysis at 80 °C. Hence, 3-diazo-3H.-1,2,4- triazole reacts similarly with bromobenzene on thermolysis and photoly sis to give predominately ortho- and para-substituted products. In summary, halogens, mild electron-withdrawing substituents, direct the aromatic substitution processes to the ortho- and para-positions. The para:ortho ratios of the halo isomers produced thermally increase from approximately 0.5 for fluorobenzene to about 1 for bromobenzene. No such trend is apparent in the photolytic reactions of _1_ with the halobenzenes. In an effort to learn more about the behavior of 2_ with electron- poor benzenes, the reactions of _1_ with trifluoromethylbenzene, a benzene containing a strong +JE substituent, were investigated. Thermolysis of _1_ in trifluoromethylbenzene at 80 °C yields a mixture of 83 N 3-(trifluoromethylphenyl)-1I1-1,2,4-triazoles (Eq 99). By HPLC analysis the molar percentage of the product is 84% of a mixture of 3-(o-tri- fluoromethylphenyl)-1H-1,2,4-triazole (132) and 3-(jn-trifluoromethyl- phenyl) -1 jl-1,2,4-triazole (131) and 16% 3-(j>-trifluoromethylphenyl)-1_H- 1,2,4-triazole (130). GLC analysis of the mixture shows only one peak which corresponds to a mixture of isomers 131 and 130. Since the GLC analysis analysis is capable of detecting 5% of 3-Co-trifluoromethyl- phenyl)-1H-1,2,4-triazole, the above results indicate that 3-(o-tri- fluororaethylphenyl)-1H-1,2,4-triazole composes less than 5% of the product mixture. 3-Diazo-3_H-1,2,4-triazole (J[) reacts photolytically with trifluoro methylbenzene at 0 °C to give a mixture of 83% 132 and 131 and 17% 130, as analyzed by HPLC. The results for photolysis of _2 with trifluoro methylbenzene therefore parallel those from thermolysis. The third and final class of electron-deficient benzenes to be reacted with _1_ have strong electron-withdrawing substituents (+I_ and +E0 such as nitro, cyano and methoxycarbonyl groups. A summary of the behavior of 3-diazo-3H_-1,2,4-triazole (_1_) with nitrobenzene will aid in presenting the varied experimental results. First, 3-diazo-3H.-1,2,4-triazole (_1_) reacts with nitrobenzene to form derivatives similar to those from 1 with other monosubstituted benzenes, i.e., C-H substitution products and no ring expanded products. Second, unlike _1_ with other monosubstituted benzenes, its reactions with nitrobenzene are extremely sensitive to the envirnoment. 3-Diazo-3HM,2,4-triazole (_1_) , as obtained from dry methylene chloride extracts of neutral aqueous solutions (pH = 7) of _1_, abstracts oxygen from and substitutes meta hydrogens of dry nitrobenzene (Eq 100). However, nitrobenzene solutions of _1_ prepared by extraction of basic aqueous solutions (pH = 9) of _1_ produce C-H substitution products having a high ortho;meta ratio of 3-(nitrophenyl)-1£[-1,2,4-triazoles (_1_34_ and 136) and little para-substituted product (133, Eq 101). Finally, when wet nitrobenzene extracts are dried (MgSO/j) prior to heating (80 °C), the major (>90%) product is 3-(m-nitrophenyl)-1H- 1,2,4-triazole (134). A detailed presentation of the above synopsis follows and is summarized in Table 21. Dissolution of solid _1_, as prepared by concentrating dry methylene chloride extracts of aqueous _1_ (pH = 7), in nitrobenzene and thermolysis at 80 °C give a mixture consisting of 48% nitrosobenzene (133) along with 3-(m-nitrophenyl)- 1H-1,2,4-triazole (134, Eq 100)'. 0 P h N 0 2 (100) + PhNO N'1 2 I53 I54 13 3 It is of further interest that the product composition of the above nitrobenzene solutions of _1_ changes to 62% nitrosobenzene and 38% 134 when the thermolysis is conducted at 185 °C. However, when solid _1_, obtained as above, is thermolyzed in an emulsion of aqueous base (NaOH, pH = 11) and nitrobenzene, the only reaction products are those of C-H substitution. Further, extraction of _1_ from an aqueous solution (pH = 9) with nitrobenzene and then thermolysis in nitrobenzene at 80 °C yield substitution products consisting (HPLC analysis) of 72% 3-(o-nitro- phenyl)-1H-1,2,4-triazole (136) and 28% of a mixture of 3-(m-nitro- phenyl)-1j1-1,2,4-triazole (134) and 3-(£.-nitrophenyl)-1J1-1,2,4-triazole (135, Eq 100). When _1_ is extracted from an aqueous solution at pH = 11-12 and decomposed in nitrobenzene at 80 °C, a mixture of 88% 3-(o.- nitrophenyl)-1H-1,2,4-triazole (136) and 12% 3-(rn-nitrophenyl)-1_H- 1,2,4-triazole (134) and 3-(j3-nitrophenyl)-1F1-1,2,4-triazole (135) is obtained (Eq 101). The products from several thermolyses with _1_, as n o 2 N2 CgH5N02 (101) 'N' 'N' rt I35 I34 I36 obtained by extraction of aqueous solutions of pH 9, were combined and separated by MPLC to give 136, 134, and 135 in 32%, 24%, and 6% yields, respectively. Comparison (mp, NMR and MS) with authentic samples result in confirmation of 134, 135 and 136. The yields of 134 - 136 based on the isolation experiment indicate that the 28% mixture of 134 and 135 as determined by HPLC analysis is about 80% 134. The substitution product is thus estimated to be 72% 136, 22% 134 and 6% 135. The nitro group is therefore an ortho and meta directing in the reactions of _1_, as obtained from aqueous solutions of _1_ at pH = 9, with nitrobenzene at 80 °C. Study has also been made of the effects of temperature on the reactions of nitrobenzene with _1_ as extracted from aqueous solutions at pH greater than 9— _1_ thermolyzed in nitrobenzene at 210 °C (the bp of nitrobenzene) yields 83% 136 and 17% of a mixture of 13*4 and 135. On the basis of the prior MPLC separation the isomer distribution is estimated as 83% J36, 13% .134, and 4% 135. The photolytic and thermal reactions of 3-diazo-3H-1 ,2,4-triazole (_1_) as extracted from aqueous solutions at pH = 9-11 with nitrobenzene are generally similar. Thus irradiation of _1_ in nitrobenzene gives, by HPLC analysis, 87% 136 and 13% of a mixture of 134 and 135, when the pH of the aqueous diazo solution is 9. When the pH of the aqueous diazo solution is 11-12, the photolytic reactions produce 93% 136 and 7% of 13*4 and 135. The estimated isomer percentages in the photolysis experi ments are 87% J_36, 10% V3±, and 3% J35 and 93% 136, 6% 13*4, and 1% 135, respectively. Hence, in the photolysis of nitrobenzene with alka line _1_ the nitro group is behaving primarily as a ortho-directing group. Thermolysis and photolysis of _1_ in benzonitrile give mixtures of 3-(cyanophenyl)-1H-1,2,4-triazoles (Eq 102). Thus 3-diazo-3H-1,2,4- triazole (_1_) and benzonitrile at 80 °C result in 11% 3-(£-cyanophenyl)- 1H-1,2,4-triazole (87), 75% 3-(rn-cyanophenyl)-141-1,2,4-triazole (138), and 14% 3-(£-cyanophenyl)-1H-1,2,4-triazole (137) by HPLC analysis. That benzonitrile reacts selectively at its meta-position indicates that the overall behavior of _1_ or its subsequent carbene (2) is as an electrophile. As stated previously, 137 and 138 have not been independently synthesized. The mixtures from several thermolyses, on combination and separation by MPLC, however yield 16% _87, 21% 138, and 15% 137. The structure of isolated §7_ is established by comparison of its physical properties to an authentic sample. The structures of 137 and 138 are assigned from their MS, IR and 1H FT-NMR. The MS of the individual isomers show molecular ions for 3-(cyanophenyl)-1F[-1^jH-triazoles and degradation patterns characteristic of compounds containing a triazole nucleus and a benzene ring. The IR spectra of 137 and 138 reveal triazole rings (N-H stretch), cyano groups (CN stretch) and character istic double bond stretches. Further, the aromatic regions of the FT-NMR spectra of 137 - 138 are similar to that of other 3-(ortho-, meta- and para-substituted phenyl)-1H-1,2,lJ-triazoles. The behavior of _1_ with benzonitrile at higher temperatures is also of importance. Thermolysis of _1_ in refluxing benzonitrile (191 °C) gives, by HPLC analysis, §]_ (2%), 138 (96%), and 137 (2%). Also, _1_ reacts photolytically with benzonitrile to form (by HPLC) _87 (2C%), 138 (62%), and JI37 (18%). Thermolysis of _1_ at 80 °C and photolysis of _1_ at 0 °C in benzoni trile are thus similar and the principal substitution reaction occurs at the meta-position. Of particular interest is that thermal reactions of _1_ and benzonitrile show the same unusual behavior that _1_ does with ani- sole, i.e., an increase in the selectivity of aromatic substitution with an increase in reaction temperature. In low temperature thermolysis, 3-(o- and j)-cyanophenyl)-1H-1,2,4-triazoles are produced in substantial and virtually equal quantities but there is a strong preference for meta-substitution. At higher temperatures the quantities of the meta- isomer produced increase at the expense of the others. The behavior of methyl benzoate with _1_ i-s nOM considered. 3-Diazo- 3H,-1,2,4-triazole (_1_) reacts with methyl benzoate thermally and photo- lytically to give products of aromatic substitution of hydrogen (Ea 103). At 80 °C _1_ and methyl benzoate yield 3-(.o-methoxycarbonyl- > co2'ch3 (103) kN A I39 I40 phenyl)-111-1,2,4-triazole (1*10, 33%) and 3-(nwnethoxycarbonylphenyl)- 1H-1,2,4-triazole (139, 67%). Surprisingly none of the para-isomer, [3-(£_-methoxycarbonylphenyl)-1H-1,2,4-triazole], is detectable. The methoxycarbonyl group therefore is a meta director. Several mixtures obtained from thermolyses at 80 °C on combination and separation by MPLC result in 140 in 15% yield and 139 in 63 % yield. The structures of 139 and 140 are assigned from their MS, IR and •1 H FT-NMR spectra. Proper molecular ions for 3-(methoxycarbonylphenyl)- 1H-1,2,4-triazoles and degradation patterns for compounds containing a triazole nucleus and a benzenoid ring are exhibited by 139 and 140. 89 The FT-NMR spectra of 1*40 and 139 are virtually identical to those of other 3-(ortho- and meta-substituted phenyl)-1ji-1,2,4-triazoles. The IP spectra of 139 and 1 HO reveal the presence of triazole rings (N-H stretch) and ester carbonyls (C=0 stretch). The results from thermolysis at 198 °C are similar to those at 80 °C in that C-H substitution gives rise to the ortho- and meta products. Thermolysis of _1_ in refluxing methyl benzoate (198 °C) is different than at 80 °C in that 39% 140 and 61% 139 are formed. Diazo compound _1_ thus substitutes primarily in the meta-position of methyl benzoate at 80 °C and at 198 °C. Irradiation of J_ in methyl benzoate at 0 °C yields 1*40 (53%) and 139 (47%) - The meta:ortho ratio from photolysis is thus dissimilar to that from the low and high temperature thermolyses. In summary, 3-diazo-3H-1,2,4|-triazole (JO reacts thermally and photochemically with monosubstituted benzenes to produce 3-(substituted phenyl)-1H-1,2,4-triazoles. The isomers produced in the C-H substitu tion reactions vary with the benzenic substituent and the experimental conditions. Products are not obtained from ring expansion of benzene or any substituted benzene. Methoxy and methyl groups cause substitution primarily at ortho- and para-positions. Ortho-substitution is the principal process and the ortho-product increases with an increase in the reaction temperature. The major reaction of tert-butylbenzene with J_ is para-substitution; meta-attack is appreciable whereas ortho-substitution is small. As the temperature of reaction of tert-butylbenzene with J_ is increased, meta- substitution increases mainly at the expense of ortho-substitution. 90 Further, the results of photolysis of _1_ in anisole and in toluene are virtually identical to those of the thermal reactions at 80 °C. Halogens direct substitution by 2_ to the ortho- and para-positions and the ortho products are produced in greater quantities than the para. The para:ortho ratios of the isomers from the thermal reactions increase slightly within the halobenzene series from fluorobenzene to bromobenzene. In thermolysis of _1_ in chlorobenzene the para:ortho ratio decreases with an increase in the reaction temperature. There does not seem to be any general trend in the para:ortho ratios from photolysis of _1_ in haloben- zenes other than that the ratios of the substitution products are small. The strongly electron-deficient benzenes— benzonitrile, trifluorome- thylbenzene, methyl benzoate and nitrobenzene— react thermally at 80 °C with to give products resulting mainly from meta-substitution and a varying amount of ortho- and para-substitution. Meta-substitution occurs in the photolytically initiated reactions of _1_ with benzonitrile and increases when the thermolysis of _1_ and benzonitrile is performed at 188 °C. As stated above, the ortho- and para-substitution patterns of _1_ with highly electron-deficient benzenes are complex. Ortho- and para-substi- tution occurs essentially equally with _1_ and benzonitrile. A major point however is that the preferred site of substitution of methyl ben zoate by _1_ changes from meta to ortho when the reaction is photolyti cally initiated. There is no para-substitution in the reactions of _1_ with methyl benzoate. Para-substitution accounts for less than a quar ter of the product from photolysis of _1_ in trifluoromethylbenzene. Certain generalizations may be drawn regarding the nature of 2_ and its reactions with monosubstituted benzenes. Table 21 shows that the ortho- and para-positions of benzenes containing inductive (methyl) and resonance (methoxy, fluoro, chloro and bromo) electron-donor substi tuents are more reactive to substitution than are the meta positions. The reactions of _1_ with benzenes bearing inductive electron donor groups, like tert-butyl, are affected by steric interactions with the substituent. Further, with benzenes bearing inductive (trifluoromethyl) or linear unsaturated (cyano) electron-withdrawing groups the meta-posi- tions of the ring are more reactive than the ortho- and para-positions. Finally, strong electron-withdrawing non-linear unsaturated functions, such as the nitro and methoxycarbonyl groups, cause the ortho- and meta- positions to substitute faster than the para-position. By comparison of thermal phenylation of monosubstituted benzenes with benzoyl peroxide (Table 22) with the data in Table 21, it can be concluded that substitution of benzenes by 2_ is not occurring by a free- radical mechanism. With the exception of tert-butylbenzene it is seen (cf. Table 22) that phenyl radicals tend to substitute the ortho- and meta-positions of benzenes bearing inductive and resonance electron- donating groups. The substitution patterns, however, differ consider ably from that for 2^with such benzenes. Further, strong electron- withdrawing substituents (cyano, nitro and methoxycarbonyl) direct phenylation to ortho- and para-positions. Again, this is in contrast to the ortho;meta selectivities with which 2 substitutes methyl benzoate and nitrobenzene and the meta selectivity for benzonitrile. The only reactions of 2^ and phenyl radicals which are similar are the reactions with trifluoromethylbenzene. Both occur with meta; para selectivity, although the former occurs with predominant meta substitution. 92 Table 22 Phenylation of Monosubstituted Benzenes with Benzoyl Peroxide at 80°C. Product Percentage Substrate ortho meta1 para ref. Toluene 67 19 14 a t^Butylbenzene 24 49 27 b Fluorobenzene 54 31 15 c Chlorobenzene 50 32 18 d,e,f Bromobenzene 49 33 17 c Nitrobenzene 63 10 28 d,e,g Benzonitrile 60 10 30 d,f Methyl Benzoate 58 17 25 h Tri fluoromethyl- benzene 20 40 40 a) D. H. Hey, B. W. Penfilly, and G. H. Williams, J_. Chem. Soc., 1463 (1956); b) J. I. Codogan, D. D. Hey, and G. H. Williams, _J. Chem. Soc., 3352 (1954); c) D. R. Augood, J. I. Cadogan, D. H. Hey, and G. H. Williams, jJ. Chem. Soc., 3412 (1953); d) S. H. Chang, D. H. Hey, and G. H. Williams; Chem. Soc., 1885, 2600, 4403 (1958); e) D. R. Augood, D. H. Hey, and G. H. Williams, J_. Chem. Soc., 2094 (1952); f) R. L. Dannley and E. C. Greeg, Am. Chem. Soc., 76, 2997 (1954); g) D. H. Hey, A. Nechvatal, and T. S. Robinson, jJ. Chem. Soc., 892 (1951); h) G. H. Williams, "Homolytic Aromatic Substitution", Pergamon Press, New York, 1960, p. 60; i) R. L. Dannley and M. Sternfeld, _J. Am. Chem. Soc., 7 6, 4543 (1954); j) C. S. Rondestvedt and H. S. Blanchard, ^J. Org. Chem., 21_, 229 (1956) The substitution patterns of monosubstituted benzenes by J_ are fairly similar, however, to that by 2-azadiazoazoles (cf. Table 21 to Tables 4 - 7 in the Introduction), 3,5-dichloro-1,4-diazooxide (cf. Table 21 to Table 23) and various nitration and halogenation electro- philes (cf. Table 21 to Tables 24 to 27). Resonance electron-donor groups cause 3,5-dichloro-1,4-diazooxide to substitute primarily in the ortho position and secondarily in the para position. The methoxy carbonyl group leads mainly to ortho- and meta-substitution, a minor 93 Table 23 Reactions of 3,5-Dichloro-1 ,4-diazooxide with Monosubstituted Benzenes* Product Percentage Substrate ortho meta para Anisole 72 23 Fluorobenzene 62 38 Chlorobenzene 62 32 Bromobenzene 42 32 Benzonitrile 45 17 39 Methyl Benzoate 35 47 18 *M. J. S. Dewar and K. Narayanazwami, J. Am. Chem. Soc., 86, 2422 (1964). Table 24 Nitration of Monosubstituted Benzenes with Nitric Acid in Sulfuric Acid Product Percentage Substrate ortho meta para ref. Toluene 59 5 38 a 1-Butylbenzene 16 12 73 b Fluorobenzene 12 0 88 c Chlorobenzene 30 1 70 d Bromobenzene 37 1 63 d Nitrobenzene 6 93 0 c Benzonitrile 17 81 2 e Methyl Benzoate 21 73 6 f Ethyl Benzoate 24 72 4 f Trifluoromethyl- benzene 0 99 0 g a) V/. W. James and M. Russell , J. Chem. Socs., 921 (1947); b) K. L. Nelson and H. C. Brown, J. Ami. Chem . Soc., 73, 5605 (1951); c) A. F. Holleman, Chem. Rev., 1, 187 (1924) ; d) J. D. Roberts, J. R. Sanford, F. L. J. Sixma, H. Cerfontain, and R. Zagt, _J. Am. Chem. Soe., 76 4525 (1954); e) A. Baker and C. K. Ingold, J_. Chem. Soc., 436 (1928); f) K. L. Nelson, J_. Org. Chem., 21 , 145 (1956); g) J. S. Reese, Chem. Rev., 14, 55 (1934) Table 25 Nitration of Monosubstituted Benzenes using Different Nitrating Agents Product Percentage Substrate ortho meta para ref. Toluene AcNOo, 30 °C 58 4 37 a HNOo, 30 °C 58 4 37 a HNOo/AcOH 57 3 40 b HMOo/Ac20 61 2 37 b h n o 3/c h 3n o 2 62 3 35 b 62 3 35 b _t-Butyl benzene HN03/Ac0H 12 9 80 c Fluorobenzene AcN03/H2S04(cat) 6 94 d n 2o 5 28 72 d Chlorobenzene HN03/Ac 0H 36 67 d Ac N03 22 78 d AcN03/CH3CN 27 73 d AcN03/H2S01)(cat) 20 80 d AcN03/HC10i,(cat) 20 80 d AcN03/CHC13 18 82 d AcN03/CC1i, 15 85 d Bromobenzene a c n o 3/c h 3n o 2 37 1 62 e 42 58 f h n o 3, 0 °C 38 1 62 ff Nitrobenzene h n o 3, 0 °C 4 93 1 h Benzonitrile h n o 3, 0 °C 17 81 2 i Methyl Benzoate HN03, 30 °C 26 70 5 j Tri fluoromethyl- benzene 0 89 0 k 95 Table 25, continued a) C. K. Ingold, A. Lapworth, E. Rothstein, and D. Ward, Chem. Soc., 1951 (1931); b) G. A. Olah, S. J. Kuhn, S. M. Flood, and J. C. Evans, _J. Am. Chem. Soc., 84, 3687 (1962); c) H. Cohn, E. D. Hughes, M. H. Jones, and M. A. Peeling, Nature, 16 9, 291 (1952); d) A. K. Sparks, £. Org. Chem., 31, 2299 (1966); e) J. D. Roberts, J. K. Sanford, F. L. Sixma, H. Cerfontain, and R. Zogt, J^. Am. Chem. Soc., 76, 4525 (1954); f) M. L. Bird, C. K. Ingold, J^. Chem. Soc., 918 (1938); g) A. F. Holleman, Rec. trav. Chim., 24, 140 (1905); h) A. F. Holleman and B. R. deBruyn, Rec. trav. Chim., 19, 79 (1900); i) J. W. Baker, K. E. Copper, and C. K. Ingold, J_. Chem. Soc., 426 (1928); j) A. Holleman, Rec. trav. Chim., 18, 267 (1899); k) Chem. Abstr. 33, 6271 (1939). Table 26 Nitration of Monosubstitutgd Benzenes with Nitronium Tetrafluoroborate in Tetramethylene Sulfone. Product Percentage Substrate ortho meta para Toluene 65 3 32 _t-Butylbenzene 14 11 75 Fluorobenzene 9 92 Chlorobenzene 22 1 77 Bromobenzene 26 1 73 *G. A. Olah, S. J. Kuhn, and S. H. Flood, _J. Am. Chem. Soc., J33, 4571 (1961); G. A. Olah, S. J. Kuhn, and S. H. Flood, J^. Am. Chem. Soc., 8 3 , 4581 (1961) 96 Table 27 Halogenations of Monosubstituted Benzenes with Different Halogenating Agents. Product Percentage Substrate/Reagent ortho meta para ref. Anisole t-BuOCl/CCl!, 23 77 a Js-BuOCl/Dioxane 20 80 a t-BuOCl/CHoCN 20 80 a _t-BuOCl/HOAc 34 66 a Toluene AlCl3/Br2 40 60 c HCLOji/AgClO^ 75 2 23b Chlorobenzene FeCl3/Br2 15 9 76 c AlCl3/Br2 11 2 87 c No Catalyst/Br2 18 1 81 c FeCl3/Cl2 30 4 66 c a i c i 3/c i 2 39 5 56 c t-BuOCl/HOAc 45 1 54 a HClO^/AgClOj, 36 1 62 b Bromobenzene FeCl3/Br2 13 2 85 c AlCl3/Br2 8 30 62 c FeCl3/Cl2 42 7 51 c a i c i 3/c i 2 30 5 65 c HC10^/AgC10i| 40 3 57 b Nitrobenzene HC10ij/AgC10i| 18 81 1 b Benzonitrile HClOjj/AgClOi, 23 74 3 b Trifluoromethyl- benzene HClO^/AgClOii 16 80 4 b a) P. R. Harvey and R. 0. C. Norman, J^. Chem. Soc., 3604 (1961); b) P. B. D. de la Mare, J. T. Harvey, M. Hassan, and S. Varma, Chem. Soc., 2756 (1958); c) A. F. Holleman, Chem. Rev., _1_» 18? C1924) and L. N. Ferguson, Chem. Rev., 50, 47 (1952). amount of para-substitution also occurs. These patterns are the same as for _1_ with monosubstituted benzenes (cf. Tables 21 and 23). The substitution patterns for nitration and halogenation are as comparable to that for _1_ with monosubstituted benzenes as are those from 3,5-dichloro-1,4-diazooxide with monosubstituted benzenes (cf. Table 21 to Tables 24 through 27). The aromatic C-H substitution patterns of _1_, the diazoazoles (discussed in the Introduction) and nitrating and halogenating electrophiles indicate that, in the product controlling steps, the influences of substituents in these various reactions are similar. Although the substituent effects in the reactions of _1_ with benzenes reveal the overall nature of the substitutions, they do not establish the reaction mechanisms. Additional information as to the process by which J_ reacts with benzenes might be obtainable from competition experiments involving and two or more benzenes. Such experiments should confirm whether 2_ is an electrophile since such reagents usually react faster with electron-rich than with electron-poor benzenes. Competition Experiments of 2_ with Substituted Benzenes To determine the relative reactivities of 2_ with benzenes, was decomposed at 80 °C in a large excess of known mixtures of benzene and monosubstituted benzenes. The behavior of cyclohexane versus benzene was also studied to determine the relative abilities of _2 to effect substitution of sp^ C-H bonds compared to sp^ C-H bonds. The products from these reactions were analyzed by GLC methods, since, as previously 98 mentioned, HPLC is inadequate. The experimental results are presented in Table 28. Thermolysis of _1_ in benzene and cyclohexane (1:1 by volume) leads to 3-phenyl-111-1,2,4-triazole and 3-cyclohexyl-1F^-1,2,4-triazole in 80% and 20% of the total peak areas. Conversion of the percent peak areas to percent moles reveals that the molar composition of cyclohexyltria- zole to phenyltriazole is 0.77 to 1.00. From the cyclohexane and ben zene initially in the experiment the molar reactivity of cyclohexane to benzene is 0.93 to 1.00. Correcting the molar reactivities for the number of C-H bonds in cyclohexane and benzene gives a relative Table 28 Molar Reactivities of 3-Diazo-3H.- 1,2,4-triazole (1) with Cyclohexane and Monosubstituted Benzenes Relative to Benzene at 80 C Substituted Volume of Product Molar Benzene, Solvents Reactivities Composition Ratio X PhX/PhH Molar Relative o_ in f £ o/(m_ y jd) cyclohexane 1:1 0.93 0.46 0CH, 1:4 2.88 3.46 0.35 0.24 1.45 OCHo 1:1 1.10 1.32 0.45 0.45 1.00 o c h 3* 1: - 0.52 0.41 1.26 CHo 1:1 0.91 1.09 0.48 0.30 1.60 1: - 0.58 0.41 1.41 c h 3* Cl 1:1 0.56 0.67 0.25 0.33 0.76 Cl 4:1 0.52 0.63 0.89 0.97 0.92 Cl* 1: - 0.52 0.48 1.08 c f 3 1:1 0.52 0.63 0.05 0.34 0.15 c f 3 1 :- 0.00 1.00 1:1 1.04 d6 *Percentages determined by HPLC analysis, see Table 21 and the related text. 99 reactivity of cyclohexane to benzene, on a C-H basis, of 0.46 to 1.00. p That is, _2 substitutes a C-H bond in benzene (sp C-H bonds) essentially twice as fast as it inserts into a C-H bond of cyclohexane (sp^ C-H bonds). Decomposition of _1_ in benzene and anisole (1:1 by volume) yields 3-phenyl-1^-1,2,4-triazole (87) and 3-(methoxyphenyl)-1H-1,2,4-triazoles (116 - 118). The GLC chromatogram shows that the percent total peak areas of the products are 62% 3-phenyl-11[-1,2,4-triazole (106), 27% 3- (£-methoxyphenyl)-1H-1,2,4-triazole (114) and 11% 3-(in- and jD-methoxy- phenyl)- 1H-1,2,4-triazoles (113 and 112). The molar composition is 0.45 3-(^-methoxyphenyl)-1H_-1,2,4-triazole (114) and 0.45 3-(m- and j)-meth- oxyphenyl)-1H-1,2,4-triazoles (113 and 112) to 1.00 phenyltriazole (106)♦ Also, the molar composition of the 3-(methoxyphenyl)-1H-1,2,4- triazoles (112 to 114) is 50% 3-(oHnethoxyphenyl)-1fl-1,2,4-triazole (114) and 50% 3— (in— and jD-methoxyphenyl)-1H-1,2,4-triazoles (113 and 112). Computation using the moles of anisole and benzene in the experi ment gives a molar reactivity of 1.10 anisole to 1.00 benzene. Correct- p ing for the number of sp C-H bonds in anisole and benzene gives a rela tive molar reactivity of anisole to benzene of 1.32 to 1.00. That is, 2_ reacts faster with anisole than it does with benzene. To study the effects of solvent ratio on relative reactivities, _1_ was thermolyzed in benzene and anisole (4:1 by volume). GLC analysis reveals the products— 3-phenyl- 1J1-1,2,4-triazole (106), 3-(o_-methoxy- phenyl)-111-1,2,4-triazole (114), and 3-(m- and jo-methoxyphenyl)-1H- 1,2,4-triazoles (113 and 112)— as 72%, 20%, and 8%, respectively, of the total peak area. Conversion of the peak areas to moles yields a composition of 0.35 mole of 3-(o_-methoxyphenyl)-1H-1,2,4-triazole (114) 100 and 0.24 mole of 3-(rn- and j)-methoxyphenyl)-1ji-1,2,4-triazoles (113 and 112) per 1.00 mole of phenyltriazole. The molar composition of the 3- (methoxyphenyl)-111-1,2,4-triazoles (112 to 114) is 59% 3-(o-methoxy- phenyl)-111-1 ,2,4-triazole (114) and 41% 3-(m.- and ]5-methoxyphenyl)-111- 1,2,4-triazoles (113 and 112) From the anisole and benzene initially in the experiment, the molar reactivity is 2.88 anisole to 1.00 benzene. On the p basis of the sp C-H bonds in anisole and in benzene, the relative reactivity of anisole to benzene is 3-46 to 1.00. Again, anisole reacts faster than benzene. The change in the molar and relative reactivities with solvent com position indicates that the reactions of _1_ with monosubstituted benzenes are not true competitive reactions. If the reactions were competitive the reactivities would be independent of solvent composition. Further, there is an increase in the reactivities of anisole with a decrease in the anisole concentration, which implies the reactions of _1_ with anisole become relatively favored as the concen tration of anisole decreases. Finally, the composition of the 3-(methoxyphen- yl)-111-1,2,4-triazoles (112 to 114) produced changes with the composition of the solvent. The ratio of the ortho-isomer to the sum of the meta- and para-isomers produced decreases with an increase in the anisole concentration. That is, as the concentration of anisole is increased, its relative substitution at the meta- and para-positions increases. It is troubling that there is not a linear relationship between the ortho:(meta + para) ratio with anisole concentration. To learn more about the relative reactivities of electron-rich benzenes _1_ was decomposed in a mixture of benzene and toluene (1:1 by volume). By GLC, the product is 3-phenyl-1 H_-1,2,4-triazole (106), 3-(o-tolyl)-111-1,2,4-triazole (117), and 3-(m- and £-tolyl)-1H_-1,2,4-triazoles (116 and 115) in total peak area percentages of 55%, 27% and 18%, respectively. The area percentages 101 corresponds to a composition of 0.48 mole 3-(o-tolyl)-1H--1,2,4-triazole (117) and 0.30 mole 3-(m.- and j3-tolyl)-1j1-1,2,4-triazoles (116 and 115) per mole of phenyltriazole. Thus, the product of substitution is 61% 3-(o_-tolyl)-1H-1,2,4-triazole (117) and 39% 3-(in- and jD-tolyl)-1H- 1.2.4-triazoles (116 and 115). Calculations based on the toluene and benzene in the experiment give a molar reactivity of toluene to benzene of 0.91 to 1.00. Correcting for the phenyl C-H bonds in toluene and benzene gives molar relative reactivities of toluene and benzene of 1.09:1.00. That is, toluene reacts with _2 slower than benzene on a molar basis and faster than ben zene statistically on the basis of C-H bonds available for substitution. To determine the relative reactivity of _2 with an electron deficient benzene, _1_ was decomposed in benzene and chlorobenzene (1:1 by volume). 3-Phenyl-1J1-1,2,4-triazole (106), 3-(o-chlorophenyl)-1I1-1,2,4-triazole (126), and 3—(m— and j)-chlorophenyl )-1H-1,2,4-triazoles (125 and 124) are produced in 71, 16 and 13 GLC peak area percentages, respectively. The composition of the product is 0.25 mole 3-(o-chlorophenyl)-1H-1,2,4- triazole (126) and 0.33 mole 3-(m- and £-chlorophenyl)-1_H-1,2,4-tria zoles (125 and 124) per 1.00 mole of phenyltriazole; thus, the 3-(chlor- ophenyl)-1,2,4-triazoles (124 to 126) are 43% 3-(o-chlorophenyl)-1H- 1.2.4-triazole (126) and 57% 3-(in- and £-chlorophenyl)-1j1-1,2,4-tria zoles (125 and 124). From the initial chlorobenzene and benzene the molar reactivity of chlorobenzene to benzene is 0.56:1.00. The reactivity ratio of chlorobenzene to benzene on the basis of statistically substitutable hy drogen is 0.67:1.00. The reactivity of 2_ with chlorobenzene is thus less than with benzene. To test the dependency of chlorobenzene reactivity on solvent compo sition, _1_ was heated in a different mixture of benzene and chlorobenzene (1:4 by volume). GLC of the product show it to be, by peak area, 29% 3-phenyl-1H-1,2,4-triazole (106), 42% 3-(o-chlorophenyl)-1H-1,2,4-tria zole (126), and 29% 3-(in- and £-chlorophenyl)-111-1,2,4-triazoles (125 and 124). The percent peak areas convert to 0.89 mole 3-(o-chloro- phenyl)-111-1,2,4-triazole (126) and 0.97 mole 3-(m- and jD-chlorophenyl)- 111-1,2,4-triazoles (125 and 124) per 1.00 mole of phenyltriazole. The molar composition of the 3-(chlorophenyl)-111-1,2,4-triazoles (124 to 126) is 47% 3-(c^-chlorophenyl)-121-1,2,4-triazole (126) and 53% 3— (m_— and jD-chlorophenyl)-1H-1,2,4-triazoles (125 and 124). Based on the chlorobenzene and benzene in the mixture, the reactivity is 0.52 mole of chlorobenzene per 1.00 mole of benzene. Correcting the molar reactivi- p ties for the number of sp C-H bonds in chlorobenzene and benzene gives a relative C-H reactivity of 0.63 for chlorobenzene to 1.00 for ben zene. This set of experiments indicates, also, that chlorobenzene reacts slower with._1_ than does benzene. In experiments of _1_ with chlorobenzene and benzene the relative molar and C-H reactivities of chlorobenzene increase with a decrease in the concentration of chlorobenzene. The solvent effect, although it is small, indicates that the reactions of _1_ with chlorobenzene become more selective kinetically as the concentration of chlorobenzene decreases. Finally, the ortho:(meta + para) ratio of the 3-(chlorophenyl )-1H_-1,2,4-triazoles (124 to 126) produced increases with an increase in the chlorobenzene concentration. The relative reactivities of benzene and trifluoromethylbenzene (1:1 by volume) with _1_ were then determined at 80 °C. The GLC peak area 103 percentages of the product amount to 70% 3-phenyl-1H-1,2,4-triazole (106), 6% 3-(_o-trifluoromethylphenyl)-1H-1,2,4-triazole (132), and 24% 3-(in- and j>-trifluoromethylphenyl)-1H-1,2,4-triazoles (131 and 130). The peak area percentages convert to 0.05 mole 3-(o-trifluoromethyl- phenyl)-1j1-1,2,4-triazole (132) and 0.3^ mole 3-(m- and j3-trifluoro- methylphenyl)-1H-1,2,4-triazoles (131 and 130) per 1.00 mole of phenyl- triazole. The molar composition of the product is 13% 3-(o-trifluoro- methylphenyl)-1H-1,2,4-triazole (132) and 87% 3-(m- and j)-trifluoro- methylphenyl)-11[-1,2,4-triazoles (131 and 130). Calculations based on the trifluoromethylbenzene and benzene in the experiment gives a molar reactivity of 0.52 for trifluoromethylbenzene to 1.00 of benzene. Further computations, as based on the substitutable hydrogens in the arene pair, give a reactivity of trifluoromethylbenzene to benzene on a C-H basis of 0.62 to 1.00. This experiment thus reveals that trifluoromethylbenzene reacts slower with _1_ than does benzene. It is surprising that 3-(.o-trifluoro- methylphenyl)-1J1-1,2,4-triazole (132) is produced (11%) in the reac tions of with a mixture of trifluoromethylbenzene and benzene, and not in the reactions of _1_ with neat trifluoromethylbenzene. An attempt was made to determine the relative reactivities of nitrobenzene and benzene with _1_. 3-Phenyl-111-1,2,4-triazole (106) and 3-(m- and j>- nitrophenyl)-1H^1,2,4-triazoles (134 and 135) are produced in 70% and 30% peak areas from benzene and nitrobenzene (1:1 by volume) at 80 °C. The peak area percentage converts to 0.39 mole of 3— (m— and jwiitrophenyl)- 1H-1,2,4-triazole (134 and 135) per mole of 3-phenyl-1H^1,2,4-triazole (106). On the basis of these results one can conclude only tentatively that nitrobenzene reacts slower with 1 than does benzene does with 1. 104 However, since 3-(o-nitrophenyl)-1J3-1,2,4-triazole (136) is not stable in the GLC conditions required to separate the mixture, one can try to estimate the amount of 3-0o-nitrophenyl)-1H^1,2,4-triazole (136) formed in the competition experiments by using the information in Table 21, i.e., the percentages of the 3 -(nitrophenyl)-1IL-1,2,4-triazoles (134 to 136 ) formed in the single solvent experiments. Using the information in Table 21, one can determine that the maximum amount of 3-(o_-nitrophenyl)-1ltt-1,2,4-triazole (136 ) formed in the mixed solvent experiments is 1.0 mole per 0.39 mole of 3 -(m- and £-nitrophenyl)-1IL-1,2,4-triazole (134 and 135) and per 1.00 mole of 3- phenyl-1fl-1,2,4-triazole (106). Hence, by the above interpretation, one could conclude that nitrobenzene reacts faster with _1_ than does benzene. An additional and important factor to take into consideration in interpreting the above experiment is that the composition of the 3-(substituted phenyl) — 1_H—1,2,4-triazoles produced in the mixed solvent experiments are different than the composition produced in the single solvent experiments. Further, from the information in Table 28, no general correlation can be made between the solvent composition and the ratio of the 3-(substituted phenyl)-1H-1,2,4-triazoles produced, i.e., the ortho:(meta + para) ratio. Hence, one cannot accurately estimate the amount of 3-(o-nitrophenyl)-IH-l,2,4-triazole (136) produced in the above mixed-solvent experiment. Thus, one can conclude only tentatively that nitrobenzene reacts slower with _1_ than does benzene. In summary, therefore, the reactivity of 3-diazo-3.H-1>2,4-triazole (7) is greater with electron-rich benzenes than with electron-deficient benzenes. 105 Table 29 Reactivities of Carbenes for Monosubstituted Benzenes Relative to Benzene Carbene Substrate 2 I66a I67b 168° Anisole 1.32 1.2 1.9 1.6 Toluene 1.09 Chlorobenzene 0.67 0.6 0.54 Nitrobenzene 0.8 Methyl Benzoate 0.78 Benzonitrile 0.4 0.4 Trifluoromethylbenzene 0.62 a) W. L. Magee, Ph. D.Thesis, The Ohio State University, Columbus, Ohio., 1974; b) T. Amiok, Ph. D. Thesis, The Ohio State University, Columbus, Ohio., 1983; e) M. J. S. Dewar and A. N. James, J. Chem. Soc., *1265 (1958). Having established the substrate selectivity of _1_, it is of interest to compare the substitutive reactivities of _2 with other carbenes. From Table 29 it can be seen that the reactivity pattern of 2_ is generally similar to that of 3-tert-butyl-5H-pyrazol-5-ylidene (166), 4H-imidazol- 4-ylidene (167), and 1Hr3,5-dibromocyclohexa-2,5-dieneon-1-ylidene (168), with varied benzenes. Also, the substrate selectivity of 2_ is compatible in kind with what is known about common electrophiles in aromatic substitution (Table 30). Further, the behavior of _2 differs from that of most substituted phenyl radicals, but is similar to that of 106 Table 30 Relative Reactivies of Electrophiles in Aromatic Substitution of Monosubstituted Benzenes Electrophilic Substrate Reagents Anisole Toluene Chlorobenzene CH^0N02a 18? 26 0.03 N02 BF!,b 1.76 0.14 N02 C10i, 1.60 no2 pf6 1.40(0.91) 0.21(0.50) N02 AsFf; 1.52(0.97) 0.12(0.4) N02 HS20 i| 1.48 0.14 j)-N02 -PhCH2 Cl, AlCl^0 1.64 0.47 Br2 -FeCl3d 2.3 0.35 a) Conducted in nitromethane: G. A. Olah and H. C. Lin, J^. Am. Chem. Soc., 96, 2892 (1974); b) These experiments were performed using tetramethylene sulfone as solvent; the figures in parentheses are from experiments in nitromethane: G. A. Olha and S. J. Kuhn, J_. Am. Chem. Soc., 84, 3684 (1962); c) G. A. Olah, S. J.Kuhn, and S. H. Flood, _J. Am. Chem. Soc., 84, 1688 (1962); d) Bromine was added neat to the suspension of the catalyst in a solution of nitromethane and monosubstituted benzene at 25 °C: G. A. Olah, S. J. Kuhn, S. H. Flood, and B. A. Hardie, J. Am. Chem. Soc., 86, 1039, 1044 (1964). jwiitrophenyl, a highly electron-deficient radical (Table 31). Hence one can conclude that 2_ is behaving as an electrophilic carbene. Having established the relative molar reactivities of several mono substituted benzenes toward and despite the fact that the reactions are not truly competitive, this information is used to describe the rates of attack of _2 on individual ortho-, meta- and para-positions of monosubstituted benzenes relative to the rate of attack on any one position in benzene, i.e., the partial-rate factors for reaction of _2 at 107 Table 31 Relative Reactivities of para-Substituted Phenyl Radicals Toward Monosubstituted Benzenes. para-Substituent in the Phenyl Radical Substrate N02 Cl H CHg OCH3 Anisole 2.39 1.88 1.71(1.2b ) 1.85 1.79 Toluene 1.80 1.56 1.68(1.9°) 1.65 1.56 Chlorobenzene 0.89 1.41 1.61(1.4d ) 1.57 1.92 Trifluoromethyl benzene 1.0e Benzonitrile 3.7f a) N-nitroso-(jD-substituted)-acetanilides were decomposed in mixtures of aromatic substrates with benzene at 20 °C: R. Ito, T. Migita, N. Morikawa, and 0. Simamura,Tetrahedron, 21, 955 (1965); b) Benzoyl peroxide was decomposed in equimolar amounts of pyridine and anisole at 83-85 °C; C. S. Rondestvedt, Jr. and H. S. Blanchard, _J. Org. Chem., 21, 229 (1956); c) C. S. Rondestvedt, Jr. and H. S. Blanchard, iJ. Am. Chem. Soc., 77, 1769 (1955); d) D. R. Augood, J. I. G. Cadogan, D. H. Hey, and G. H. Williams, J_. Chem. Soc., 3412 (1953); e) R. L. Dannley and M. Sternfeld, _J. Am. Chem. Soc., 76, 4543 (1954); f) R. L. Dannley and E. C. Gregg, J^. Am. Chem. Soc., _76, 2998 (1954). each ring position of monosubstituted benzenes (Op , Mg and pg). The partial-rate factors are defined as follows: og = k(PhX/phH)(6/2)(% ortho/100) (104) Mg = k(Phx/phH)(6/2)(% meta/100) (105) Pg = k(Phx/phF)(6/1)(% para/100) (106) where (1) k (PllX/phH^ as fche ratio of the molar reactivities, and (2 ) % ortho, % meta, and °/° para are the percentages of the ortho, meta and para isomers produced in the reactions of _1_ with a monosubstituted benzene, respectively in the competition experiments. 108 Table 32 Estimation of the Percentages of 3-(Substituted phenyl)-1H-1,2,4- triazoles Formed in the Mixed-solvent Experiments Substituted Solvents Volume Product Composition Benzene, X (PhX/PhH) o_ in jd OCHo 1:4 59 10 31 och3 1:1 50 10 40 ch3 1:1 62 10 28 Cl 1:1 43 10 47 Cl 4:1 48 10 42 cf3 1:1 12 72 16 As discussed previously and summarized in Table 21 , the 3 -(in-sub- stituted phenyl)-1H-1,2,4-triazoles produced from _2 with anisole, chlor obenzene and toluene (113, 125, 116), respectively, are less than 10% of the total of the 3 -(substituted phenyl)-1J£-1,2,4-triazoles formed. Also, the 3-(j>-trifluoromethylphenyl)-1I1-1 ,2,4-triazole (130) from _2 and trifluoromethylbenzene is about 16% of the 3 -(trifluoromethylphenyl)- 1H-1,2,4-triazoles (130 to 132) produced. Hence, the percentages of the 3- (methyoxyphenyl)-, 3 -(chlorophenyl)-, 3 -(tolyl)-, and 3 -(trifluoromethylphenyl)- 1H-1,2,4-triazoles formed per 1.00 mole of 3-phenyl-1H-1,2,4-triazole in the mixed-solvent experiments discussed above can be estimated (Table 32). The information in Table 32 and Equations 104-106 allows determina tion of the partial-rate factors of 2 _ for the monosubstituted benzenes in the mixed solvent experiments. These partial-rate factors are sum marized in Table 33. An interpretation of the partial-rate factors of 2_ with anisole, toluene, chlorobenzene, and trifluoromethylbenzene 109 Table 33 Summary of the Partial-rate Factors for the Monosubstituted Benzenes Used in the Mixed-solvent Experiments Substituted Volume of Benzene, Solvents Partial-rate Factors X PhX/PhH 0R PR F Hf F OCHo 1:4 5.1 0.9 5.4 och3 1:1 1.7 0.3 2.6 ch3 1:1 1.7 0.3 1.5 Cl 1:1 0.7 0.2 1.6 Cl 4:1 0.7 0.2 1.3 CF3 1:1 0.2 1.1 0.5 requires a knowledge of the partial-rate factors' of other 2 -azolylidenes and electrophiles towards the same substituted benzenes. Table 34 is a summary of such partial-rate factors. Table 34 indicates: that (1) electrophilic reagents, with the exception of nitronium tetrafluoroborate and 4-diazoimidazole, substi tute any single position in electron-rich benzenes faster than any single position in benzene, (2 ) electrophilic reagents, with the excep tion of 3-diazo-5-tert-butylpyrazole, substitute any single position in electron-deficient benzenes slower than in benzene, and (3 ) the partial- rate factors of extremely electrophilic reagents, such as nitronium tetrafluoroborate and 3-diazo-5-tert-butylpyrazole, are small and relatively invariant as compared to weaker electrophiles. Comparison of Tables 33 and 34 indicates that 3H.-1 ,2,4-triazol-3- ylidene (_2 ) is behaving as an extremely electron deficient reagent. 110 Table 34 Partial-rate Factors of 2-Azolylidenes and Electrophilic Reagents for the Monosubstituted Benzenes Used in the Mixed-solvent Experiments Partial--rate Factors 0R m r PR Reagents3 F F Anisole 3-Diazo-5-J>-butylpyrazolek 1.8 2.8 4-Diazoimidazolec 0.8 0.1 Br2 ,H0Ac-H20 8.7x 107 2 1.1x1012 C12 ,H0Ac 6 .1x 10 4.6x10 7 Toluene Br2 ,H0Ac-H20 600 5 2420 C12 ,H0Ac 617 5 820 HN0o,H2 S0i|d,e 52 3 58 HN0o ,H0Ac-H20 42 3 58 AcORO^* AcjjO 40 3 51 N02 BFi4a,f 3 0.1 3 Chlorobenzene 3-Diazo-5-J>-butylpyrazolek 1.0 1.0 Br2 ,H0Ac-CHoN02 5x10“^ 0.1 ci2 ,hoac-h2o 0.1 2 x 10"3 0.4 N02 BFi,d ' 0.09 3 x 10“ 3 0.6 Trifluoromethylbenzene 4-Diazoimidazolec 0.1 0.3 — a) L. M. Stock and H. C. Brown in "Advances in Physical Organic Chem istry," V. Gold, Ed., Academic Press, New York, N. Y., 1963 unless otherwise stated; b) W. L. Magee, Ph. D. Thesis, The Ohio State University, Columbus, Ohio., 1974; c) These partial-rate factors are derived from the information in T. Amick's Ph.D. Thesis, The Ohio State University, Columbus, Ohio., 1983; d) These experiments were performed using sulfolane as the solvent; e) J. C. Hoggett, R. B. Moodie, J. R. Penton, and K. Schofield, "Nitration and Aromatic Reactivity," Cambridge University Press, 1971, p 64; f) G. A. Olah, S. J. Kuhn, S. Flood, and J. C. Evans, J. Am. Chem. Soc., 84, 3687 (1962) 111 Further, the reactions of 2_ with electron-rich benzenes are similar in character to that of nitronium tetrafluoroborate with such benzenes. In addition to the above, the partial-rate factors in Table 33 can be interpreted as follows. The ortho and para partial-rate factors for reactions of 2_ with anisole and toluene indicate that behaves formally as an electophilic reagent; the partial rate factors are all greater than 1. However, the meta partial-rate factors for the reactions of 2_ with anisole and toluene are less than one. That is, since the meta partial rate factors are less than one, 2_ substitutes any single meta position of anisole and toluene slower than any single hydrogen in benzene. This overall behavior and interpretation are different than that formed traditionally for reactions of electrophiles and electron- rich aromatics. Anomalous partial rate factors behavior as above (Table 31)) has been observed previously in the reactions of the nitronium tetrafluoro borate and toluene. Olah explained such reactions by rationalizing that the rate-determining step involves weak-coordination of the iT-electrons of the benzenes by the nitrating agent and not a-complex formation.^ In such competition of an electrophile for aromatic compounds, sub strate selectivity should reflect the electron-donor abilities of the tt- electron systems. A measure of the 7T-donor ability of an aromatic com pound is stability of its molecular complexes. From the information in Tables 29 and 35, the relative reactivities of 2_ with monosubstituted benzenes can for the most part be correlated with the stabilities of the silver nitrate complexes of the benzenes. Hence, it is tempting to attribute the relative reactivities of 2 with monosubstituted benzenes 112 Table 35 Equilibrium Constants for Formation of Silver Nitrate-Complexes with Substituted Benzenes* Compound Equilibrium Constant Toluene 2.95 Anisole 2.5 Benzene 2.41 Chlorobenzene 0.69 Nitrobenzene 0.19 * L. J. Andrews and R.M. Keefer, J^. Am. Chem. Soc.,72, 3113 (1950). to the electron-donor abilities of the benzenoids. Thus 2 reacts as an electron-deficient reagent with a benzene to form addition complexes, which then isomerize with great selectivity to give C-H substitution products. The variations in the positional selectivities in aromatic substitu tion that 2_ displays with solvent composition are, perhaps, surprising, but certainly are not unique. Dannley has observed that the positional selectivity in the phenylation of chlorobenzene using benzoyl peroxide _ Qa at 80 C varies with the concentration of chlorobenzene. The effect has been attributed to association of the solvent. The origins of the solvent aggregation and the implications of the above interpretation, however, were not considered further. The variations that 2_ displays with solvent concentration will be discussed later in this thesis. 113 ESR Study Determination of the ground-state multiplicity of _2 then became of interest. Of major concern was whether _2 as generated has diradical character. The ESR spectra of the products of irradiation of _1_ in matrix however give no evidence for the triplet form of ylidene 2. Photolysis of _1_ in tetrahydrofuran at 77 °K produces a strong ESR signal at 3255 G. Undoubtedly the signal is that of a "free-radical" resulting from hydrogen abstraction from the solvent.The absence of a triplet carbene signal indicates that 2 is a ground-state singlet at 77 °K and probably a ground-state singlet at higher temperatures. Kinetic Deuterium Isotope Study To aid in establishing the rate-determining step with which 2_ reacts with benzenoids it became of interest to determine if there is a kinetic deuterium-isotope effect. 3-Diazo-3H.-1,2,4-triazole (_1_) was decomposed in a solution of benzene and benzene-dg (48:52 as determined by the relative mass spectral intensities of the m/e 78 and m/e 84 peaks) to give 3-phenyl-1jl-1,2,4-triazole and deuterated 3-phenyl-1H-1,2,4-tri- azole. In order to exchange the acidic deuterium in the triazole moie ties of the product for protons, the mixture was refluxed in excess methanol for 5 min, and the methanol removed by distillation. The resulting mixture consists of 47% 3-phenyl-1Il-1,2 ,4-triazole and 53% 3- phenyl-1H-1,2,4-triazole-dg as determined by mass spectral analysis of the relative intensities of the m/e 145 and m/e 150 absorptions. It is important to point out that the analysis of the mixture of 114 3-phenyl-111-1,2,4-triazole and 3-phenyl-1_H-1,2,4-triazole-dg is reproducable. This experiment shows that benzene-dg reacts 1.04 times faster than benzene. The lack of a primary kinetic-isotope effect indicates that the rate-determining step of the reaction of _2 with benzene does not involve rupture of a C-H bond. The small inverse kinetic-isotope effect may indicate that the rate determining step involves an addition complex involving 2_ and benzene. This idea will be developed in the following paragraphs. Small inverse kinetic isotope effects have been observed in other aromatic C-H substitution reactions. Reactions of nitronium tetra- fluoroborate with benzene®^ and with fluorobenzene®^ show k^/k^ reac tivity ratios of 1.12 and 1.22, respectively. Also, the kD/kH ratio for Oh silver perchlorate-catalyzed chlorination of benzene is 1.15. Further, the kT/kH ratio for azo coupling of 1,3>5-trimethoxybenzene Or with jD-chlorobenzenediazoniumion is 1.13- Hammond rationalized these findings to mean that the transition state of the overall reaction is not entirely reached before the pertinent C-H bond has lost an appre- ciable amount of its zero point energy. Berliner has suggested that a small inverse kinetic isotope effect may arise in the step leading to formation of an intermediate addition complex.®^ Melander and Streitwieser, propose that secondary isotope effects are due to changes in out-of-plane bending vibrations, which are low in aromatic C-H bonds (675 - 900 cm“^) and much higher in tertiary C-H bonds (1450 cm 1 ). ftfi In rehybridization during reaction, vibra tional frequencies in the transition state, which are higher than in the 115 reactant, cause the heavier molecule to react faster than the lighter one. That is, the change in the zero point energy of the bond under going rehybridization from sp^ to sp^ is smaller for a C-D bond than for a C-H bond. Halevi and Nussim have a different explanation for small inverse isotope effects in aromatic substitution.^ The increased rates with which deuterated compounds react are attributed to the greater electron- releasing inductive effect of deuterium in comparison to hydrogen. The interpretation implies that the rate determining step for such reactions is capture of the ir-electron system of the aromatic by the electrophile. Evidence supporting that deuterobenzenes are electron-rich in comparison to protiated benzenes being: (1) pentadeuterophenol is a weaker acid than phenol; (2) deuteroformic acid is a weaker acid than formic acid; (3) 2,4,6-trideuteroaniline is a stronger nucleophile than aniline, and (4) deuteriums on carbonium ion carbons stabilizes the carbonium ions. Extension of the above facts and theory to the observed inverse kinetic-isotope effect for reaction of 2_ with benzene thus raises the possibility that the rate-determining step involves formation of an addition complex in which the C-H bond eventually substituted is not appreciably distorted from the plane of the benzene ring. It has been pointed out that the position of the transition state along a reaction coordinate is dependent on the nature of the electrophile and the q 1 substrate.y Aromatic substitution may thus be correlated by a modified Hammett linear free-energy relationship which takes into consideration both the electronic influence of the substrate and the demand of the 116 reagent for the electrons in the n-system of the aromatic. Further, it has been generally accepted that, in various aromatic substitutions, the rate-controlling transition states increasingly resemble a complexes (Wheland intermediates) as the electrophilicity of the reagent decreases.92,93 implication of these observations is that the transition state of the reaction of _2 with benzenes is early along the reaction coordinate and, hence, does not resemble a Wheland interme diate . It then became of interest to determine if there is a kinetic- isotope effect in the reactions of _1_, as obtained from aqueous solutions of J_ (pH = 9), with nitrobenzene. Decomposition of _1_, as obtained above, was then effected in a mixture of nitrobenzene. Decomposition of _2 was then effected in a mixture of nitrobenzene and nitrobenzene-d^ (49:51 as determined by mass spectral analysis of the relative intensitites of the m/e 123 and m/e 128 peaks) at 80 °C. After deuterium-hydrogen exchange as described in the previous experi ment, a mixture of 49% 3-(nitrophenyl)-lH-1,2,4-triazoles and 51% 3-(nitrophenyl)-11[-1,2,4-triazoles-d/j was obtained, as determined by mass spectral analysis. This experiment indicates that nitrobenzene-d^ reacts as fast as nitrobenzene, i.e., the molar reactivity of nitro- benzene-d^ is 1.00 relative to nitrobenzene. As in the previous experiment, the lack of a primary kinetic-isotope effect indicates that the rate-determining step for the reaction of 2_ with wet-basic nitrobenzene is not rupture of the C-H bonds of nitrobenzene. Though more reactions involving deuterated aromatics must be examined before a reliable theory regarding the position of the transi tion state along the reaction coordinate of _2 with benzenes can be developed, the above results allow the tentative conclusion that the transition states for reactions of _2 with electron-rich benzenes occur earlier than with electron-deficient benzenes. MECHANISM Four conclusions have been drawn from the present study: (1) 3H- 1, 2,14-triazol-3-ylidene (2) reacts with benzenes by low activation ener gy processes to give addition complexes; (2 ) additional intermediates are generated further along the reaction coordinates in product-deter mining steps; (3 ) in the transition states of the product-determining steps, the ground-state electronic influences of the substituents are retained, and (4) proton migrations occur in, or in steps subsequent to, the product-determining steps. What remains to be considered are the nature of the intermediates and the factors which control the substitution process. There are two discrete structures which might represent the interme diates in the reaction of 2 _ with benzene: (1) 3 -benzenium-1j1~ 1,2 ,^- triazolide (m i ), and spiro[norcara-2,4-diene-7,3,-[1,2,^]triazole] 0)42). I4I 142 The high positional selectivities for reactions of 2 with monosub stituted benzenes (Table 21, page 77) imply that the species in the transition states of the product determining steps have dipolar char acter. The dipolar species are probably similar in structure to Wheland 118 119 intermediates. Hence, the dipolar intermediate in the reaction of _1_ with benzene can probably be represented by 3 -benzenium-1j1- 1,2 ,H-tria- zolide (1*11). In the reactions of _2 with a monosubstituted benzene there can be four such intermediates represented as 3 -(substituted cyclohexadienylium-1-yl)-1HM ,2,4-triazolides 1*13 - 1U6 ; Hh N^ >—N N NX0,N H J _ N 143 144 145 Intermediate 1*13 could decompose to substituted-5-phenyl-1]1-1,2,*4- triazole (1*47) by migration of the substituent (Z) to the triazolide moiety. Additionally, 1*43 might isomerize to 3-(substituted N 143 144 + 145 + 146 + ~ ~ ~ Ph (^ (107) 147 Z cyclohexadienylium-1-yl)-1l[-1,2, *4-triazolides 1*4*4 - 146. The inter mediates 144, 1*15, and 1*46 can aromatize to 3 -(substituted phenyl)-1jl- 1,2,*4-triazoles by hydrogen migration (Eq 107). The lack of a primary kinetic isotope effect implies that (1) formation of the carbenic adducts and (2 ) intramolecular migration or ionization and capture of a proton— are faster than collapse of the carbenic adducts to dipolar intermediates. That is, the transition states for the rate determining steps of the substitution reactions occur prior to formation of the dipolar intermediates. 120 It has been demonstrated that, for nitrations in aqueous acids, the rates of isomerization of the nitrobenzenium ions are slow in comparison to their rates of proton loss.Further, comparison of the substitu tion patterns of nitrations of monosubstituted benzenes in organic solvents (Table 25) with those in aqueous acids (Table 27) shows that, in general, the percentages of isomers produced are similar. These results imply that proton loss from a nitrobenzenium ion is faster than formation of the nitrobenzenium ion, and that the controlling features of the nitrations are not appreciably affected by the solvent. Since these selectivity patterns are also generally observed in other electro- philic aromatic substitution reactions, the isomers produced in electro- philic aromatic substitutions are probably determined by the rates of formation rather than equilibration of the Wheland intermediates. Because of the structural similarities between Wheland intermediates and 3-(substituted cyclohexadienylium-1-yl)-1H^1,2,4-triazolides 144, 145, and 146, it might thus be expected that 144, 145 and 146 rearrange to 3-(substituted phenyl)-111-1,2,4-triazoles faster than they interconvert. Further, the proportions of the isomeric 3-(substituted phenyl)-1H- 1,2,4-triazoles produced from J_ and monosubstituted benzenes are not similar to those in which the rate determining steps are formation of Wheland intermediates (Compare Table 21 with Tables 24, 25 and 27). These results indicate that there is at least one intermediate in the reaction coordinate between free carbene Z_ and a 3-(substituted cyclo- hexadienylium-1-yl)-1H-1,2,4-triazolide 144 - 146. The mechanism for reaction of 2_ with benzene is thus presumed to involve two intermediates as formulated in Scheme III. 121 Free Addition Wheland Carbene Complex Intermediate Product Scheme III The primary factors controlling the ratio of 3-(substituted phenyl)- 1FI-1,2,4-triazoles produced from reaction of _1_ with a monosubstituted benzene are presumably formation and decomposition of addition complexes. Hence it is important to analyse the nature and the factors controlling formation of the addition complexes from _1_ and benzenoids. The factors controlling decompo sition of the addition complexes have been discussed previously. Since 3H-1 ,2,4-triazol-3-ylidene (2) should be produced in singlet form 108, it is tempting to represent the addition complex from _1_ and benzene as spiro[2,J1-norcaradiene-7,3,-[1 ^j^l-triazole] (1*12). Sim ilarly, there are additional isomeric substituted spiro[2 ,11-norcara- diene-7,3'-[1 ^^Jtriazoles] (1*18, 1*19 and 150) which can be produced by addition of 3.H-1,2,4-triazol-3-ylidene (2) to monosubstituted benzenes. I4 8 I49 I50 Once formed spiro[2,it-norcaradiene-7,3'-[1,2,4]triazole] (141) can collapse to 3-benzenium-1H-1,2,4-triazolide (1*12) with subsequent con version to 3-phenyl-1J1-1,2,4-triazole (106). Substituted spiro[2,4- norcaradiene-7 ,3 '-[1 ,2,4]triazoles] 148 - 150 can collapse to 3 -(substi- tuted phenyl)-1H-1,2,4-triazoles via 3-(substituted cyclohexadienylium- 1-yl)-1j1-1,2,4-triazolides (144 - 146). The activation energy for aromatization of spirans 148 - 150 are probably 25 - 30 kcal/mole since 122 substituted spiro[2,4-norcaradiene-7,3'-[1,2,4]triazoles] 148 - 150 are similar in structure to substituted 2,3,4,5-tetrachloro spiro[cyclo- penta-2,4-diene~1,7'-noreara-2' ,4'-dienes] (57, Table 3). Hence substi tuted spiro[2,4-norcaradiene-7,3'-[1,2,4]triazoles] 148 - 150 are proba bly good representations of the carbenic addition complexes. Having postulated as to the behavior of carbenic addition complexes, possible factors controlling their formation will now be discussed. Substituted spiro[2,4-norcaradiene-7,3'-[1 ,2,4]triazoles] 148 - 150 can form in at least one of three ways: by addition of carbene j2 (1 ) equally to all the C-C bonds of the benzene rings, (2) to positions in the ben zene rings according to its electron densities, and (3 ) to the aromatic ring-forming substituted spiro[2,4-norcaradiene-7,3'-[1,2,4]triazoles] in the thermodynamic or near thermodynamic distribution. Equal formation of spiro[2,4-norcaradiene-7,3’-[1,2,4]triazoles] 1H8, 1*19 and 150 followed by each adduct decomposing essentially exclusively to the more stable 3 -(substituted cyclohexadienylium-1-yl)- 1H-1,2,4-triazolide (144, 145 and 146) would give the following substi tution patterns. For resonance electron-donating substituents, 3-0- and 3-substituted cyclohexadienylium-1-yl)-11[-1 ,2,4-triazolides (144 and 146) will be more stable than 3 -(2 -substituted cyclohexadienylium-1-yl)- 1H-1,2,4-triazolide (145). Hence, the percentages of 3-(substituted phenyl)-1H-1,2,4-triazoles formed from _2 and monosubstituted benzenes bearing resonance electron-donor substituents will be 66% ortho and 33% para, subject to reduction by the meta isomer produced. However, if the substituents are resonance electron-withdrawing, then 3 -(2 -substituted cyclohexadienylium-1-yl)-111- 1 ,2 ,4-triazolide (145) will be more stable than 3 — C1— or 3 -substituted cyclohexadienylium-1-yl)-1jf-1 ,2,4-triazo- lides (1 M and 146). Hence the 3-(substituted phenyl)-1H-1,2,^-tria- zoles produced will be 33 % ortho and 66% meta plus some ortho isomer and all of the para isomer as produced at the expense of the meta isomer. Comparison of these predictions to the results in Table 21 indicate that spiro[2,l1-norcaradiene-7,3,-[1,2 ,H]-triazoles] do not form equally and then isomerize under control of the substituents. Hence either carbene 2 ^ adds to benzenoid positions according to their electron densities or give spiro[2 ,11-norcaradiene-7 ,3 ,-[ 1 ,2 ,^1] triazole] in which their stabilities are reflected. Prior to discussion of addition of carbene _2 to positions in benzene rings according to electron densities, (1 ) the interaction of a carbene with the highest occupied molecular orbital (HOMO) of a benzene is to be examined, and (2 ) the electron densities in benzenoid rings and the variation with substituents will be described. Reaction of _2 with benzene can occur by interaction of the HOMO of p the benzene ring with the empty sp orbital of the carbenic carbon of 2 ^, forming a two-electron three-centered bond (151, Eq 108). The 151 ir-electrons of the triazolide moiety then overlap with the three- centered two-electron bond to produce a spiro[2,4-norcaradiene-7,3'- [1,2,4]triazoles] (142, Eq 108). 124 Taking symmetry principles^ into consideration, the empty orbital of the carbenic center must interact with the ir-electrons in the aro matic ring in orbitals having the same sign, i.e., C-|-C2, C-|-Cg, Cg-Cjj and Cjj-Cg, but not C2-Cg or Cg-Cg (152). Addition across C.|-C2 or Z 152 /■V/ Cj-Cg bonds leads to 1-substituted spiro[2,4-norcaradiene-7,3'- [1 ,2,4]triazoles] (148), while addition to C^-Cij or C^-Cg results in 3- substituted spiro[2,4-norcaradiene-7,3'-[1,2 ,4]triazole] (150) ♦ Combining the above hypothesis with the supposition that spirans 148 - 150 decompose faster than they isomerize indicates the follow ing. 3-(o-Substituted phenyl )-1f1-1,2,4-triazoles form as a result of addition of carbene 2_ to the C^-C2 or C^-Cg bonds of monosubstituted benzenes. The 3— (rn— and ^-substituted phenyl)-111-1,2,4-triazoles result from addition of carbene 2 ^ to bonds Cg-Cij and C^-Cg of benzenoid rings. Hence, the percentage of each 3-(o-, rn- and ^-substituted phenyl)-1H-1,2,4-triazole in the product is ultimately determined by the relative electron densities in bonds C^-C2 (C 1—Cg) and C^-Cjj (C^-Cg). Various attempts have been made to determine the electron densities on the carbons of benzenes.Most of the attempts have resulted in little more than the qualitative predictions of resonance theory. Hence, the electron density in benzenoid rings remains a matter of speculation. However, as a result of nitration and halogenation studies, the following generalizations are widely accepted. ^ 125 Electron-donating substituents cause a differential increase in the electron-density at ortho- relative to meta- and para- carbons. Similarly electron-withdrawing substituents decrease differentially the electron density at ortho- relative to meta- and para- positions. These generalizations indicate that electron-donating groups (methyl, methoxy and tert-butyl) increase the electron densities in C 1-C2 (C.|-Cg) relative to Cg-Cij (CipCg) bonds. Electron-withdrawing substituents (cyano, nitro, methoxycarbonyl and trifluoromethyl) cause the electron densities in bonds Cg-Ci| (Cjj-Cg) to be greater than in bond C-J-C2 (C-|- Cg). Within the halobenzene series, the electron-density at C^-C2 (C.j-Cg) relative to that in C^-Cjj (Cjj-Cg) increase from fluorobenzene to bromobenzene. Since the electronegativities of halogens are in the order F > Cl > Br the electron densities in the benzene rings of the halobenzenes will be as follows. In fluorobenzene the electron density in the C-J-C2 (Ci—Cg) bond should be less than in the Cg-Cij (Cjj-Cg) bond. The electron density in the C^-C2 (C.|-Cg) bond of chlorobenzene should be intermedi ate between that in the C-pCg (C^-Cg) bonds of fluoro- and bromobenzenes. Having discussed the interactions of _2 with the HOMO's of benzenes and the electron densities in monosubstituted benzenes, the results of adding 2_ to benzene positions on the basis of electron density will now be analyzed. Thus carbene 2_ should add to anisole, toluene and tert- butylbenzene to form spirans 1*18 in greater than 50% and spirans 150 in less than 50% propositions. Hence in the reactions of 2_ with anisole, toluene and tert-butylbenzene, 3 -(_o-substituted phenyl)-1Ji-1,2,4-tria- zoles (114, 117, and 1 2 0 ) should comprise greater than 50% of the products. Also, since the above spirans 148 are expected to decompose 126 primarily to 3-(4-substituted cyclohexadienylium-1-yl)-1H-1,2,4-triazo- lides (_1_44), the remaining products will be mainly 3 -(j3 -substituted phenyl)-1H-1,2,4-triazoles (112, 115, and 118). Further 2_ should add to the aromatic rings of benzonitrile, nitro benzene, methyl benzoate and trifluoromethylbenzene, respectively, to give greater than 50% spirans 150 and less than 50% spirans 148. Hence 3-(_o-substituted phenyl)-1H^1,2,4-triazoles (87, 136, _1JU), and 132) should be less than 50% of the product from reactions of 2_ with the above electron-deficient benzenes. The remainder of the product will be principally 140, 3 -(j3 -substituted phenyl)-1H-1,2,4-triazoles (137, 135, and 1 3 0 ), since spirans 150 should decompose almost totally to 3 -(3 - substituted cyclohexadienylium-1-yl)-1jl-1 ,2,4-triazolides (145). Extension of the above rationalizations to the reactions of _1_ with halobenzenes leads to the prediction that 3-(o-fluorophenyl)-1H-1,2,4- triazole (123) should be less than 50% of the product from decomposi tion of _1_ in fluorobenzene; the remaining product should be 3 -(£.-fluoro- phenyl)-111-1,2,4-triazole (121). Also, less than 50% of the product from _1_ and bromobenzene should be 3-(o^-bromophenyl)-IH--l ,2,4-triazole (129), and 3-(j)-bromophenyl)-111-1,2,4-triazole (127) will be the remain der. In the reactions of _1_ with chlorobenzene the percentage of 3-(o.- chloro phenyl )-1JH-1 ,2,4-triazole produced is expected to be between that of the 3-(o.-fluorophenyl)- and 3-(o-bromophenyD-IH^I ,2,4-triazoles (123 and 129) formed as above. Table 21 reveals that the above predictions agree with the results from _1_ with anisole, toluene, benzonitrile, methyl benzoate, trifluoro methylbenzene and dry nitrobenzene, respectively. The above hypotheses seriously fail to account for the distribution of C-H substitution pro ducts from _1_ with tert-butylbenzene, the halobenzenes, and wet nitroben zene and the formation of nitrosobenzene in reactions involving dry ni trobenzene. The discrepancies between the predicted and observed pro duct distributions can be reconciled, however, as follows. The above hypothesis can account for the reactions of _1_ with tert- butylbenzene if steric factors are considered. The bulk of the tert- butyl group can (1 ) prevent formation of 1-tert-butyl spiro[2 ,4-norcara- diene-7,3'-[ 1,2,4]triazole] 048, Z = _t-Bu) and in so doing cause 2- or 3-tert-butyl spiro[2,4-norcaradiene-7,3'-[1,2,4]triazoles] (149 and 150, Z = J^-Bu) to form in larger amounts than predicted above, (2) cause 1- tert-butyl spiro[2,4-norcaradiene-7,3'-[ 1,2,4]triazole] (144, Z = J>-Bu) to isomerize to 2 - and/or 3 -tert-butyl spiro[2,4-norcaradiene-7,3'- [1,2,4]triazoles] (149 and 150, Z = _t-Bu), or (3) prevent formation of 3-(2-tert-butyl cyclohexadienylium-1-yl)-1H-1,2,4-triazole (144, Z = t_- Bu). Any of these explanations could account for the small yield of 3- (o-tert-butylphenyl) — 1H— 1,2,4-triazole (1 2 0 ) and the yields of 3-(in- and p-tert-butylphenyl)-1H-1 ,2 ,4-triazoles (114 and 1 1 2 ) to be larger than predicted previously. Formation of nitrosobenzene (133) in the reactions of _1_ with dry nitrobenzene can be explained as follows. As depicted in Equation 109, C6H5N02 PhNO + (109) 128 carbene _2 could coordinate with oxygen of the nitro group in nitroben zene to give ylide 153 which subsequently collapses to nitrosobenzene (133) and 3H-1,2,4-triazol-3-one (15*0. 3H-1,2,4-Triazol-3-one (15*0 is apparently unstable and would collapse to hydrogen cyanide, carbon monoxide and nitrogen. This interpretation is in agreement with the chemistry of 3-diazo-5-phenyl-3JH-1,2,4-triazole (5C^).^ The distri bution of the products from the reactions of _1_ with wet nitrobenzene will be explained later. Application of the above coordination hypothesis to the reactions of _1_ with chlorobenzene and bromobenzene may account for the greater than 50% and the rather invariant percentages of 3 -(o-bromo- and jD-chloro- phenyl) - 1j1-1,2,4-triazoles (129 and 126) produced. Coordination however does not readily explain 3 -(o-fluorophenyl)-12 I-1 ,2,4-triazole (123) being formed in essentially the same percentages as 3 -(o^bromophenyl)- and 3-(o-chlorophenyl)-1H-1,2,4-triazoles (129 and 126). Thus, coordi nation succeeds marginally at reconciling the differences in the predicted and observed product distributions for reactions of _1_ with halobenzenes. However, to account for the invariant product distribution in the reactions of _1_with the halobenzenes, the above hypothesis can be modi fied further, as follows. The symmetry requirements for addition of _2 to the HOMO of fluorobenzene are relaxed so as to permit addition of carbene 2_ across the C2 -Cg bond. Also the electron density in the C-|-C2 , C2 “Cg and Cg-C^ bonds of fluorobenzene must be similar and invariant. This allows halospirans 148 - 150 to be produced in equal amounts, i.e., statistically. As discussed previously, fluorospiran 148 decomposes to 3-(jo-fluorophenyl)-IH-l,2,4-triazole (123) and fluoro 129 spiran 150 converts almost exclusively to 3-(£.-fluorophenyl)-1H-1,2,4- triazole (121). Fluoro spiran 149 would have to isomerize almost equally to 3-(o- and in-fluorophenyl)-1FF-1,2,4-triazoles (123, 122). Thus, decomposition of fluoro spiran 149 would be responsible for the yield of 123 being as large as that of 3 -(o.-chloro- and ^-bromophenyl )- 1 FI-1 , 2 , 4-triazoles ( 126 and 129) . Hence, by invoking statistical forma tion of fluoro spirans 148 - 150 in the reactions of _1_ with fluoroben zene, the hypothesis that 2_ adds preferentially to the most electron- rich positions of benzenes can account for the invariant percentages of 3-(.o-substituted phenyl)-1H-1, 2 , 4-triazoles produced in the reactions of _1_ with halobenzenes. With minor modifications, therefore, the hypotheses that 2_ adds preferentially to the Ci-C2 or C^-C4 positions having the greater electron density can be made to explain the product distributions from reactions of _1_ with monosubstituted benzenes. However, relaxing the symmetry requirements for reactions of 2_ with the halobenzenes suggests that they be relaxed with all the monosusbtituted benzenes studied. This allows the product distribution to be explained on the basis that addition of 2_ to monosubstituted benzenes reflects the stabilities of substituted spiro[2,4-norcaradiene-7,3'-[1,2,4]triazoles] formed. In this hypothesis, formation of the carbenic addition complexes will be controlled by the ground state electronic influences of the substituents. A measure of the ground state electronic influences of substituents are the relative stability of analogous isomeric substituted cyclo- hexadienes (155 - 157): Information on the stabilities of cyclohexadienes comes from differ ent sources. In the gas phase dihydrotoluenes equilibrate at >300 °C to 1-methyl-1,3-cyclohexadiene (158), 2-methyl-1,3-cyclohexadiene (159) and 5-methyl-1,3-cyclohexadiene (160) in the ratio 4:2:1 (Eq 119) CH3 ^^3 ^^3 ^^3 (110) I58 I59 I60 r v rvj Pyrolysis of methyl cis-2-acetoxy-3-cyclohexene-1-carboxylate (161) at 435 °C yields methyl 1,3-cyclohexadiene-1-carboxylate (162), methyl 1,3-cyclohexadiene-2-carboxylate (16 3 ), and methyl 1,3-cyclohexadiene-5- carboxylate (164) in a 6:2:1 ratio (Eq 1 1 1 ).99 OAc C02 CH3 CO2 CH3 CO^CHj CO2 CH3 (111) ' 6 ! 162 163 Equilibration of methyl cyclohexa-1,3-dienecarboxylates (162 - 164) with tri(acetonitrile)chromium tricarbonyl gives mixtures of substituted 1,3- cyclohexadienes containing 62% 1-substituted (162), 26% 2-substituted (163), and 12% 5-substituted 1,3-cyclohexadienes (16 3 )» Isomerizations of 2,4-dihydrotoluene and 2,4-dihydroanisole using potassium amide in liquid ammonia show, further, that the thermodynami cally preferred substituted 1,3-cyclohexadiene is the 1-substituted 131 101 isomer. Unfortunately, the number and nature of substituted 2,4-di- hydrobenzenes acoessable via Birch reduction are limited. Substituents such as nitro, cyano, methoxycarbonyl and the halogens are more easily reduced, under conditions of Birch reduction, than a benzene ring. Hence, experimental determination of the stabilities of such substituted 1.3-cyclohexadienes has not been achieved. However, in an effort to overcome these experimental problems, Birch, et^ al^., performed standard ab initio SCF-MO calculations on substituted 1,3-cyclohexadienes which can not be generated by Birch reductions or equilibrated using potassium amide in liquid ammonia.'*02 The results of the calculations are presented in Table 37. These results indicate that substituents are generally destabilizing (compared with their effects in benzene) at the saturated position (5-substituted 1.3-cyclohexadienes), and stabilize 1-substituted more than 2-substi- tuted 1,3-cyclohexadienes. Further, the nitro group is stabilizing in all positions in that 5-nitro-1,3-cyclohexadiene is more stable than 2-nitro- 1.3-cyclohexadiene, and 1-nitro-1,3-cyclohexadiene is the most stable isomer. Table 37 Stabilization Energies of Substituted-1,3-Cyclohexadienes (kJ/mol) Position of Substituent in a 1,3-Cyclohexadiene Substituent 1- 2- 5- H 0 0 0 OH 6.4 -2.2 -30.1 CHo 4.6 2.3 -12.0 F 3 4.3 -1.8 -27.0 CN 4.9 1.4 -26.1 N0? 7.4 2.9 4.2 132 In summary, the stabilities of 1,3-cyclohexadienes are predicted to be: 1-substituted 1,3-cyclohexadiene > 2 substituted-1,3-cyclohexadiene » 5 substituted-1,3-cyclohexadiene— except when the substituent is a nitro group, in which case the stabilities should be 1-nitro-1,3-cyclo hexadiene > 5-nitro-1,3-cyclohexadiene > 2-nitro-1,3-cyclohexadiene. Since these predictions remain to be verified experimentally, they can not be used to predict quantitatively the stabilities of substituted spiro[norcaradiene-7,31 — C1,2,4]triazoles]. However, when the calcula tions are combined with the above experimental results, the following general predictions are allowed. A 2-substituted spiro[norcaradiene-7,3'-[1,2,4]triazoles] (_149_) should be the most stable substituted spiro[norcaradiene-7,3'-[1,2,4]- triazole], regardless of the substituent, and constitute the majority (60% to 70%) of the addition complexes from 2_ and substituted ben zenes. For all substituents except the nitro group, 1-substituted spiro[nor- caradiene-7,3'-[1,2,4]triazole] (148) should be the least stable substituted spiran, possibly constituting from 10% to 20% of the addition complexes, and the spiran 150 should compose the remainder of the addition com plexes. In the case of the nitro group, the stabilities of the 1-nitro- and 3-nitro-spiro[norcaradiene-7,3'-[1,2,4]triazoles] (148 and 150, Z = NO2 ) may be similar, or the 1-nitro spiro[norcaradiene-7,3'-[1,2,4]-tri- azole] (148, Z = NO2 ) may be even more stable than the 3-nitro-spiro- [norcaradiene-7,3'-[1,2,4]triazole] (150, Z = NO2 ). Thus 1- and 3-nitro spiro[2,4-norcaradiene-7,3'-[1,2,4]triazoles] (148 and 159) might be formed nearly equally in reactions of _1_ with nitrobenzene. Hence, the majority of the 3-(substituted phenyl)-1H-1,2,4-triazoles produced from 133 2_ and monosubstituted benzenes will be expected to be derived from 2- substituted spiro[norcaradiene-7,3'-[1,2,4]triazoles] (149), irrespec tive of the substituent or the manner in which the substituted spiro- [norcaradiene-7,3'-[1,2,4]triazoles] decompose. Further, predictions concerning the reactions of _2 with monosubstituted benzenes based on this hypothesis will be presented after substantiating that the equili brium mixtures of isomeric norcaradienes and isomeric cyclohexadienes are similar and that a carbene can react with a monosubstituted benzene to form norcaradienes in a nearly thermodynamic distribution. Evidence for the proposition that the thermodynamic distribution of isomeric norcaradienes will be similar to that for isomeric substituted- 1,3-cyclohexadienes is the following. 7,7-Dicyano-2-methylbicyclo- [4.1.0]hepta-2,4-diene (166) isomerizes at 100 °C to 18% 7,7-dicyano-1- methyl- (165), 64% 7,7-dicyano-2-methyl- (166), and 8% 7,7-dicyano-3- methylbicyclo[4.1.0]hepta-2,4-dienes (167) (Eq 111); also, tolylmalono- nitriles (168, 169 and 170) form during the thermolysis in a 10% I6 5 I66 167 (112) CH(CN), CH(CN). CH(CN)2 I68 I69 |70 r v j yield (Eq 112).^^ Additionally, when heated between 55 and 100 °C mixtures of methyl-7,7-dicyanonorcaradienes (165, 166, and 167) and 1314 tolylmalononitriles (168, 169, and 170) starting with varied concentra tions of individual methyl-7,7-dicyanonorcaradienes (165, 166, and 167) give a steady-state mixture of 165, 166, and 167 in a 2:6:1 ratio. When the steady-state mixture is heated for 1.6 times the time required to obtain it, the composition changes to 1:4.8:1.5, respectively. In experiments similar to 165 - 167 above, methyl 2,7-dimethyl- norcara-2,4-diene-7-carboxylate (172) rearranges at 180 °C to methyl 1,7-, 2,7- and 3,7-dimethylnorcara-2,4-diene-7-carboxylates (171, 172, and 173) in the ratio 1:16:13, respectively (Eq 113).^^’^ ^ ,7Z ------3 . f * S x CH3 “W / n s ~ tc^ T C02CH3 Kj^C02CH3 k > ^ C02CH3 <113> 171 172 173 / v ; r s j Additionally, heating of 7-cyano-2,7-dimethylnorcaradiene (175) at 180 °C yields 7-cyano-1,7-, 7-cyano-2,7-, and 7-cyano-3,7-dimethyl- norcaradienes (174, 175, and 176) in the ratio 1.3:29:1, respec tively.^^ The ratio of isomeric norcaradienes from these experiments are thus similar to that for gas-phase equilibration of dihydrotoluenes! CH CH CH 175 .CN CN CN CH 'CH •CH (114) I74 I75 I76 Having shown that the stability order of isomeric norcaradienes and 1,3-cyclohexadienes are similar, there is some evidence for addition of a carbene to a benzene to produce norcaradienes in a ratio approaching the thermodynamic ratios of isomeric norcaradienes and of 135 1»3-cyclohexadienes as follows: dicyanodiazoraethane and toluene at 75 °C (1 hr) give 7,7-dicyano-1- (165), 7,7-dicyano-2- (166), and 7,7- dicyano-3-methylbicyclo[4.1,0]hepta-2,4-dienes (167) in the ratio 10P 1:2:1.5, respectively. Since the composition of methyl-7,7-dicyano- norcaradienes 165, 166, and 167 from thermolysis of dicyanodiazomethane in toluene resembles the equilibrium mixture produced from heating raethyl-7,7-dicyanonorcaradienes, it is likely that dicyanomethylene adds to toluene to give methyl-7,7-dicyanonorcaradienes in a ratio reflecting the stability of the methyl-7,7-dicyanonorcaradienes. Hence, it is conceivable that a carbene and a benzenoid can produce norcaradienes in a ratio approaching the thermodynamic ratio of the norcaradienes. The above discussion establishes some precedent for the proposal that _2 reacts with monosubstituted benzenes to produce substituted spiro[2,4-norcaradiene-7,3'-[1,2,4]triazoles] in ratios reflecting the stabilities of the corresponding 1,3-cyclohexadienes and in which the most stable substituted spiro[2,4-norcaradiene-7,3'-[1,2,4]triazoles], spirans 149, are the major components. Support for the proposal that 2_ reacts with monosubstituted benzenes to yield 2-substituted spiro[2,4-norcaradiene-7,3'-[1,2,4]triazolides] (149) comes predominately from the product distribution in Table 21. The previous discussion implies that substituted spiro[norcaradienes- 7,3* — C1,2,4]triazoles] 148, 149, and 150 will be formed in 10-20, 60-70 and 10-30 percentages, respectively. Thus, the major product will be determined primarily by the quantity of spiran 149 produced. When Z is electron-donating, a 3-(o-substituted phenyl)-1H-1,2,4-triazole will be the major product (60% - 80%) from 148 and principally 149, a 136 3-(j5-substituted phenyl)-1F[-1,2,^-triazole will be the minor product (0% - 30%) as derived from 150. When Z is electron-withdrawing, a 3-(in-substituted phenyl) — 1_H— 1,2,^-triazole will be the major product (70% - 90%) from 1^9 and 150; a 3-(.o-substituted phenyl)-111-1,2,4- triazole will be the minor product (10% - 20%) from 1H9. Hence, the products from reactions of 2^ with anisole, toluene, the halobenzenes, trifluoromethylbenzene, methyl benzoate, benzonitrile and dry nitrobenzene (See Table 21) are acceptably explained by the above hypothesis. However, the hypothesis fails to account for the behavior of 2_ with tert-butylbenzene and wet-basic nitrobenzene. The differences between the predicted and observed product distributions for the reactions of 2_ with tert-butylbenzene can be accounted for on the basis of steric factors discussed previously. Explanations for the behavior of nitrobenzene with _1_ as derived from aqueous solutions of pH = 9-11 center on addition of sodium hydroxide to nitrobenzene to give 177 which then reacts with _1_ and/or 2. n o 2 I77 The observed chemistry, hence, is influenced by interaction of adduct 177 with _1_ and/or 2_ and not solely the result of direct attack of 2_ in nitrobenzene. The exact nature of adduct 177 is speculative. However, alkoxides add para to the nitro group in nitrobenzenes giving "Meisenheimer Complexes" and nitrotoluenes react with bases to give radical anions. 137 The implications of these possibilities on the reactions of J_ with wet- basic nitrobenzene will now be considered. It is possible that sodium hydroxide reacts with nitrobenzene to give adduct 178 and that the observed chemistry of _1_ with wet-basic nitrobenzene results from the behavior of 2_ with 178. ® 0 ® 0 H OH Incorporation of 178 into the previous theory for reactions of _1_ with dry nitrobenzene (Eq 110) leads to coordination of carbene j? with oxygen of the nitronate group in 178 to give 179 (Eq 115). Nucleophilic 0 o © A N N > ( / A / n - n U SH (115) -NaOH OH OH I78 79 I80 rv attack of the triazolide moiety on an ortho benzenoid position in 179 with expulsion of sodium hydroxide would yield 180. Spiran 180 could then under rapid (base-catalyzed) conversion to 136 (Eq 116) such that isomerization of 180 to 181 (_1j19_, Z = NO2 ) and possible 182 (150, Z = NO2 ) is limited (Eq 116). Even if 180 does rearrange to 181, the inter mediate spironorcaradiene (181) could undergo base-catalyzed isomeriza tion to 136 (Eq 117). Also, carbene 2_ could react directly with 178 to give spiran 183 which could convert to spiran 181 upon loss of sodium hydroxide (Eq 118). Spiran 181 could then proceed to 138 as described previously. H O H OH 178 183 The major assumption in the above hypotheses is that 2_ reacts with 178 in preference to nitrobenzene. Possible behavior of _1_ with 178 will now be considered. Reactions in wet-basic nitrobenzene might proceed by coordination of diazo nitrogen of _1_ with oxygen of nitronate 178 to give 184. Ortho- ring closure via attack of the triazolide moiety with expulsion of 139 sodium hydroxide would then yield 185 (Eq 121). Spiran 185 might then eliminate nitrogen to give 3-(2-nitro cyclohexadienylium-1-yl)-1H-1,2,4- triazole (186; 1 M , Z = N02) or diradical 187 or by base-catalysis to form the sodium salt of 3-(.o-nitrophenyl)-1H-1,2,4-triazole (188, Eq 120). Intermediate 186 and 187 could then collapse to 3-(.o-nitro- phenyl)-1J3-1,2,4-triazole (136) or spiran 181. The fate of spiran 181 has been discussed and 188 would convert to 136 on protolysis. 0 0 0 . ® 0 " N s' ° s © /° N ft N Nam ® N - ^ 2 (119) V" -NoOH o $ >'N I78 I85 (120 ) NaOH -H_0 I88 A mechanistic possibility which might have major significance in volves radical anion transfer processes as now summarized. Electron- transfer from 178 to J[ may yield radical 18H and the radical anion of _1_, namely 190 (Eq 121). 140 NO2 N=N 0 (121 ) H OH H OH 178 184 I90 Loss of nitrogen from 190 is presumed to give radical anion 191 which would then add to nitrobenzene yielding radical anion 192 (Eq 122), which might transfer an electron to _1_ propagating the radical anion sequence and forming 186 and/or 187. Conversions of 186 and 187 to 3-(nitrophenyl)-1j1-1,2,H-triazoles have been discussed previously. (122) I9I 192 As is recognized, the above hypothesis requires that radical anion 191 adds virtually exclusively to an ortho position of nitrobenzene. The validity of such a requirement is unknown. However, nitrobenzene is substituted mainly in the ortho position by phenyl radicals (Table 22). Given that radical anion 191 is more electron-rich than the phenyl radi cal and the ortho position in nitrobenzene is more electron-deficient than the para position, the above radical anion mechanism can account for the product distribution in the reactions of _1_ with wet-basic nitro benzene . Finally, it is emphasized that 2_ could attack the aromatic ring of 177 yielding spiran 193 selectively (Eq 123). Spiran 103 could then proceed to 1-nitro spiro[2,4-norcaradiene-7,3'-[1,2,4]triazole] (19^; 1^8, 7, = NC^) and subsequently to 3-(£-nitrophenyl)-1f1-1,2,4-triazole (136; Eq 123) ♦ In addition to explaining the differences in product distribution in the reactions of _1_ with wet-basic nitrobenzene, the above hypothesis accounts for the increase in 3-(£-nitrophenyl)-121-1, 2,11-triazole (136) in the product as the pH of the aqueous solutions from which J_ is extracted increases. As the pH of the aqueous solution increases so would the concentra tion of adduct 177. Hence, the increase in the concentration of adduct 177 in solution should be reflected by an increase in its chemistry with _1_ and/or 2. The factors which yet remain for explanation are (1) the increase in the positional selectivity in the reactions of _1_ with benzene as the temperature is raised and (2) the solvent effects in the competition experiments. As has been summarized previously (Table 21), one of the most inter esting aspects of the present research is that the directional influence of a substituent in a substituted benzene leading to ortho- or to meta- substitution becomes more dominant as the temperature of reaction of 2_ (or decomposition of _1_) is increased. The usual circumstances in elec- trophilic aromatic substitutions, however, are that reactions with varied benzenes became less selective or more indiscriminate as tempera ture is increased.However, an increase in the selectivity for 1^2 alkenes by carbenes has been observed^®® and attributed to the "Enthal- py-Entropy Relationship". The intriguing question then arises as to how a substituent in a substituted benzene can be more specifically directing as the temperature at which the substitution by 2_ is occurring is raised. It has been emphasized previously that 2_ is a highly reactive elec- trophile which attacks benzenes, by rate-determining processes of low activation energy, via transition states such as 195 (Eq 12H) that re flect the structural features of 2 and the initial substituted benzenes. N - Y C' ' N Nr (12H) I95 It is now considered that _2, an electrophile and therefore an acid, is selectively and perhaps highly solvated (185) by substituted benzenic environments as illustrated in Equation 125. As discussed previously, Z-Solv( Nf0>.»Z-Solv(<£) + |] 5J| (125) 3^-1,2,!J-triazol-3-ylidene (2) is expected to be a highly dipolar and sterically accessible singlet carbene. In the present work, it has been previously proposed that there is significant coordination of 2_ with benzenic substituents that contain nonbonded electron pairs such as nitro (NC^) • Coordination of 2_ with the hetero atom in anisole and in halobenzene (X = F, Cl, and Br) was also discussed. Further, there is 143 direct evidence that other 2-azolylidenes interact extensively with electron-pairs of varied benzene substituents (see pages 15 - 28). It is thus presumed that in carbenic substitutions at relatively low temperature (80 °C), _2 is highly solvated by electron-donor benzenes. Further,the transition states leading to norcaradienes 148 to 150 do not sense the effect of the substituent in a monosubstituted benzene under going addition because of the presence and the organization of the electron-donor solvent. Such an interpretation leads to the expection that 2_ will not be as extensively solvated at higher temperatures. Thus, relatively naked can attack the aromatic ring of a substituted benzene and make greater relative use of the substituent effects, particularly at the ortho position. This proposal is supported by the observations (Table 21) that the directional effects of substituents leading to ortho-substitution are greater for reactions of benzenes with 2_ gener ated photolytically at 0 °C rather than thermally at 80 °C. The assump tion therefore is that 2_ as generated photolytically is less effectively solvated than _2 as formed at 80 °C. An alternate interpretation of the increase in positional selectiv ity of _2 in its substitutions with an increase in temperature comes from the possibility that the reactions of _1_ with benzenes involve mechanis tic processes in addition to those previously discussed. The question is now raised whether, in addition to rate-determining unimolecular decomposition of _1_ to _2, which then reacts rapidly with the benzenes, there is a competitive electrophilic bimolecular mechanism by which _1_, a poorer electrophile than _2, attacks the benzenoids with eventual expulsion of nitrogen and aromatic substitution. This proposal receives support from the literature.11® It is suffi cient to say that the reaction of _1_ with benzenoids is occurring by two simultaneous reactions. These reactions are: (1) unimolecular reaction in which _1_ decomposes to the free carbene 2 which then reacts with the substrate; and (2) a bimolecular reaction in which nitrogen is eliminated from _1_, as _1_ and the benzenoid react. The mechanistic possibilities for the unimolecular reaction have been discussed previously in this thesis. The mechanistic possibilities for the bimolecular reactions can be illustrated as follows (Eq. 126). I48 «■ I49 ♦ I50 (126 ) Alternately, the bimolecular reactions might involve direct attack of _1 as an electrophile on benzenes to give intermediates of type 197 which lose nitrogen and give products of electrophilic aromatic substitution. I97 There are two major implications of a bimolecular reaction on the course of the reaction of _1_ with benzenoids: (1) the greater the Lewis base capability of the substrate, the more prevelant the bimolecular reaction; and (2) the transition state of the rate determining step will 145 tend to resemble the transition state for electrophilie aromatic substi tution involving molecular complexes, i.e., Wheland intermediates 197. Some of the ramifications of competing reactions of _1_ and 2_ with benzene are: (1) at higher temperatures, unimolecular decomposition of _1_ will be en hanced relative to bimolecular substitution, and thus the formal carbenic substitution process will be of increased prominence as the temperature is raised, as discussed previously; (2) the bimolecular substitution process invol ving _1_ will be favored kinetically with electron-rich, over electron-poor, ben zenes; (3) the substitution processes involving _1_should be more sensitive to steric effects than with 2, and _1_ will be a relatively discriminating electro- phile, attacking preferentially at unhindered sites according to their electron- donating abilities, and (4) reactions of _1_ with benzenoids' TT-electron systems should reflect in part the stabilities of Wheland intermediates (cf. Tables 24, 25, and 27). More specifically, on the basis of the unimolecular and the bimolecular mechanistic processes, in the reactions of _1_ with anisole, toluene and the halobenzenes, the percentages of the 3-(^-substituted phenyl)-1H-1,2,4-triazoles produced should be enhanced at 80 °C in comparison to that formed at reflux tem peratures (cf. Table 21 with Tables 24-27). Similarly, the percentage of 3-(o_~ cyanophenyl)-1H-1,2,4-triazole (87) in the reaction of _1_ with benzonitrile at 80 °C being greater than the percentage in the reactions performed at 191 °C can be reconciled (cf. Table 21 with Tables 24, 25, and 27). Additionally, the per centages of 3-(m-substituted phenyl)-1H-1,2,4-triazole formed in the reactions with trifluoromethylbenzene, methyl benzoate and nitrobenzene being smaller from substitution at 80 °C than at higher temperatures can be rationalized (cf. Table 21 with Tables 24, 25 and 27). EXPERIMENTAL GENERAL COMMENTS Melting points were determined on a Thomas Hoover capillary tube apparatus or on a Fisher-Johns melting point apparatus and are not corrected. Ultraviolet spectra were obtained using a Varian DMS 100 UV- Visible spectrophotometer, infrared spectra were recorded using a * Perkin-Elmer Model 457 grating spectrophotometer, routine H NMR spectra were taken on a Varian Associates nuclear magnetic resonance spectro meter (Model EM-360 or EM-390), and FT-NMR spectra were obtained using an 80.06 MHz IBM NR 80 nuclear magnetic resonance spectrometer. Mass spectral data were determined using a Kratos model MS 30-BB spectrometer and a Kratos model DS-55 data system. Column chromatography was effected on NM-silica gel 60 (0.05-0.2 mm/70-270 mesh ASTM); NM-silica gel P/UV25 H was used for thin layer chromatography (TLC). Medium pressure liquid chromatography (MPLC) was performed on a Lobar C Column (Li Chroprep Si 60, purchased from EM Reagents) eluting with ethyl acetate (20 ml/min) and collecting 20 ml fractions. Analytical high pressure liquid chromatography (HPLC) was conducted on a Waters Associates high-pressure liquid chromatographic system con sisting of a model 6000 A Advanced Design Solvent Delivery System, a 146 147 septumless IJ6K non-stop-flow high-pressure injector, two Waters Associates micro-porasil liquid chromatography columns (I) mm x 30 cm) in series, and a dual beam UV detector (model 440) eluting with 20% chloroform-ethyl acetate at 3 ml/min. Analytical gas-liquid chroma tography (GLC) was performed on a Hewlett Packard 5790 A Series instru ment using a 15% SE 30 column (1/8M x 12', column temperatures and helium flow rates are described in the individual experiments). Materials Commercial Chemicals Salicylic acid, in-hydroxybenzoic acid, ]D-hydroxybenzoic acid, jo-toluic acid, m-toluic acid, j>-toluic acid, o^-nitrobenzoic acid, m-nitrobenzoic acid, j3-nitrobenzoic acid, anthranilic acid, m-amino- benzoic acid, jD-aminobenzoic acid, 2-bromobenzotrifluoride, 3-bromo- benzotrifluoride, 4-bromobenzotrifluoride, o-fluorobenzonitrile, jn-fluorobenzonitrile, £-fluorobenzonitrile, jD-cyanobenzyl chloride, jD-eyanobenzaldehyde, 3-amino-111-1,2,4-triazole, piperidine, pyrrolidine, morpholine, cyclohexanone, cyclopentanone, phenyl isocyanate, phenyl isothiocyanate, potassium cyanate, and thiosemicarbazide were purchased from Aldrich Chemical Company and used without purification. Phenylhy- drazine and ammonium thiocyanate were obtained from J. T. Baker. Hydra zine hydrate, cyclohexanol, phthalimide and benzil were purchased from Matheson Coleman and Bell Manufacturing Chemists and used without fur ther purification. Ethyl chloroformate was obtained from Eastman Organ ic Chemicals and used without purification. Benzene, chlorobenzene, toluene and methyl benzoate were purchased from Fisher Scientific Co. 148 and were distilled prior to use. Anisole, cumene, tert-butylbenzene, fluorobenzene, bromobenzene, iodobenzene, benzonitrile, and trifluoro- methylbenzene were purchased from Aldrich Chemical Company and distilled prior to use in individual experiments. Nitrobenzene, purchased from J. T. Baker, was distilled before each reaction. General Syntheses of Reagent Chemicals j>-Methoxybenzonitrile,111 m-methoxybenzonitrile,^12 jwnethoxyben- zonitrile,^3 o^tolunitrile,1 ^ m-tolunitrile,1 ]D-tolunitrile,11 b o-nitrobenzonitrile, 11 ? rn-nitrobenzonitrile, ^ ^ jD-nitrobenzonitrile, ^ ® ethyl o^-nitrobenzoyl hydrazide, and ethyl ^-iodobenzoyl hydrazide were prepared from salicylic acid, m-hydroxybenzoic acid, j>-hydroxybenzoic acid, jD-toluic acid, m-toluic acid, j3-toluic acid, o_-nitrobenzoic acid, in-nitrobenzoic acid, and j}-nitrobenzoic acids were obtained by litera- 11q 1?n 121 ture procedures. o^-Chlorobenzonitrile, m-chlorobenzonitrile, jj-chlorobenzonitrile, ^22 ^-bromobenzonitrile, ^2^ m-bromobenzonitrile, "*21* jD-bromobenzonitrile^21*, o^iodobenzonitrile, ^2^ rn-iodobenzonitrile, ^2b j)-iodobenzonitrile,^2^ ethyl jD-cyanobenzoate, and ethyl m-cyanobenzoate were synthesized from the corresponding aminobenzoic acids according to literature procedures. o-Isopropylbenzonitrile, ^2^ jn-isopropyl- benzonitrile,"^0 j)-isopropylbenzonitrile,^ 1 p-tert-butylbenzoni- trile,^2 jn-tert_-butylbenzonitrile, ^3 ancj p-tert-butylbenzonitrile1^ were made from cumene and tert-butylbenzene by literature proce dures. 135,136,137 2-(Trifluoromethyl)benzonitrile,3-(trifluoro- methyl)benzonitrile^3® and 4-(trifluoromethyl)benzonitrile were synthesized from 2-bromobenzotrifluoride, 3-bromobenzotrifluoride and 149 4-bromobenzotrifluoride according to literature procedures. 138 Cyclohexylcarbonyl c h l o r i d e 1^9 was obtained from cyclohexanol. 1l*° 2-Carboxybenzaldehyde^ was prepared from phthalimide.*^ Detailed Syntheses of Reagent Chemicals 2-Cyano-4-nitro-tert-butylbenzene The procedure for preparation of 2-cyano-4-nitro-tert-butylbenzene was identical to that by Friedman and Shechter for benzonitrile.A stirred suspension of copper(I) cyanide (3.9 g, 43 mmole) and 2-bromo-4- nitro-tert-butylbenzene135 (7.5 29 mmole) in dimethylformamide (10 ml) was refluxed for 3 hr, cooled below 100 °C and dumped into a solu tion of iron trichloride hexahydrate (17 g, 63 mmole), hydrochloric acid (4 ml) and water (28 ml). The resulting black mixture was heated on a steam bath for 20 min, cooled and vacuum filtered. The filter cake was extracted with ethyl ether (three 200 ml portions). The combined organic layers were dried (NagSO^), gravity filtered and concentrated in vacuo. The oily black residue was vacuum distilled to give 4.14 g (20.3 mmole, 70% yield) of 2-cyano-4-nitro-tert-butylbenzene: bp 155— 157 °C/1.5 mm; IR (KBr) cm-1 2220(s), 1600 (m, C=C ring stretch) 1520 (s, NO2 asymmetric absorption) and 1340 (s, NO2 symmetric absorption); 1H NMR (CDC13) Hz 6 1.5 (s, 9H) and 8.2 (m, 4H). 4-Amino-2-cyano-tert-butylbenzene The procedure used for preparing 4-amino-2-cyano-tert-butyl-benzene was the same as that described by Shoesmith and Mackie for 4-amino-2- nitro-tert-butylbenzene. ^5 x0 a solution of stannous chloride (7.76 g, 150 3^-4 mmole) in hydrochloric acid (5 ml) was added 2-cyano-4-nitro-tert- butylbenzene (1.75 g, 8.6 mmole) at a rate such that the temperature of the mixture remained below 30 °C. When the exothermic reaction sub sided, excess concentrated hydrochloric acid (about 10 ml) was added and the mixture was left to stir in an ice bath overnight. The solution was vacuum filtered. The filtrate was diluted with 10% sodium hydroxide (about 30 ml), filtered, and neutralized with concentrated hydrochloric acid. The aqueous solution was extracted with ethyl ether (three 50 ml portions). The combined extracts were dried (Na2S0^), gravity filtered and concentrated to a solid. Vacuum distillation of this solid gave 1.0 g (6.0 mmole, 70% yield) of 4-amino-2-cyano-tert-butylbenzene: bp 135-137 °C/0.7 mm Hg; IR (KBr) cm"1 3440(s, NH stretch), 2220(s, CN stretch). This procedure gave 4-amino-2-cyano-tert-butylbenzene in yields ranging from 60 to 80%. 2-Cyano-tert-butylbenzene The procedure for deamination of 4-amino-2-cyano-tert-butylbenzene to produce 2-cyano-tert-butylbenzene was the same as that of Shoesmith 1R5 and Mackie. J To a stirred solution of 2-cyano-4-amino-tert-butylben- zene (0.76 g, 4.3 mmole) in ethanol (3 ml) and concentrated sulfuric acid (3 ml) at 0 °C was added a solution of sodium nitrite (0.32 g, 4.7 mmole) in water (1 ml). The mixture was stirred for 10 min at 0 °C, then slowly warmed to and stirred at room temperature for 30 min, heated with a steam bath for 30 min and cooled to room temperature. The solu tion was extracted with ether (three 200 ml portions). The combined extracts were concentrated, dried (Na2 S0|j), gravity filtered, and concentrated to a black solid in vacuo on a rotary evaporator. The black solid was vacuum distilled to give 0.44 g (2 mmole, 61% yield) of 2-cyano-tert-butylbenzene: bp 155-158 °C/1.5 mm Hg; IR(KBr) cm"^ 2220 (s, CN stretch), 1400 (m), 1370 (s, CH tert- butyl group), 770 (s, out- of-plane bending of the ring CH bonds of a 1,2-disubstituted mononuclear aromatic). 4-Amino-4H-1,2,4-triazole 4-Amino-4ji-1,2,4-triazole was prepared according to the procedure in Organic Synthesis.^ To a stirred solution of ethyl formate (149 g, 2.01 mole) in ethanol (150 ml) was added 64% hydrazine hydrate (165.8 g, 2.09 mole, 64% mono hydrazine) in 1 hr. The slightly pink solution was refluxed on a steam bath for 19 hr and then concentrated (150 ml) by simple distillation. The resulting solution was refluxed at 150 °C for 3 hr, cooled to room temperature and vacuum stripped (4 mm) until no more liquid distilled. The residue was then cooled to room temperature and extracted with a solution of ethanol (240 ml) and methylene chloride (3 1). The combined extracts were concentrated on a rotary evaporator to give 59 g (0.70 mole, 35% yield) of 4-amino-4H-1,2,4-triazole: mp 61-68 °C; 1H NMR (CDClg/DMSO-dg) Hz 6 8.4 (s, 1H) and 6.2 (s, bd, 1H). General Procedure for Preparation of Substituted-N-s^triazol-4-yl- benzamldine3: The procedure used for preparation of substituted-N-s^triazol-4- ylbenzamidines was the same as that described by Becker, et. al.^: To 152 a stirred solution of 4-amino-4H-1,2,4-triazole (1.44 g, 17 mmole) in dry ethanol (10 ml) at room temperature was added a 2.09 N solution of sodium ethoxide in ethanol (8.2 ml, 17 mmole of sodium ethoxide) and the mixture was stirred for 5 min. A substituted benzonitrile (17 mmole) was then added. The resulting solution was refluxed for 6 hr and cooled to room temperature. The solvent was removed in vacuo on a rotary-evap- orator and the residue recrystallized from water. Some specific exam ples of the preparations and properties of substituted-N-s^triazol-4-yl- benzamidines are presented here and are partially summarized in Table 18. N-^-Triazol-4-ylbenzamidine N-j3-Triazol-4-ylbenzamidine was produced from benzonitrile (1.7 ml, 1.72 g) in 48% yield (1.5 g, 8.0 mole): mp 244-245 °C (lit65 262 °C); MS (70 eV), m/e (relative intensity, M+-fragment) 188.0890 (M++1, 17.87), 187.0833 (M+ , 100.00; calcd for CgH9N5 187.08578), 119.0832 ( M ^ C g H ^ , 1.06), 118.0483 (M+-C2H3N3, 2.53), 105.0565 (M+-C2H2N4, 55.64), 104.0488 (M+-C2H3N1}, 86.50), 103.0434 (M+-C2H1|Nlp 13.77); 1H NMR (CDCl3/DMS0-dg) Hz 6 7.5 (m, 5H), and 8.2 (s, 1H); IR(KBr) cm-1 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610 and 1560 (m, C=C ring stretch), 1460 (s, C=C and SasCH3), and 1380 (s, SgCH3). N-s-Triazol-4-yl-p-toluamidine N-j3-Triazol-4-yl-j3-toluamidine was prepared from ]D-tolunitrile (2 ml, 2 g) in 54% yield (1.84 g, 9.2 mmol): mp 274-275 °C (lit55 278 °C); MS (70 eV), m/e (relative intensity, M+-fragment) 201.103^ (M 14.62; calcd for C 1QH 11N5 201.10143), 119.0727 (M+-C2 H2 N1}, 7.04), 118.0655 (M+.'CgHgN],, 12.37), and 117.0583 (M+-C2 HiiNi(, 18.90); 1H NMR (CDCl3 /DMS0-dg) Hz 6 2.4 (s, 3H, CH3 ), 6.3 (s, bd, 1H, NH), 7.5 (AA’XX 4H, *^AX=t^A*X* ^ Hz, *“^xX*= ^ Hz, ,^^undetermined• N-s_-Triazol-4-yl-m-toluamidine N-^-Triazol-4-yl-m-toluamidine was obtained from rn-tolunitrile (2 ml, 2 g) in 49% yield (1.67 g, 8.3 mmole): mp 247-248 °C; MS (70 eV), m/e (relative intensity, M^-fragment) 201.1006 (M+ , 10.75; calcd for C 10H 11N5 201.10143), 133.0745 (M+-C2 H2 N3, 9.65), 132.0683 (M+-C2 H3 N3, 42.81), 119.0693 (M+-C2 H2 Ni,, 14.04), 118.0643 (M+-C2 H3 N4 , 100.00), and 117.0571 (M+-C2 H11N1(, 34.85); 1H NMR (CDClg/DMSO-dg) Hz 6 2.73 (s, 3H, CH3), 7.4 (m, 4H, aromatic), and 8.23 (s, 2H, CH of the triazole ring) IR (KBr) cm~^ 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmet ric NH stretch), 1640 (s, C=N stretch), 1610 and 1560 (m, C=C ring stretch), 1460 (s, C=C and 6agCH3), and 1380 (s, SsCH3). N-^-Triazol-4-yl-o-toluamidine N^s-Triazol-4-yl-o-toluamidine was obtained from o^tolunitrile (2 ml, 2 g) in 49% yield (1.67 g, 8.3 mmole): mp 232-233 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 201.1006 (M+ , 11.26; calcd for C 10H1 1 % 201.10143), 133.0745 (M+-C2 H2 N3, 9.56), 132.0683 (Jf^-CgH^, 48.71), 119.0693 (M+-C2 h2 N4, 13.64), 118.0643 (M+-C2 H3 Nlp 100.00), and 117.0571 (M+-C2 H1,Ni,, 35.12); 1H NMR (CDClg/DMSO-dg) Hz 6 2.73 (s, 3H, 154 CHg)j 7.4 (ra, 4H, aromatic), and 8.23 (s, 2H, CH of the triazole ring); IR (KBr) cm"1 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmet ric NH stretch), 1640 (s, C=N stretch), 1610 and 1560 (m, C=C ring stretch), 1460 (s, C=C and <$asCH3), and 1380 (s,6sCH3). p-tert-Butyl-N-s-triazol-4-ylbenzamidine p-tert-Butyl-N-s-triazol-4-ylbenzamidine was produced from p-tert- butylbenzonitrile (2.70 g) in 24% yield (1.0 g, 4.1 mmole): mp 293- 294 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 243.1470 (M+ , 100.00; calcd for C13H 17N5 243.14838), 228.1241 (M+-CH3 , 10.90), 175.1257 (M+-C2H2N2, 3.70), 174.1094 (M+-C2H3N3, 2.01), 161.1164 (M+- C2H2N4» 30.42),and 160.1087 (M+-C2H3N|j, 45.47); 1H NMR (CDCl3/DMS0-dg) Hz 6 1.5 (s, 9H, CH3), 7.2 (m, 4h , aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm"1 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch), and 1380 (s, tert-butyl bending). m-tert-Butyl-N-s-triazol-4-ylbenzamidine m-tert-Butyl-N-s-triazol-4-ylbenzamidine was prepared from m-tert- butylbenzonitrile (2.7 g) in 46% yield (1.91 g, 7.0 mmole): mp 221 — 222 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 243.1525 (M+ , 36.49; calcd for C13H 1?N5 243.14838), 228.1277 (M+-CH3, 7.97), 175.1253 (M+-C2 H2N2, 1.60), 174.1144 (M+-C2H3N3, 2.1), and 161.1163 (M+-C2 H2 N1,, 10.53); 1H NMR (CDCl3/DMSO-d6) Hz 6 1.5 (s, 9H, CHg), 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm"1 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch), and 1380 (s, tert- butyl bending). o-tert-Butyl-N-s-triazol-4-ylbenzamidine o-tert-Butyl-N-s-triazol-4-ylbenzamidine was obtained from o-tert- butylbenzonitrile (2.45 g) in 22% yield (0.82 g, 3.4 mmole): mp 212- 214 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 243.1559 (M+ , 3.49; calcd for C 13H1?N5 243.14838), 161.1141 (M+-C2H3N1), 13.94), and 160.1115 (M+-C2Hj|Ni}, 100.00); 1H NMR (CDCl3/DMSO-d6) Hz 6 1.5 (s, 9H, CH3), 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm"^ 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch), and 1380 (s, tert-butyl bending). jD-Methoxy-N-j3-triazol-4-ylbenzamidine j)-Methoxy-N-s^triazol-4-ylbenzamidine was synthesized from j3-meth- oxybenzonitrile (2.26 g) in 52% yield (1.9 g, 8.8 mmol): mp 246- 247 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 217.0989 (M+ , 28.49; calcd for C ^ H ^ N g O 217.09634), 149.0699 (M+-C2H2N3, 2.32), 148.0663 (M+-C2H3N3, 6.57), 135.0672 (M+.CgHgNjp 10.36), 134.0600 (M+- CgHgNj,, 25.16), and 133.0492 ( M ^ C ^ N ^ , 20.73); 1H NMR (CDClg/DMSO-dg) Hz 5 3*9 (s, 3H, CH3), 7.2 (m, 4h , aromatic), and 8.2 (s, 1H, triazole ring); IR(FCBr) cm- ^ 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, 156 C=C ring stretch), and 1250 (s, asymmetric C-0 stretch), and 1040 (s, symmetric C-0 stretch). m-Methoxy-N-s_-triazol-4-ylbenzamidine rn-Methoxy-N-j3-triazol-4-ylbenzamidine was produced from rn-methoxy- benzonitrile (2.26 g) in 35% yield (1.29 g, 5.9 mmole): mp 237-238 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 217.0974 (M+ , 5.68; calcd for C ^ H ^ N g O 217.09634), 135.0707 (M+-C2 H2 Nj|, 3-15), and 134.0590 ( M ^ C ^ N i p 7.84); 1H NMR (CDClg/DMSO-dg) Hz 6 3-9 (s, 3H, CH3 ), 1.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm- "* 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 16 10, 1560, and 1460 (m, C=C ring stretch), and 1250 (s, asymmetric C-0 stretch) and 1040 (s, symmetric C-0 stretch). o-Methoxy-N-s^triazol-4-ylbenzamidine £-Methoxy-N-s^-triazol-4-ylbenzamidine was prepared from o-methoxy- benzonitrile (2.26 g) in 33% yield (1.22 g, 5.6 mmole): mp 242- 243 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 217-0991 (M+ , 6.33; calcd for C-^HpNgO 217.09634), 149.0734 (M+-C2 H2 N3, 4.35), 148.0645 (M+-C2 H3 N3, 1.06), 135.0668 (M+-C2 H2 N2,, 4.33), 134.0606 (M+- C2 H3 Ni!, 42.19), and 133.0538 ( M ^ C ^ N i , , 5.39); 1H NMR (CDCl^DMSO-dg) Hz 6 3.9 (s, 3H, CH3), 7.2 (m, 4h, aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm- ^ 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, 157 C=C ring stretch), and 1250 (s, asymmetric C-0 stretch) and 1040 (s, symmetric C-0 stretch). jD-(Trifluoromethyl)-N-j3-triazol-4-ylbenzamidine £-(Trifluoromethyl)-N-s_-triazol-4-ylbenzamidine was obtained from 4-(trifluoromethyl)benzonitrile (2.66 g) in 39°/° yield (1.31 g, 5.13 mmole): mp 276-277 °C; MS (70 eV), m/e (relative intensity, M+- fragment) 255.0701 (M+ , 52.32; calcd for C 10HgN5F3 255.07315), 187.049^ (M+-C2H2N3 , 2.85), 173-0440 (M+-C2H2Ni,, 54.97), 172.0362 (M+-C2H3Ni,, 100.00), 171.0585 (M+-C2HhNi,, 5.59), and 236.0723 (M+-F, 5.45); 1H NMR (CDCl3/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm-1 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch). m-(Trifluoromethyl)-N-s-triazol-4-ylbenzamidine in-(Trifluoromethyl)-N-s_-triazol-4-ylbenzamidine was synthesized from 3-(trifluoromethyl)benzonitrile (2.91 g) in 67% yield (2.91 g, 11.4 mmole): mp 204-205 °C; MS (70 eV), m/e (relative intensity, M+-frag ment) 255.0767 (M+ , 15.66; calcd for C 10HgN5F3 255.07315), 173.0468 (M+- C2H2Nip 12.67), 172.0382 (M+-C2H3Nij, 19.22), and 171 .0328 (M+-C2H2Nj4, 1.97); 1H NMR (CDCl3/DMSO-d6) Hz 6 7.2 (m, 4H, aromatic), and 8.2 (s, ■1 1H, triazole ring); IR(KBr) cm" 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch). 158 £-(Trifluoromethyl)-N-s-triazol-4-ylbenzamidine o-(Trifluoromethyl)-N-s_-triazol-4-ylbenzamidine was produced from 2- (trifluoromethyl)benzonitrile (2.91 g) in 43% yield (1.85 g, 7.3 mmole): mp 233-235 °C; MS (70 eV), m/e (relative intensity, M+-frag- ment) 255.0777 (M+ , 14.50; calcd for C 10H8N5F3 255.07315), 173.0848 (M+- C2H2Ni,, 8.13), 172.0377 ( M ^ C g H ^ , 6.67), and 171.0311 (M^C^Ni,, 6.67); NMR (CDCl^/DMSO-dg) Hz 6 7.2 (m, 4h , aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm-1 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch). £-Fluoro-N-s^triazol-4-ylbenzamidine £-Fluoro-N-s_-triazol-4-ylbenzamidine was prepared from jD-fluoroben- zonitrile (2.06 g) in 48% yield (1.63 g, 8.0 mmole): mp 254-255 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 205.0790 (M+ , 34.50; calcd for CgHgNgF 205.07635), 137.0514 (M+-C2H2N3, 3-24), 136.0453 (M+- C2H3N3, 3.34), 123.0474 (M+-C2H2Nip 36.70), 122.0404 (M+-C2H3N1(, 19.96) and 121.0317 (M+.CgH^Njp 24.84); 1H NMR (CDCl3/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm“^ 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch). m-Fluoro-N-s-triazol-4-ylbenzamidine m-Fluoro-N-^-triazol-4-ylbenzamidine was obtained from m-fluoroben- zonitrile (2.06 g) in 67% yield (2.38 g, 11.3 mmole): mp 229-230 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 205.0772 (M+ , 21.04; caled for C9H8N5F 205.07635), 123.0478 (M+-C2H2N1), 15.59), 122.045 (M+- C2H3Ni}, 19.96), and 121.0344 (M+-C2HI|Ni4, 3.53); 1H NMR (CDCl3/DMSO-d6) Hz 6 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm”1 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch). o^-Fluoro-N-s-triazol-4-ylbenzamidine o^Fluoro-N-s-triazol-4-ylbenzamidine was synthesized from o^fluoro- benzonitrile (2.06 g) in 48% yield (1.68 g, 8.2 mmole): mp 217-218 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 205.0756 (M+ , 78.16; calcd for CgHgNgF 205.07635), 137.0506 (M+-C2H2N3, 3.58), 123.0479 (M+- C2H2N4, 69.44), 122.0405 (M+-C2H3N4, 100.00), and 121.0360 (M+-C2H4Nlj, 8.42); 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm-1 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch). jD-Chloro-N-j3-triazol-4-ylbenzamidine jD-Chloro-N-s^triazol-4-ylbenzam.idine was produced from j>-chloroben- zonitrile (2.3 g) in 45% yield (1.69 g, 7.6 mmole): mp 270-271 °C (lit*^ 277 °C); MS (70 eV), m/e (relative intensity, M+-fragment) 223.0440 (M++2, 6.98), 221.0458 (M+ , 19.21; calcd for CgHgN5Cl 221.0468), 139.0139 (M+^HgNi,, 12.36), 138.0080 (M+-C2H3N4, 15.24), and 137.1180 (M+-C2Hi,Nij, 1.06); 1H NMR (CDCl3/DMS0-dg) Hz m-Chloro-N-js-triazol-4-ylbenzamidine m-Chloro-N-s-triazol-4-ylbenzamidine was prepared from jn-chloroben- zonitrile (2.3 g) in 66% yield (2.49 g, 11.3 mmole): mp 253-254 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 223.0472 (M++2, 24.60), 221.0492 (M+ , 70.42; calcd for CgH8N5Cl 221.0468), 139-0164 (M+-C2H2N1}, 32.61), 138.0108 (M^C^Ni,, 44.30), and 137.0032 (M+-C2H1}N1|, 6.94); 1H NMR (CDCl^/DMSO-dg) Hz 6 7.2 (m, 4h , aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch). o^-Chloro-N-^-triazol-4-ylbenzamidine o-Chloro-N-s^triazol-4-ylbenzamidine was obtained from £-chloroben- zonitrile (2.3 g) in 46% yield (1.72 g, 7.8 mmole): mp 231-232 °C; MS (70 eV), m/e (relative intensity, NT^-fragment) 223.0487 (M++2, 10.91), 221.0571 (M+, 27.82; calcd for C9H8N5C1 221.0468), 139.0164 (M+-C2H2N1|, 35.11), 138.0104 (M+-C2H3 N4 , 70.63), 137.0029 ( M ^ C g H ^ , 5.18), and 186.0756 (M+-C1, 100.00); 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm-1 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch). 161 jD-Bromo-N-s^-triazol-4-ylbenzamidine ]D-Bromo-N-s-triazol-4-ylbenzamidine was synthesized from jD-bromoben- zonitrile (3.09 g) in 36% yield (1.63 g, 6.1 mmole): mp 246—2-49 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 266.9956 (M++2, 2.5), 264.9951 (M+ , 3.2; calcd for CgHgN^Br 264.99625), 200.9646 (19.41), 198.9658 (21.11), 184.9464 (M++2-C2H2N1(, 46.86), 182.9483 (M+-C2H2N1|, 53.88), 157.9476 (18.19), and 154.9504 (18.17); 1H NMR (CDCl3/DMSO-d6) Hz 6 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm- ^ 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch). m-Bromo-N-£-triazol-4-ylbenzamidine m-Bromo-N-s-triazol-4-ylbenzamidine was produced from m-bromobenzo- nitrile (3*09 g) in 62% yield (2.82 g, 10.6 mmole): mp 261-263 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 266.9941 (M++2, 9.14), 264.9953 (M+ , 9.62; calcd for CgHgNgBr 264.99625), 184.9616 (M++2- C2H2N4, 6.07), 182.9615 (M+-C2H2N[|, 7.92), 183.9572 (M++2-C2H3N^, 6.93), and 181.9598 (M+-C2H3N2j, 6.46); 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (m, 4H, <1 aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch). £-Bromo-N-s^triazol-4-ylbenzamidine o^Bromo-N-s-triazol-4-ylbenzamidine was prepared from o-bromobenzo- nitrile (3.09 g) in 56% yield (2.54 g, 9.5 mmole): mp 244-245 °C; MS 162 (70 eV), m/e (relative intensity, M+-fragment) 266.9972 (M++2, 5.90), 26H.9965 (M+, 6 .HO; calcd for CgHgNgBr 264.99625), 186.0736 (M+-Br, 100.00), 183.9581 (M++2-C2 HjjNi|, 21.66), and 181.9608 ( M ^ C ^ N ^ , 21.84); 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR(KBr) cm-^ 3350 (s, bd, asymmetric NH stretch), 3150 (s, bd, symmetric NH stretch), 1640 (s, C=N stretch), 1610, 1560, and 1460 (m, C=C ring stretch). j>-Nitro-N-s^triazol-4-ylbenzamidine 4-Amino-4H-1,2,4-triazole failed to condense with jD-nitrobenzo- nitrile (2.5 g) under the conditions described above to give jD-nitro-N- s_-triazol-4-ylbenzamidine. Instead the above procedure produced 2.48 g of a slightly orange solid: mp 210-215 °C (H2 0), MS (70 eV), m/e (rela tive intensity, NT^-fragment) 202.0947 (M+ , 17.51; calcd for CgHgNg02 232.07084), 119.0568 (21.06), and 118.0507 (100.00); 1H NMR (CDClg/DMSO- dg) Hz 6 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR (KBr) cm"^ 3000-2600 (s, bd), 1600 (m, C=C ring stretch), 1520 (s, N02 asymmetric absorption), and 1340 (s, N02 symmetric absorption). in-Nitro-N-si-triazol-4-ylbenzamidine 4-Amino-4H-1,2,4-triazole failed to condense with m-nitrobenzo- nitrile (1.4 g) under the conditions described above to give m-nitro-N- ^-triazol-4-ylbenzamidine. Instead the above procedure produced 0.54 g of a slightly brown solid: mp 150-162 °C (H2 0); MS (70 eV), m/e (rela tive intensity, M+-fragment) 181.0474 (M+ , 10.99; calcd for CgHgNg02 163 232.07084), 166.0329 (64.67), and 150.0189 (100.00); 1h NMR (CDCI3 /DMSO- dg) Hz <5 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR (KBr) cm-"' 3000-2600 (s, bd), 1600 (m, C=C ring stretch), 1520 (s, NO2 asymmetric absorption), and 1340 (s, NO2 symmetric absorption). Synthesis of l-Acylthiosemicarbazides The procedure for preparation of 1-acylthiosemicarbazides was that of Cipens, et. al. ' Cyclohexanecarbonyl Thiosemicarbazide To a suspension of thiosemicarbazide (6.2 g, 68.4 mmole) in dry pyridine (50 ml) at 0 °C was added cyclohexanecarbonyl chloride (9.2 ml, 10 g, 68.5 mmole). The suspension was warmed to and stirred at room temperature for 12 hr and then poured into water (600 ml). After the resulting suspension had been stirred at room temperature for 3 hr, the solid formed was collected by vacuum filtration. The filter cake was recrystallized from water to give 2.47 g (12.2 mmole, 18% yield) of cyclohexanecarbonyl thiosemicarbazide: mp 188-189 °C. 1-g-Nitrobenzoyl Thiosemicarbazide 1-jj-Nitrobenzoyl thiosemicarbazide was synthesized in 94% yield (38.6 g, 161 mmole) from jD-nitrobenzoyl chloride (31.9 g, 172 mmole) and thiosemicarbazide (15.6 g, 171 mmole) by the procedure described above: mp 215-217 °C (H2 0) [lit62 218-219 °C (water)]. 164 1-m-Nitrobenzoyl Thiosemicarbazide 1-m-Nitrobenzoyl thiosemicarbazide was synthesized in 17% yield (35.46 g, 148 mmole) from rn-nitrobenzoyl chloride (40.28 g, 215 mmole) and thiosemicarbazide (19 g, 120 mmole) by the procedure described above: mp 190-192 °C (H2 0) [lit62 192-193 °C (water)]. Synthesis of A^-5-(Substituted)-1,2,4-triazoles-3-thlone The procedure for preparation of A^-5-(substituted)-1,2,4-triazole- 3 -thiones was that for A5_5_(j>.nitrophenyl)-1,2,4-triazole-3-thione as described by Cipens, et. al. A6-5-(Cyclohexyl)-1,2 ,4-triazole-3-thione A suspension of 1-cyclohexanecarbonyl thiosemicarbazide (2.47 g, 12.2 mmole) in 1.4 N aqueous sodium hydroxide (27 ml) was refluxed for 1 hr. The mixture was cooled to room temperature, acidified with glacial acetic acid (10 ml) and stirred for 15 min. The solid formed was collected by vacuum filtration, recrystallized from water and dried in a vacuum desiccator to give 1.47 g (8 mmole, 65% yield of A^-5- (cyclohexyl)-l,2,4-triazole-3-thione: mp 229-230 °C; Ms (70 eV), m/e (relative intensity) 183.0803 (100.00). A6-5-(£.-Nitrophenyl )-1,2 ,4-triazole-3-thione A6-5-(£-Nitrophenyl)-1,2,4-triazole-3-thione was synthesized in 32 % yield by the procedure described above: mp 255-256 °C (acetone) [lit 244 °C (water)]. 165 A^-5- (m-Nitrophenyl) -1,2, 4-triazole-3-thione A^-5-(rn-Nitrophenyl)-1,2,4-triazole-3-thione was synthesized in 82% yield by the procedure described above: mp 235-238 °C (acetone) [lit 2110 °C (water)). A^-5- (o^-Nitrophenyl) -1,2,4-triazole-3-thione A mixture of io-nitrobenzoyl hydrazide (20 g, 110.5 mmole) and ammon ium thiocyanate (30 g, 395 mmole) was heated between 170-175 °C for 5 min. The mixture was cooled and then dissolved in hot water (100 ml). The solution was acidified to pH 3 with concentrated hydrochloric acid (5 ml), stirred in an ice bath for 5 min and vacuum filtered. The white solid obtained was recrystallized from water (150 ml) to give 8.07 g (34 mmole, 31% yield) of A^-5-(c>-nitrophenyl)-1,2,4-triazole-3-thione: mp 215-216 °C (H2 0) [lit62 219-220 °C (water)]. A^-5-(]D-Cyanophenyl)-1,2,4-triazole-3-thione To prevent hydrolysis of its cyano group, the synthesis of A^-5-(j>- cyanophenyl)-1,2,4-triazole-3-thione from 1-j3-cyanobenzoyl thiosemicar- 1 i i 1 bazide was attempted by the procedure of Hoggarth, et. al., instead of that by Cipens, et. al. jv-Cyanobenzoyl thiosemicarbazide (0.62 g, 2.7 mmole) was heated between 160-180 °C for 20 min. The mixture was cooled to give a 3 component solid which was separated by column chroma tography (20 g silica gel eluting with 2 % methanol in methylene chlor ide and gradually increasing to 40% methanol in methylene chloride, collecting 200 ml fractions) to give 0.3995 g of a white solid (isolated from fractions 6-12): MS (70 eV), m/e (relative intensity) 203.0183 (M+ , 2.66; calcd for CgHgN^S 202.0313), 131.0336 (9.78), 130.0286 (100.00), and 102.0340 (30.87). Synthesis of Phthalazines 4-Hydroxyphthalazine Phthalaldehydic acid was converted into 4-hydroxyphthalazine by the procedure of Gabriel and Neumann1^ as follows: phthalaldehydic acid (150 g, 1 mole), hydrazine hydrate (50 ml, 1 mole) and sodium acetate (107 g, 1.3 mole) in water (260 ml) were heated on a steam bath until a clear solution resulted. The mixture was cooled to room temperature, neutralized with concentrated hydrochloric acid and cooled in an ice bath. The solid was collected by vacuum filtration and dried in a vacuum desiccator to give 88 g (600 mmole, 60% yield) of 4-hydroxy- phthalazine: mp 182-184 °C (lit1*11 182 °C). 4-Chlorophthalazine 4-Hydroxyphthalazine was converted into 4-chlorophthalazine follow- ing the procedure of Atkinson, Brown, and Simpson. 1 US J A suspension of U-hydroxyphthalazine (5 g, 4 mmole) and phosphorus oxychloride (15 ml), after the initial exothermic reaction subsided, was refluxed for 5 min, cooled to room temperature and poured into a fresh aqueous mixture of 2N NaOH (500 ml) and ice (500 ml). The solid was collected by vacuum fil tration. The filtrate was extracted with ether (three 500 ml portions) and the combined extracts concentrated to a solid. 167 The solids were combined, dissolved in chloroform (50 ml) and filtered through alumina (200 g) eluting with chloroform (200 ml). The eluent was concentrated to 59.1 g (30 mmole, 89% yield) of 4-chloro- phthalazine: mp 109-110 °C (lit^^ 112-114 °C). Most of the material decomposed to an unidentified compound on recrystallization. It was found expeditious to use the crude material in the next step. 4-Hydrazlnophthalazine 4-Chlorophthlazine was converted into 4-hydrazinophthalazine by the procedure of Druey and Ringeer.^1* A solution of 4-chlorophthalazine (13.55 g, 83 mmole) and hydrazine (21 ml, 21 g, 664 mmole) in ethanol (41 ml) was heated on a steam bath for 2 hr and then the hot solution was vacuum filtered. The filtrate was cooled in an ice bath for 2 hr and then in a freezer for 2 hr. The solid formed was collected by vacuum filtration to give 8.88 g (55.6 mmole, 67% yield) of 4-hydrazinoph- thalazine: mp 174-175 °C [lit11,11 172-173 °C (MeOH)]; Rf 0.3 (silica gel, methylene chloride 3 :1). js-Triazolo[3,4-a]phthalazine 4-Hydrazinophthalazine was converted into £^-triazolo-[3,4-a_]-phthal azine by the procedure of Druey and Ringier1^ as follows: A solution of 4-hydrazinophthalazine (3.2 g, 20 mmole) in formic acid was refluxed for 5 hr. The solution was concentrated in vacuo (1 mm) and the residue recrystallized from ethanol (50 ml) to give ^-triazolo[3,4-a^]phthalazine (2.5 g, 14.7 mmole, 73% yield): mp 182-183 °C [lit11*1* 190-191 °C]; Rf 168 (silica gel/ethyl acetate) 0.2; MS (70 eV), m/e (relative intensity) 170.0575 (M+ , 100.00; calcd for CgHgNi, 170.05923), 115.0413 (38.23), 114.0337 (12 .20 ), and 88.0264 (11.16). General Procedure for Preparation of 3-Substituted-1jf-1,2,4- triazole3: 3-Substituted-1J1-1,2,4-triazoles were prepared by one of three methods described below. Method A; From Substituted-N-s-Triazol-4-ylbenzamidines: The procedure used for preparing 3-substituted-1H-1,2,4-triazoles from substituted-N-j3-triazol-4-ylbenzamidines was an extension of that described by Becker, et. al.^-’ A solution of substituted-M-s^triazol-4- ylbenzamidine (0 .2 g), ethyl chloroformate (1 equiv) and nitromethane (1.3 ml) was refluxed for 12 hr, cooled to room temperature and the solvent removed in vacuo on a rotary evaporator (house vacuum). The residue was adsorbed to a TLC plate (1 mm thick) using methanol (2 ml) and the plate was developed with ethyl acetate. The band indicated in the individual preparations was scraped and extracted with methanol (100 ml) for 15 min. The extract was filtered and concentrated to a solid/oil (see the individual preparation) which was recrystallized from 1,2-dichloroethane. Some examples of the preparations and the properties of 3 -aryl-111- 1,2 ,4-triazoles are presented here and are partially summarized in Table 19. 169 3-Phenyl-1H-1,2,4-triazole The band with R^. 0.4 was worked up to give 3-phenyl-3jl-1,2,4-tria- zole (0.09 g, 0.6 mmole, 56% yield): mp 115-116 °C (lit61*' 65 117 °C, 121 °C, 123 °C); MS (70 eV), m/e (relative intensity, M+-fragment) 145.0630 (M+ , 100.00; calcd for C8H7N3 145.06399), 118.0529 (M+-HCN, 19.55), 117.0579 (M+-N2 , 4.22), and 104.0512 (M+-CHN2 , 56.12); 1H NMR (CDCl3 /DMSO-d6) Hz 6 7.3 (m, 3H), 8.0 (m, 2H), and 8.2 (s, 1H); IR(KBr) * cm-1 2700 (s, bd, characteristic of the triazole ring); UV(water), X[log(e)] 240.7 (4.1) [lit14*1 241.5 (4.1)]; retention times: HPLC 3.5 min; GLC 5.43 min (column temp 220 °C, He flow rate 18 ml/min), 8.87 min (column temp 250 °C, He flow rate 7 ml/min), 9.00 min (column temp 270 °C, He flow rate 9 ml/min), 15.29 min (column temp 200 °C, He flow rate 11 ml/min), 15.58 min (column temp 220 °C, He flow rate 7 ml/min) and 26.08 min (column temp 180 °C, He flow rate 7 ml/min). 3- (jJ-Tolyl) -1H^ 1,2,4-triazole The band with R^. 0.33 contained 3-(£-tolyl)-1j1-1,2,4-triazole (0.15 g, 0.9 mmole, 93% yield): mp 171-172 °C (lit65 172 °C); MS (70 eV), m/e (relative intensity, M+-fragment) 159.0786 (M+ , 100.00; calcd for C9HgN3 159.07964), 132 (M+-CHN, 7-94), 131 (M+-N2, 11.82), 118 (M+-CHN2 , 43.55), and 117.0550 (M+-CH2 N2 , 4.26); 1H NMR (CDCl3 /DMS0-dg) Hz 6 2.40 (s, 3H, CH3), 7.53 (AA'XX', 4H, Jax= V x '= 6 - 6 Hz» JAA'=JXX' =0*9 Hz» JAX,=J^A,X=undete^rn:i•ned, aromatic), 7.9 (s, 1H, CH proton of the triazole ring); ^H FT-NMR (acetone-dg) Hz 6 2.37 (s, 3H), 7.23 (s, 1H), 7.33 (s, 1H), 7.95 (s, 1H), 8.05 (s, 1H), and 8.29 (s, 1H); IR(KBr) cm-1 170 3000-2500 (s, bd, characteristic of the triazole ring), 1610 and 1560 (m, C=C ring stretch), 1460 (s, C=C and ^asCH^), and 1380 (s, 6SCH3); UV (water), X[log(e)] 2*16 nm (4.1) and 201.9 nm (4.3); UV (ethyl acetate) X[log(e)] 254 nm (4.1); retention times: HPLC 2.4 min; GLC 21.27 min (column temp 220 °C, He flow rate 7 ml/min). 3-(m_-Tolyl)-1H-1,2,4-triazole The band with R^ 0.36 produced on work-up 3-(in-tolyl)-1_H-1,2,4-tria zole (0.16 g, 0.98 mmole, 98% yield), an oil which solidified to a solid: mp 67 °C (lit^** 67-68 °C); MS (70 eV), m/e (relative intensity, M+-fragment) 159-0774 (M+, 100.00; calcd for C9HgN3 159.07964), 158.0699 (M+-H, 14.09), 132.0655 (M+-HCN, 8.98), 131.0610 (M+-N2 , 11.51), and 118.0631 (M+-CHN2, 43.55); 1H NMR (CDCl3 /DMSO-d6) Hz 6 2.40 (s, 3H), 7.60 (m, 4H, aromatic), and 8.20 (s, 1H, CH of the triazole ring); "*H FT-NMR (acetone-dg) Hz 6 2.39 (s, 3H), 7.28 (m, 2H), 7*96 (m, 2H), and 8.33 (s, 1H); IR(KBr) cm- ^ 3000-2500 (s, bd, characteristic of the triazole ring), 16 10 and 1560 (m, C=C ring stretch), 1460 (s, C=C and 633083 ), and 1380 (s, 6gCH3); UV (water), X[log(e)] 243.2 nm (4.0), 204.1 nm (4.3); UV (ethyl acetate) X[log(e)] 254 (3.9); retention times: HPLC 2.3 min; GLC 20.69 min (column temp 220 °C, He flow rate 7 ml/min). 3-(o-Tolyl)-1H-1,2,4-triazole The band with R^. 0.4 yielded 3-(o^-tolyl)-111-1,2,4-triazole (0.12 g, 0.77 mmole, 77% yield): mp 135-136 °C; MS (70 eV), m/e (relative intensity, NT^-fragment) 159*0786 (M+ , 100.00; calcd for CqHgNg 159.07964), 158.0711 (M+-H, 27.72), 132.0786 (M+-HCN, 44.21), 131.0609 (M+-N2 » 68.71), and 118.0644 (M+.-CHf^, 31.65); 1H NMR (CDC^/DMSO-dg) Hz 6 2.60 (s, 3H, CH^), 7.50 (m, 4H, aromatic), and 8.16 (s, 1H, triazole ring); 1H FT-NMR (acetone-dg) Hz 6 2.61 (s, 3H), 7.29 (m, 4H), 7.89 (M, 1H), and 8.34 (s, 1H); IR(KBr) cm-^ 3000-2500 (s, bd, characteristic of the triazole ring), 1610 and 1560 (m, C=C ring stretch), 1460 (s, C=C and 6asCH3), and 1380 (s, 6SCH3); UV (water), X[log(e)] 231.9 nm (3.9) and 199.5 nm (4.4); UV (ethyl acetate), X[log(e)] 254 (3.7); retention times: HPLC 2.0 min; GLC 17.82 min (column temp 220 °C, He flow rate 7 ml/min). 3-(js-Tert-butyl phenyl)-111-1,2,4-triazole The band with R^ 0.38 on work-up resulted in 3-(p-tert-butylphenyl)- 1 PI—1,2,4-triazole (0.16 g, 0.81 mmole, 98% yield): oil; MS (70 eV), m/e (relative intensity, M+-fragment) 201.1251 (M+ , 22.24; calcd for C 12H 15N3 201.12659), 186.1034 (M*-CH3, 100.00), 159.0828 ( M ^ C H ^ , 4.31), and 158.0685 (17.26); 1H NMR (CDClg/DMSO-dg) Hz 6 1.5 (s, 9H, CH^), 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR (KBr) cm” ^ 3000-2600 (s, bd), 1610, 1560, and 1470 (m, C=C ring stretch), and 1380 (s, tert-butyl bending); retention time: HPLC 4.0 min. 3- (m-Tert-butylphenyl) - 1]I-1,2,4-triazole Work-up of the band with R^ 0.40 produced 3-(m-tert-butylphenyl)-1H- 1,2,4-triazole (0.16 g, 0.81 mmole, 98% yield): oil; MS (70 eV), m/e (relative intensity, PT^-fragment) 201.1274 (M+ , 19-94; calcd for C12H 15N3 201.12659), 186.1038 (M+-CH3 , 100.00), 159.0831 (M+-CH2 N2, 2.73), and 158.0741 (15.43); 1H NMR (CDC^/DMSO-dg) Hz 6 1.5 (s, 9H, CH3), 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR (KBr) cm“ ^ 3000-2600 (s, bd), 16 10, 1560, and 1470 (m, C=C ring stretch), and 1380 (s, tert-butyl bending); retention time: HPLC 3.5 min. 3- (^-Tert-butylphenyl)-1H-1,2,4-triazole The band with Rf 0.50 contained 3-(o-tert-butylphenyl)-1H-1,2,4- triazole (0.16 g, 0.81 mmole, 98% yield): oil; MS (70 eV), m/e (rela tive intensity, M+-fragment) 201.1244 (M+, 6.84; calcd for C12 H 5N3 201.12659), 200.1177 (M+-H, 17.03), 186.1040 (M+-CH3, 37.81), 173.1085 (M+-N2, 1.47), 160.0952 (M+-CHN2, 2.99), and 159.0932 ( M ^ C H ^ , 15.05); 1H NMR (CDCl3 /DMSO-d6) Hz 6 1.5 (s, 9H, CH3), 7.2 (m, 4H, aromatic), and 8.2 (s, 1H, triazole ring); IR (KBr) cm"^ 3000-2600 (s, bd), 1610, 1560, 1470 (m, C=C ring stretch), and 1380 (s, tert-butyl bending); retention time: HPLC 2.9 min. 3-(js-Trif luoromethylphenyl)-1H-1,2,4-triazole Work-up of the band with R^ 0.38 gave 3-(j>-trifluoromethylphenyl)- 1H-1,2,4-triazole (0.16 g, 0.76 mmol, 98°/t> yield) mp 175-176 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 213.0480 (M+ , 100.00; calcd for C9H5N3 F3 213.05136), 194.0525 (M+-F, 4.99), 186.0408 (M+-HCN, 36.16), 185.0359 (M+-N2 , 2.25), 172.0370 (M+-HCN2, 24.91), and 171.0315 (M+-CH2 N2 , 1.38 ); 1H NMR (CDCl3 /DMS0-d6) Hz 6 7-2 (m, 4H, aromatic) and 173 8.2 (s, 1H, triazole ring); IR (KBr) cm"^ 3000-2600 (s, bd), 1610, 1560, and 1470 (m, C=C ring stretch); UV (water), X[log(e)] 243.5 (4.0) and 195.9 (4.2); UV (ethyl acetate), X[log(e)] 254 (4.0); retention times: HPLC 4.1 min; GLC 29.78 min (column temp 180 °C, He flow rate 7 ml/min). 3- Om-Tr if luoromethylphenyl) - 1j1-1,2,4-triazole The band with R^ 0.42 produced on work-up 3-(in-trifluoromethyl phenyl)- 111-1,2,4-triazole (0.16 g, 0.76 mmole, 98% yield): mp 76- 77 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 213.0543 (M+ , 65.00; calcd for C g H g N ^ 213-05136), 194.0524 (M+-F, 3-86), 186.0421 (M+-HCN, 25.42), 185.0437 (M+-N2, 2.13), and 172.0401 (M+-CHN2, 19.31); 1H NMR (CDCl3 /DMSO-dg) Hz 6 7-2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); IR (KBr) cm- "' 3000-2600 (s, bd), 16 10, 1560, and 1470 (m, C=C ring stretch); UV (water), X[log(e)] 240.4 (4.0) and 200.5 (4.3); UV (ethyl acetate), X[log(e)] 254 (3.9); retention times: HPLC 4.1 min; GLC 29.23 min (column temp 180 °C, He flow rate 7 ml/min). 3- (.o-Tr if luoromethylphenyl) - 1f1-1,2,4-triazole Contained in the band with Rj. 0.37 was 3 -(.o-trifluoromethylphenyl)- 1H-1,2,4-triazole (0.16 g, 0.78 mmole, 98% yield): mp 159-161 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 213.0501 (M+ , 100.00; calcd for CgH6N3 F3 213.05136), 193-0433 (M+-F, 35.67), 186.0383 (M+-HCN, 7.75), 185.0378 (M+-N2 , 5.28), 172.0373 (M+-CHN2, 32.07), and 171.0223 (M+-CH2 N2 , 1.03); 1H NMR (CDCl3 /DMSO-d6) Hz 7-2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); IR (KBr) cm-^ 3000-2600 (s, bd), 16 10, 1560, 174 and 1470 (m, C=C ring stretch); UV (water), X[log(£)] 190.0 (4.4) and 221.8 (3.7); UV (ethyl acetate), X[log(e)] 254 (3-3); retention times: HPLC 3.7 min; GLC 15.43 min (column temp 180 °C, He flow rate 7 ml/min). 3- (js-Fluorophenyl) -1]1-1,2,4-triazole The band with Rp 0.32 on work-up resulted in 3 -(j)-fluorophenyl)-1H7 1,2,4-triazole (0.16 g, 0.96 mmole, 98% yield): mp 118-119 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 163.0586 (M+ , 100.00; calcd for CgH6N3F 163.05456), 145.0794 (M”2 -F, 2.06), 136.0476 (M+-HCN, 26.91), 135.0507 (M+-N2, 3-97), 122.0444 (M+-CHN2 , 35.21), and 121.0344 (M+-CH2 N2 , 12.66); 1H NMR (CDC^/DMSO-dg) Hz 6 7-2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); IR (KBr) cm- ^ 3000-2600 (s, bd), 1610, 1560, and 1470 (m, C=C ring stretch); UV (water), X[log(e)] 240.0 (4.0) and 198.1 (4.3); UV (ethyl acetate), X[log(e)] 254 (4.0); retention time: HPLC 4.6 min. 3- (m-Fluorophenyl) - 1_H-1,2,4-triazole The band with R^. 0.40 contained 3-(im-fluorophenyl)- 1H-1,2,4-triazole (0.15 g, 0.95 mmole, 95% yield): mp 115-116 °C; MS (70 eV), m/e (relative intensity, M^-fragment) 163.0543 (M+ , 100.00; calcd for CgH6N3F 163.05456), 136.0451 (M+-HCN, 32.91), 135.0457 (M+-N2, 5.68), 122.0426 (M+-CHN2, 36.43), and 121.0341 (M+-CH2 N2 , 7.12); 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); IR (KBr) cm-1 3000-2600 (s, bd), 1610, 1560, and 1470 (m, C=C 175 ring stretch); UV (water), X[log(e)] 240.4 (4.0) and 198.1 (4.3); UV (ethyl acetate), X[log(e)] 254 (3.9); retention time: HPLC 3.8 min. 3- (c^-Fluoro phenyl)- 1H-1,2,4-triazole Work-up of the band with Rf 0.40 gave 3-(£-fluorophenyl)-1H-1,2,4- triazole (0.16 g, 0.96 mmole, 98% yield): mp 118-119 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 163.0536 (M+ , 100.00; calcd for C8H6N3F 163.05456), 145.0611 (M+-F, 1.17), 136.0431 (M+-HCN, 7-70), 135.0466 (M+-N2, 6.99), 122.0380 (M+-CHN2, 64.66), and 121.0309 (M+- CH2 N2, 3-42); 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); IR (KBr) cm- ^ 3000-2600 (s, bd), 16 10, 1560, and 1470 (m, C=C ring stretch); UV (water), X[log(e)] 238.3 (4.0) and 197.7 (4.2); UV (ethyl acetate), X[log(e)] 254 (3.9); retention time: HPLC 3.5 min. 3- (£-Chlorophenyl) - 1_H—1,2,4-triazole The band with R^. 0.38 was worked up to give 3-(j}-chlorophenyl)-1H- 1,2,4-triazole (0.15 g, 0.85 mmole, 95% yield): mp 193.5-194 °C (lit64 194 °C); MS (70 eV), m/e (relative intensity, M+-fragment) 181.0258 (M++2, 32.82), 179.0277 (M+ , 100.00; calcd for CgHgNgCl 179.02501), 152.0156 (M+-HCN, 26.19), 151.0177 (M+-N2, 2.70), 138.0119 (M+-CHN2, 28.04), and 137.0036 (M+.CH^lg, 5.15); 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); IR (KBr) cm-^ 3000- 2600 (s, bd), 1610, 1560, and 1470 (m, C=C ring stretch); 1H FT-NMR (acetone-d6) Hz 6 7-44 (s, 1H), 7.55 (s, 1H), 8.07 (s, 1H), 8.19 (s, 176 1H), and 8.44 (s, 1H); IR (KBr) cm-1 3000-2600 (s, bd), 1610, 1560, and 1470 (m, C=C ring stretch); UV (water), X[log(a)] 247.8 (4.2) and 199.1 (4.3); UV (ethyl acetate), A[log(e)] 254 (4.3); retention times: HPLC 4.5 min; GLC 16.91 min (column temp 270 °C, He flow rate 9 ml/min). 3- (in-Chlorophenyl)-111-1,2,4-triazole The band with R^. 0.40 produced 3-(rn-chlorophenyl)-1H-1,2,4-triazole (0.11 g, 0.60 mmole, 67% yield): mp 152-154 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 181.0242 (M++2, 28.83), 179.0271 (M+ , 100.00; calcd for CgHgNgCl 179-02501), 152.0162 (M+-HCN, 28.77), 151.0179 (M+-N2 , 7.60), 138.9996 (M+-CHN2, 9.53), and 137.0134 (M+- CH2 N2 , 24.44); 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); 1H FT-NMR (acetone-dg) Hz 6 7.43 (m, 2H), 8.12 (m, 2H), and 8.47 (s, 1H); IR (KBr) cm-1 3000-2600 (s, bd), 1610, 1560, and 1470 (m, C=C ring stretch); UV (water), A[log(e)] 242.1 (4.0) and 207.1 (4.4); UV (ethyl acetate), X[log(c)] 254 (4.0); retention times: HPLC 3.6 min; GLC 14.83 min (column temp 270 °C, He flow rate 9 ml/min). 3-(^-Chlorophenyl)-1H-1,2,4-triazole Contained in the band with R^. 0.43 was 3-(o^chlorophenyl)-1H-1,2,4- triazole (0.15 g, 0.85 mmole, 0.95% yield): mp 152-154 °C; MS (70 eV), m/e (relative intensity, M+~fragment) 181.0209 (M++2, 28.23), 179.0254 (M+, 100.00; calcd for CgHgNgCl 179.02501), 152.0126 (M+-HCN, 8.14), 151.0179 (M+-N2 , 13-65), 138.0099 (M+-CHN2, 73.90), and 137.0024 (M+- CH2 N2, 3.01); 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic) and 8.2 177 (s, 1H, triazole ring); ^H FT-NMR (acetone-dg) Hz 6 7.5 (m, 3H), 7.91 (m, 1H), and 8.36 (s, 1H); IR (KBr) cm-1 3000-2600 (s, bd), 1610, 1560, and 1470 (m, C=C ring stretch); UV (water), X[log(e)] 234.7 (3.9) and 203.3 (4.4); UV (ethyl acetate), X[log(e)] 254 (3.9); retention times: HPLC 3.5 min; GLC 10.84 min (column temp 270 °C, He flow rate 9 ml/min). 3- (js-Bromophenyl) -1H-1,2,4-triazole The band with Rf O.38 was worked up to give 3-(.£-bromophenyl)-1.H- 1.2.4-triazole (0.18 g, 0.81 mmole, 92% yield): mp 116-116.5 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 224.9748 (M++2, 90.23), 222.9781 (M+ , 100.00; calcd for CgHgN^Br 222.97446), 197-9655 (M++2-HCN, 24.21), 196.9700 (M++2-N2 , 3.20), 195.9665 (M+-HCN, 18.41), 194.9678 (M+-N2 , 4.06), 183.9639 (M++2-CFIN2, 20.68), 182.9585 (M++2-CH2 N2 , 4.50), 181.9642 (M+-CHN2 , 23.60), and 180.9596 (M+-CH2 N2); 1H NMR (CDCI3 /DMSO- dg) Hz 6 7.2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); IR (KBr) cm- ^ 3000-2600 (s, bd), 1610, 1560, and 1470 (m, C=C ring stretch); UV (water), X[log(e)] 250.9 (4.3) and 199-1 (4.4); UV (ethyl acetate), X[log(e)) 254 (4.2); retention times: HPLC 4.2 min; GLC 18.19 min (column temp 270 °C, He flow rate 9 ml/min). 3- (rn-Bromophenyl) - 1H-1,2,4-triazole The band with R^. 0.44 was worked up to give 3-(in-bromophenyl)-1H- 1.2.4-triazole (0.19 g, 0.87 mmole, 98% yield): mp 111-112 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 224.9736 (M++2, 96.50), 222.9733 (M+ , 100.00; calcd for CgHgNjBr 222.97446), 197-9645 (M++2-HCN, 178 16.88), 196.9595 (M++2-N2, 2.41), 195.9642 (M+-HCN, 2.41), 183.9602 (M++2-CHN2, 16.52), 182.9500 (M++2-CH2N2, 2.64), 181.9640 (M+-CHN2 , 20.32), and 180.9580 (M+-CH2N2 , 3-90); 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (ra, 4H, aromatic) and 8.2 (s, 1H, triazole ring); IR (KBr) cm-^ 3000- 2600 (s, bd), 1610, 1560, and 1470 (m, C=C ring stretch); UV (water), X[log(e)] 23.2 (4.1) and 210.0 (4.4); UV (ethyl acetate), X[log(e)] 254 (4.1); retention times: HPLC 3.6 min; GLC 16.05 min (column temp 270 °C, He flow rate 9 ml/min). 3- (^-Bromophenyl)-11t-1,2,4-triazole The band with Rf 0.40 produced on work-up 3-(.o-bromophenyl)-1j1- 1,2,4-triazole (0.10 g, 0.44 mmole, 50% yield): mp 173-174 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 224.9733 (M^+2, 97.88), 222.9767 (M+ , 100.00; calcd for CgHgNgBr 222.97446), 197.9660 (M++2-HCN, 7.29), 196.9695 ( M ^ -Ng, 5 -32), 195.9661 (M+-HCM, 7.45), 194.9743 (M+- N2, 6.01), 183.9622 (M++2-CHN2 , 9.41), 182.9588 (M++2-CH2N2, 9-41), 181.9627 (M+-CHN2 , 44.34), and 180.9566 (M+-CH2N2, 4.47); 1H NMR (CDCl^/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); IR (KBr) cm-1 3000-2600 (s, bd), 1610, 1560, and 1470 (m, C=C ring stretch); UV (water), X[log(e)] 201.9 (4.5) and 237.0 (3.8); UV (ethyl acetate), X[log(e)] 254 (3.7); retention times: HPLC 3.6 min; GLC 12.84 min (column temp 270 °C, He flow rate 9 ml/min). 179 3- (jD-Methoxy phenyl) - TH-1,2,4-triazole Contained in the band with R^ 0.34 was 3-(]3-methoxyphenyl)-1j1-1,2,4- triazole (0.14 g, 0.80 mmole, 86% yield): mp 174-175 °C (lit^^ 186 °C); MS (70 eV), m/e (relative intensity, M+-fragment) 175.0751 (M+ , 9.12; calcd for CgHgN^O 175.07455), 134.0528 (M+-CHN2, 1.44), and 133-0450 (M+-CH2N2, 1.27); 1H NMR (CDC^/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); FT-NMR (acetone-dg) Hz 6 3.85 (s, 3H), 6.97 (s, 1H), 7.07 (s, 1H), 8.00 (s, 1H), 8.08 (s, 1H), and 8.23 (s, 1H); IR (KBr) cm“1 3000-2600 (s, bd), 1610, 1560, and 1470 (in, C=C ring stretch), 1250 (s, asymmetric C-0 stretch), and 1040 (s, symmetric C-0 stretch); UV (water), X[log(e)] 254.8 (4.1); UV (ethyl acetate), X[log(e)] 254 (4.1); retention times: HPLC 4.7 min; GLC 16.87 min (column temp 250 °C, He flow rate 7 ml/min). 3-(m-Methoxyphenyl)-1H-1,2,4-triazole Produced from the band with R^ 0.38 on work-up was 3-(ni-methoxy- phenyl)-1j1-1,2,4-triazole (0.16 g, 0.9 mmole, 98% yield): mp 182— 183 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 175.0725 (M+ , 100.00; calcd for CgHgN30 175.07455), 174.0650 (M+-H, 52.19), 146.0663 (M+-CH0, 10.85), 145.0606 (M+-CH20, 23.25), 134.0572 (M+-CHN2 , 20.68), and 133-0479 (M+-CH2N2 , 8.83); 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); ^H FT-NMR (acetone-dg) Hz 6 3.86 (s, 3H), 7.03 (m, 1H), 7-38 (m, 1H), 7.66 (m, 2H), and 8.34 (s, 1H); IR (KBr) cm-1 3000-2600 (s, bd), 1610, 1560, and 1470 (m, C=C ring stretch), 1250 (s, asymmetric C-0 stretch), and 1040 (s, symmetric C-0 stretch); UV (water), X[log(e)] 252.8 (4.1) and 201.6 (4.2); UV (ethyl acetate), X[log(a)] 254 (3.9); retention times: HPLC 4.6 min; GLC 15.72 min (column temp 250 °C, He flow rate 7 ml/min). 3- (£-Methoxyphenyl)-1 _H-1,2,4-triazole The band with Rf 0.35 was worked up to give 3-(o.-methoxyphenyl)-1I1- 1,2,4-triazole (0.16 g, 0.9 mmole, 98% yield): mp 169-169.5 °C; MS (70 eV), m/e (relative intensity, M+-fragment) 175.0728 (M+ , 100.00; calcd for CgH9N30 175.07455), 174.0663 (M+-H, 64.88), 148.0608 (M+-CHN, 1.71), 147.0628 (M+-N2 , 12.06), 146.0705 (M+-CH0, 46.33), 145.0638 (M+-CH20, 39.01), 134.0579 (M+-CHN2, 3.41), and 133-0527 (M+-CH2N2, 4.83); 1H NMR (CDCl^/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); ^H FT-NMR (acetone-dg) Hz 6 4.08 (s, 3H), 7.26 (m, 3H), 7.92 (s, 1H), and 8.25 (m, 1H); IR (KBr) cm-1 3000-2600 (s, bd), 1610, 1560, and 1470 (m, C=C ring stretch), 1250 (s, asymmetric C-0 stretch), and 1040 (s, symmetric C-0 stretch); UV (water), X[log(e)] 293.2 (3.7) and 207.6 (4.4); UV (ethyl acetate), X[log(e)] 254 (4.1) retention times: HPLC 3.8 min; GLC 11.75 min (column temp 250 °C, He flow rate 7 ml/min). Method B; From A-^-5-Substituted-l,2,4-triazole-3-thiones The procedure for preparation of 3-substituted-1H-1,2,4-triazoles from A^-5-substituted-1,2,4-triazole-3-thiones was described by Cipens, 181 3- (Cyclohexyl) -111-1,2,4-triazole 3-(Cyclohexyl)-1H-1,2,4-triazole was prepared by the same procedure as that described for 3-(j3-nitrophenyl)-1H-1,2,4-triazole. To A^-5- (cyclohexyl)-1,2,4-triazole-3-thione (1.41 g, 7.7 mmole) in glacial acetic acid (8 ml) was added aqueous 30% hydrogen peroxide (2.5 ml, 30.0 mmole). The mixture was stirred 30 min at room temperature and then concentrated in vacuum (1 mm Hg) to an oil. This oily residue was taken up in methanol (10 ml), adsorbed on silica gel (10 g) and chromatographed over silica gel (20 g) eluting with ethyl acetate (200 ml). Concentration of the eluent gave 0.58 g (3.8 mmole, 50% yield) of 3-(cyclohexyl)-1H^-1,2,4-triazole which remained as an oil: MS (70 eV), m/e (relative intensity, M+-fragment) 151.1113 (M+ , 13.73; calcd for C8H 13N3 151.11075), 150.1056 (M+-H, 13.78), 124.0931 (M+-HCN, 2.67), 123.0823 (M+-N2, 17.05), 122.0755 (35.31), 110.762 (M+-CHN2 , 11.89), and 109.0673 (M+-CH2N2, 9.02); retention time: GLC 11.54 min (column temp 220 °C, He flow rate 11 ml/min). 3- (jo-Nitro phenyl )-1H-1,2,4-triazole A6-5-(j3-Nitrophenyl)-1,2,4-triazole-3-thione was converted, as described in the previous experimental procedure, to 3-(j>-nitrophenyl)- 1H-1,2,4-triazole in 57% yield (0.5g, 2.3 mmole), MP 216-217 °C (1,2- dichloroethane) [lit62 222 °C (water)]; 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); 1H FT-NMR (acetone-dg) Hz 6 8.36 (s, 4h ) and 8.59 (s, 1H); IR (KBr) cm"1 3000-2600 (s, bd), 1600 (m, C=C ring stretch), 1520 (s, N02 asymmetric absorption), and 1340 (s, N02 symmetric absorption); UV (water), X[log(e)] 295.4 (3.8) and 216.7 (3-7); UV (ethyl acetate), X[log(e)] 254 (3.2); retention times: HPLC 4.1 min; GLC 18.85 min (column temp 280 °C, He flow rate 18 ml/min). 3- (m-Nitrophenyl) - 1H-1,2,4-triazole 3-(m-Nitrophenyl)-1H-1,2,4-triazole was prepared, as described above, in 47% yield (0.5g, 2.3 mmole) from A^-5-(in-nitrophenyl)-1,2,4- triazole-3-thione, MP 210-211 °C (1,2-dichloroethane) [lit*^ 213 °C (water)]; 1H NMR (CDClg/DMSO-dg) Hz 6 7.2 (m, 4H, aromatic) and 8.2 (s, 1H, triazole ring); ^H FT-NMR (acetone-dg) Hz 6 7.77 (m, 1H), 8.55 (m, 3H), and 8.92 (s, 1H); UV (water), X[log(e)] 237.9 (4.1) and 190.0 (4.0); UV (ethyl acetate), X[log(e)] 254 (4.1); retention times: HPLC 4.1 min; GLC 18.46 min (column temp 280 °C, He flow rate 18 ml/min). 3- (^-Nitrophenyl)-TH-1,2,4-triazole 3-(o-Nitrophenyl)-1H-1,2,4-triazole was synthesized, as described above, in 10% yield (1.0 g, 4.2 mmole) from A^-5-(o-nitrophenyl)-1,2,4- triazole-3-thione, MP 170-171 °C (1,2-dichloroethane) [lit*^ 167 °C (water)]; ^H FT-NMR (acetone-dg) Hz 6 7.70 (m, 3H), 8.03 (m, 1H), and 8.54 (s, 1H); IR (KBr) cm-1 3000-2600 (s, bd), 1600 (m, C=C ring stretch), 1520 (s, M02 asymmetric absorption), and 1340 (s, N02 symmetric absorption); UV (water), X[log(c)] 213-9 (3-9) and 263-2 (3-5); UV (ethyl acetate), X[log(e)] 254 (3.6); retention times: HPLC 3.6 min; GLC 17.43 min (column temp 280 °C, He flow rate 18 ml/min). 183 Method C; from £^-Triazolo[3,4-a]phthalazine A solution of s^triazolo[4,3-a_]phthalazine (0.81 g, 0.7 mmole) and barium hydroxide octahydrate (0.64 g, 2.0 mmole) in water (34 ml) was refluxed for 12 hr and then cooled to room temperature and neutralized with ammonium carbonate. The suspension was filtered and the filtrate concentrated in vacuo (1 mm Hg) to a solid. The solid was separated by TLC (two 1 mm thick plates were used and each plate developed twice using ethyl acetate). The bands with Rf 0.6 were scraped and extracted with methanol (150 ml) for 15 min. The extracts were filtered and concentrated to 3-(o-cyanophenyl)-IH-l,2,4-triazole (0.26 g, 1.5 mmole, 34% yield): mp 189.5-190 °C (lit67 193 °C); MS (70 eV), m/e (relative intensity, M+-fragment) 170.0591 (13.68; calcd for CgHgNjj 170.05923), and 128.0380 (11.41); 1H FT-NMR (acetone-dg) Hz 6 7-80 (m, 3H), 8.18 (m, 1H), and 8.60 (s, 1H); UV (water), X[log( )] 288.3 (3*3) and 241.4 (3.9), 211.5 (4.4); UV (ethyl acetate), X[log( )] 254 (4.0). Preparation of 3H-1,2,4-Triazole-3-diazonium Salt To a solution of concentrated nitric acid (2 ml) between 0 to 10 °C was added a solution of 3-amino-3.H-1,2,4-triazole (1.0 g, 11.9 mmole) and sodium nitrite (1.0 g, 14.4 mmole) in water (10 ml) cooled so the temperature of the diazotizing mixture remained below 0 °C. The resulting slightly yellow degassing solution was stirred for 5 min in an ice bath. This procedure consistently gave a solution of 3JH-1,2,4-tria- zole-3-diazonium ions which was immediately usable for preparation of 3- diazo-3H.-1,2,4-triazole or for thermolysis in various organic solvents. 184 Preparation of 3-Diazo-3H.-1,2,4-triazole An aqueous solution of 1_H—1,2,4-triazole-3-diazonium ions, prepared as described above, was cooled below -4 °C and made basic (pH 9 to 11) by dropwise addition of 2.6 N aqueous potassium hydroxide; the tempera ture of the diazotized solution remained below 2 °C. The resulting red degassing solution was diluted with water to a volume of 40 ml. This procedure led to the destruction of any precipitate formed and consis tently gave an aqueous solution of 3-diazo-3H-1,2,4-triazole usable immediately. Isolation of 3-Diazo-3H-1,2,4-triazole An aqueous solution of 3-amino-1H-1,2,4-triazole (0.869 g, 1.03 mmole) was diazotized with potassium nitrite (0.0984 g, 1.2 mmole) and tetrafluoroboric acid (0.68 g, 7.7 mmole). The aqueous solution was stirred for 5 min at 0 °C, neutralized with solid sodium bicarbonate and extracted with methylene chloride (three 10 ml portions) at 0 °C. The organic phase was dried (Na2S0ij) and concentrated to 3-diazo-3H.-1,2,4- triazole, a white solid (0.0635 g, 0.67 mmole, 65% yield.) Explosive Behavior of 3-Diazo-3H.-1,2,4-triazole A freshly prepared aqueous solution of 3-diazo-3H.-1,2,4-triazole was extracted with methylene chloride (three 50 ml portions) at 0 °C. The combined extracts were dried (Na2S0i,), filtered and concentrated in vacuo to a slightly orange solution (<5 ml). This solution was applied to a TLC plate (1 mm thick) and the plate developed with ethyl acetate 185 to give one band (R^. 0.3). The plate was allowed to dry in the air for less than a minute. When the band was touched with a spatula the band exploded producing a small white cloud of silica gel. Infrared Spectrum of 3-Diazo-3JH-1,2,4-Triazole A freshly prepared methylene chloride solution of 3-diazo-3H.-1,2,4- triazole was prepared and concentrated as described in the previous ex periment. A portion of this concentrate was placed in one cell of a set of matched IR cells and the IR spectrum of the solution taken. The IR 1 spectrum had a major peak at 2200 cm indicating the solution contained a diazo compound. The complete IR spectrrum is as follows: IR(NaCl, methylene chloride) cm“ ^ 2200 (s), 1640 (w), 1560 (w), 1000 (m). Determination of the Amount of 3-Diazo-3H-1,2,4-triazole in Organic Solutions A freshly prepared aqueous solution of 3-diazo-3.H-1,2,4-triazole, at pH 9, was extracted with methylene chloride (three 100 ml portions) at 0 °C. The combined extracts were allowed to warm to room temperature overnight while the gases evolved were collected. Simultaneously an equal volume of methylene chloride (300 ml) at 0 °C was warmed to room temperature overnight while the vapor evolved was collected. The difference in the volumes of gases trapped (about 40 ml) was attributed to nitrogen evolved by decomposition of 3-diazo-3H.-1,2,4-triazole. From the ideal gas law, this difference in volume indicates that about 0.16 mmole of diazo compound was extracted into the methylene chloride. 186 Similarly, the amounts of 3-diazo-3j1-1,2,4-triazole extracted into cyclohexane, benzene and toluene were determined to be approximately 1.6 mmole. The amounts of 3-diazo-3JH-1,2,4-triazole extracted into chloro- benzene, bromobenzene, benzonitrile, methyl benzoate, anisole and nitrobenzene were determined by warming individual solutions of 3- diazo-3.H-1,2,4-triazole from 0° to 80 °C in 1 hr. The volumes of gas evolved and hence the mmoles of 3-diazo-3.H-1,2,4-triazole extracted into the monosubstituted benzenes are similar as shown in Table 8. ESR Spectra A freshly prepared aqueous solution of 3-diazo-3H.-1,2,4-triazole, at pH = 9, was extracted with methylene chloride (ten 50 ml portions) at 0 °C. The combined extracts were dried (Na2S0ij), filtered and concen trated in vacuo to a pale yellow solid. Dry tetrahydrofuran (5 ml) was added to the solid to give a white suspension in a yellow solution. The solution was transferred to a 4-mm Suprasil quartz ESR sample tube and immediately frozen in liquid nitrogen. This sample was sealed under vacuum, following 3 freeze-pump-thaw cycles to remove traces of oxygen, and returned the sample to the liquid nitrogen until the ESR spectrum could be obtained (about 5 min). The sample was then immersed in liquid nitrogen in a quartz dewar positioned in the cavity of a Varian E— 112 X-band ESR spectrometer equipped with a modified microwave cavity which admitted light through a series of louvres on one side. The sample was irradiated for a brief time (60-100 s) using a Sohoeffel 1000-W high-pressure Hg-Xe lamp and a water-cooled aqueous CuSOjj filter (pyrex, 0.1 M, 2 cm path length) to remove ultraviolet and infrared 187 radiation. Coincident with shuttering the lamp the ESR spectrum of the sample was obtained at 10 mW of microwave power. The spectra showed only one signal at 3255 G. Following this the sample was removed from the cavity and the solution was observed to degass on warming. The solid was dissolved in toluene (100 ml) and the mixture warmed to 80-90 °C for 1 hr producing 150 ml of gas. The solution was cooled to room temperature and concentrated in vacuo to a solid. The residue was adsorbed on silica gel (5 g) using ethyl acetate (5 ml) and methanol (5 ml) and chromatographed over silica gel (20 g) eluting with ethyl acetate (250 ml). The eluent was concentrated to 353.4 mg (2.2 mmole, 20% overall yield) of 3-(tolyl)-111-1,2,4-triazoles. HPLC analysis showed the mixture to be 37% ortho, 11% meta, and 51% para. General Procedure for Effecting Coupling and Cycloaddition Reactions of 3-Diazo-3H-1,2,4-triazole A freshly prepared aqueous solution of 3-diazo-3H-1,2,4-triazole was extracted with methylene chloride (four 50 ml portions) at 0 °C. To the combined extracts was added the reagent to be coupled or to undergo cycloaddition and the resulting solution was left standing in a refrig erator (12 to 18 h). The mixture was concentrated to a solid under house vacuum on a rotary evaporator. The residue was worked up as described in the individual experiments. 188 Coupling with N,N-dimethylaniline 3-Diazo-3H-1,2,4-triazole was coupled with N,N-dimethylaniline (1.5 ml, 1.44 g, 11.9 mmole) to give a red residue which was concentrated to a solid under vacuum (1mm Hg). The solid was recrystallized from methanol to give 1H.-1,2,4-triazole-3-azo-1,-[4'-(N,N-dimethylaniline)] as a red solid in 80% yield (172 mg, 0.8 mmole): mp 226-226.5 °C (methanol) [lit11a 230°C (EtOH)]; 1H NMR (CDClg/DMSO-dg) Hz 6 8.2 (s, 1H), 7.9 and 6.7 (AB quartet, J = 0.9 Hz, 4H), and 3.1 (s, 6H); IR(KBr) cm-1 3110 (m), 2900 (m), 1600 (s), 1530 (m), 1410 (m), 1370 (m), 1250 (four overlapping peaks, m), 1150 (s), 980 (w), 950 (w), 830 (m). Coupling with 8-Naphthol A solution of 8-naphthol (1.71 g> 11.9 mmole) in methylene chloride (100 ml), on coupling with 3-diazo-3H.-1,2,4-triazole, gave a brown- orange residue. This residue was triturated with benzene (10 ml), vacuum filtered and the cake washed with cold ethanol (5 ml) and ether (10 ml). The orange solid was dried in a drying pistol to give IH7 1,2,4-triazole-3-azo-1'-(2 '-naphthol) in about 40% yield (100 mg, 0.4 mmole): mp 264-265 °C (lit1,2,10b 269-272 °C); IR(KBr) cm" 1 3400 (m), 3110-2700 (s, bd), 1660 (m), 1530 (s), 1470 (m), 1300 (m), 1250 (m), 1200 (s), 970 (m), 820 (m), 760 (m), 730 (m, bd). Reaction with 1-Cyclohexenyl Ethyl Ether 3-Diazo-3H.-1,2,4-triazole was coupled with 1-cyclohexenyl ethyl ether (5 ml). The concentrate was chromatographed over silica gel (20 g) eluting with ethyl acetate (100 ml) to give 189 [ 1,2,4]triazolo[5,1-c2 ]cyclohexa[e^l [ 1,2,4]-triazine (152.0 mg, 0.87 mmole): mp 18U— 185 °C (1,2-dichloroethane); "*H NMR (CDCl^) Hz 6 7.8 (s, 1H, triazole ring), 2.2 (4H, m) and 1.8 (4H, m); IR (KBr) cm-1 3250-2800 (s, bd), 1650 (m), 1600 (s), 1550 (s), 1530 (s), 1200 (s), 970 (m), 910 (m), 900 (m), 800 (s); MS (70 eV), m/e (M+-fragment, relative intensity) 175.0861 (M+ , 100.00); retention time: HPLC 2.2 min. Reaction with 1-(Piperidino)cyclohexene 1-(Piperidino)cyclohexene (5 ml) was added to 3-diazo-3H_-1,2,4- triazole. The oily residue was chromatographed over silica gel (25 g) eluting with ethyl acetate (300 ml) to give 0.4271g (2.4 mmole) of [1,2,4]triazolo[5,1-c]cyclohexa[e][1,2,4]triazine as described previous ly: 1H NMR (CDCl^) Hz 6 7.8 (s, 1H, triazole ring), 2.2 (4h, m) and 1.8 (4H, m). Reaction with 1-(Morpholino)cyclohexene 3-Diazo-3_H-1,2,4-triazole and 1-(morpholino)cyclohexene (5 ml) yielded a solid. Chromatography employing silica gel and eluting with ethyl acetate (150 ml) gave 281.3 mg (1.6 mmole) of [1,2,4]triazolo[5,1- cJcyclohexa[e_] [ 1,2,4]triazine: 1H NMR (CDCl^) Hz 6 7.8 (s, 1H, triazole ring), 2.2 (4H, m) and 1.8 (4H, m). Reaction with 1-(N-Pyrrolidinyl)cyclohexene 1-(N-Pyrrolidinyl)cyclohexene (5 ml) was added to 3-diazo-3H.-1,2,4- triazole. The oily product was placed on two TLC plates and the plates developed with ethyl acetate. The bands with R^ 0.3 were scraped and 190 extracted with methanol (100 ml) for 15 min. The extracts were filtered and concentrated to 248.1 mg (1.4 mmole) of [1,2,4]triazolo[5,1-c_]cyclo- hexa[ 2.2 (4H, m) and 1.8 (4H, m). Cycloaddition to 1-Ethoxypropyne Addition of 3-diazo-3j1-1,2,4-triazole to 1-ethoxypropyne (25 ml) yielded a black oil (0.66 g) which was chromatographed over silica gel (10 g) eluting with ethyl acetate (100 ml) to give 78.5 mg of a red oil. This oil was placed on two TLC plates and the plates developed with ethyl acetate. The bands with Rj, 0.5 were scraped and the combined scrapings were extracted with methanol (150 ml) for 15 min. The extracts were filtered and concentrated to 7-ethoxy-6-methyl[1,2,4]triazolo[5,1- £.] [1,2,4]triazine: mp 97-98 °C (1,2-dichloroethane): 1H NMR(acetone- d6) Hz 6 8.0 (s, 1H), 4.2 (q, J = 0.6, 2H), 2.2 (s, 3H), 1.0 (t, J = 0.6, 3H); IR (KBr) cm"1 3100 (w), 2890 (w), 1700 (m), 1580 (m), 1540 (m), 1260 (s), 1200 (m), 1090 (m); MS (70 eV), m/e (M+-fragment, relative intensity) 179.080 (M+, 24.66), 151.0568 (33*98). Addition to Phenyl Isocyanate Reaction of 3-diazo-3H.-1,2,4-triazole and phenyl isocyanate (15 ml) yielded a black oil which was concentrated to a brown solid under vacuum (1 mm Hg). This solid was triturated with hexane (200 ml) and chromato graphed over silica gel (20 g) eluting with ethyl acetate. The first fraction (700 ml) concentrated to 90 mg of diphenyl urea, the second fraction (500 ml) yielded 170 mg of 6-phenyl-[1,2,4]triazolo[5,1-e]- 191 [1,2,3,5]tetrazin-7-one as an orange solid: mp 148-149 °C (dec); NMR (acetone-dg) Hz 6 6.5-7.5 (aromatic), IR (KBr) cm“ ^ 3600-3400 (m, bd), 1640 (s), 1600 (m), 750 (m), 730 (m, shoulder), 700 (m); MS (70 eV), decomposed. The producted decomposed on attempted recrystallization from 1,2-dichloroethane. General Procedure for Thermolysis of 3-Diazo-3H.-1,2,4-triazole in Alcohol/Water Solutions A freshly prepared aqueous solution of 3-diazo-3H.-1,2,4-triazole at 0 °C and pH = 9 was added to an alcohol (40 ml). The degassing solution/emulsion was cooled to 0 °C and stirred for 2 hr. The gas evolved was passed through a solution of 2,4-dinitrophenylhydrazine (2,4-DNP; 3.8 g, 19 mmole), concentrated sulfuric acid (15 ml), ethanol (70 ml), and water (20 ml). The resulting mixture was distilled into the 2,4-DNP solution. (The reactions were run in a sealed 250 ml round bottom flask. The aqueous solution of 3-diazo-3H-1,2,4-triazole. was added via an addition funnel through one neck of the flask and the gases were directed through the other neck into the 2,4-DNP solution via a one piece distillation head and condenser fitted with a long stem vacuum adapter. The stem of the vacuum adaptor was inserted to the bottom of the 2,4-DNP solution so all the gases and the distillate were introduced below the surface of the 2,4-DNP solution.) The resulting orange sus pension gave a homogeneous solution on heating which deposited crystals on cooling. The orange 2,4-dinitrophenylhydrazone derivative was col lected by vacuum filtration and dried in a vacuum desiccator. Some 192 examples of thermal decompositions of 3-diazo-3H.-1,2,4-triazole in mix tures of alcohols and water are presented here and are summarized in Table 9. Thermolysis in Methanol Thermolysis of 3-diazo-3H-1,2,4-triazole in methanol led to formal dehyde 2,4-dinitrophenylhydrazone in 14% yield (0.35 g, 1.7 mmole): mp 160— 161 °C (lit**1*® 166 °C). No effort was made to maximize the overall yield in this experiment. Caution: Decomposition in methanol is so rapid that the rate of addition of the solution of 3-diazo-3H.-1,2,4- triazole must be carefully monitored in order to keep gas evolution under control. Thermolysis in Ethanol Decomposition of 3-diazo-3H.-1,2,4-triazole in ethanol produced acetaldehyde 2,4-dinitrophenylhydrazone in 61% overall yield (1.63 g, 7.2 mmole): mp 146-147 °C (lit146 147 °C). Thermolysis in 2-Propanol Thermolysis of 3-diazo-3H.-1,2,4-triazole in 2-propanol resulted in production of acetone 2,4-dinitrophenylhydrazone in 50% overall yield (1.43 g, 6.1 mmole): mp 123-124 °C (lit146 126 °C) Thermolysis in Cyclohexanol Thermolysis of 3-diazo-3H-1,2,4-triazole in cyclohexanol produced cyclohexanone 2,4-dinitrophenylhydrazone in 34% overall yield (1.13 g> 4.1 mmole): mp 157-158 °C (lit1116 160 °C). 193 Thermolyses of 3-Diazo-3j1-1,2,4-triazole in Benzenoid Solvents General Procedure A freshly prepared aqueous solution of 3-diazo-3H_-1, 2,*l-triazole (pH = 9 unless otherwise indicated) was extracted with an organic solvent (three 70 ml portions) at 0 °C. The resulting extract was (1) left in a refrigerator at 0 to 5 °C overnight (12 to 18 hr), (2) added dropwise (via an ice-cooled addition funnel) to additional solvent at 79 to 81 °C and heated there for 0.5 hr and, (3) added dropwise (via an ice cooled addition funnel) to additional solvent heated to reflux and then the mixture was refluxed further for 0.5 hr. The solution was cooled to room temperature and concentrated in vacuo (2 mm Hg). The solid residue was dissolved in methanol (20 ml), adsorbed on silica gel (5 g) and then chromatographed over silica gel (25 g) with ethyl acetate (150 ml). The eluent was concentrated in vacuo (20 mm Hg) to a solid. The existence and identity of the ortho, meta, and para 3-(substi tuted phenyl)-1H-1,2,4-triazoles produced in all reactions but from benzonitrile and methyl benzoate were established by comparison with authentic samples. The major isomers from the thermolyses in anisole, toluene, chlorobenzene and nitrobenzene at 80 °C were separated by MPLC 1 and their melting points, H-NMRs, IRs, and HPLC, and GLC retention times were determined and compared with those of appropriate authentic samples. The major isomers from the thermolyses in benzonitrile and methyl benzoate were isolated by MPLC and identified by NMR spectro scopy. The minor isomers from the decompositions in anisole, toluene, chlorobenzene, and nitrobenzene and all isomers from decomposition in 194 the remaining benzenoid solvents were identified by comparison of the HPLC and GLC retention times of authentic samples with the materials produced from the thermolyses. The ratios of the isomeric 3-(substituted phenyl)-1H-1,2,4-triazoles produced were determined by HPLC and GLC methods and application of the standard curves described from pages 53 to 55. Each chromatogram was examined for the total product peak area and the percentage each product peak contributed to the total peak area. The ratios of the peak areas of the 3-(substituted phenyl)-1ji-1,2,4-triazoles were used in conjunc tion with the standard curves to determine the moles and the percent isomer ratio of the substituted triazole produced. Specific examples of thermolysis of 3-diazo-3H-1,2,4-triazole in various organics are pre sented here. The results are summarized in Table 21 and are discussed in detail in the text. Thermolysis in Benzene, 80 °C Thermolysis of 3-diazo-3H.-1,2,4-triazole in benzene was performed according to procedure 2. Isolation of the product as described above gave 67 mg (0.5 mmole, ca 36% yield) of 3-phenyl-1H-1,2,4-triazole. Thermolyses in Toluene, 0 °C Thermolyses of 3-diazo-3.H-1,2,4-triazole in toluene were effected twice according to procedure 1 to give 3-(tolyl)-1jtf-1,2,4-triazoles separable by HPLC as follows: (1) 60 mg (0.4 mmole); HPLC peak areas: 36% ortho, 8% meta, and 56% para, (2) 50 mg (0.3 mmole); HPLC peak 195 areas: 32% ortho, 17% meta, and 46% para. The HPLC results average as follows: 37% ortho, 13% meta, and 50% para. The above products were also scanned by GLC (column temp 220 °C, He flow rate 7 ml/min). The meta isomer did not separate from the para isomer under these conditions. The GLC peak areas for products 1 and 2 are: (1) 62% ortho and 37% meta and para, and (2) 60% ortho and 40% meta and para. Thermolyses in Toluene, 80 °C Thermolyses of 3-diazo-3H.-1,2,4-triazole, obtained from an aqueous solution having the indicated pH, were conducted 6 times in toluene according to procedure 2 to give 3-(tolyl)-1Jl-1 ,2,4-triazoles separable by HPLC as follows: (1) pH = 9, 90.0 mg (0.6 mmole); HPLC peak areas: 37% ortho, 7% meta, and 56% para, (2) pH = 9, 87.1 mg (0.5 mmole); HPLC peak areas: 34% ortho, 8% meta, and 58% para, (3) pH = 9, 70.7 mg (0.4 mmole); HPLC peak area: 38% ortho, 8% meta, and 54% para (4) pH = 9, 80.0 mg (0.5 mmole); HPLC peak area: 37% ortho, 10% meta, and 53% para, (5) pH = 11, 41.0 mg (0.5 mmole); HPLC peak area: 36% ortho, 11% meta, and 52% para, and (6) pH = 12, 8.0 mg (0.45 mmole); HPLC peak areas: 33% ortho, 7% meta, and 59% para. The average isomer percen tages by HPLC were 3i% ortho, 8% meta, and 57% para. The products of the first four thermolyses were also scanned by GLC (column temp 220 °C, He flow rate 7 ml/min). The meta isomer did not separate from the para isomer under these conditions. The GLC peak areas for the first three experiments were: (1) 69% ortho and 31% meta and para, (2) 62% ortho and 38% meta and para, (3) 67% ortho and 33% 196 meta and para and (4) 68% ortho and 32% meta and para. The average isomer peak area percentages are 67% ortho and 33% meta and para. The residues from the first four thermolyses were combined (318 mg) and separated by MPLC to give (1) 145-9 mg (0.9 mmole) of 3-(.o-tolyl)- 1H-1,2,4-triazole (isolated from fractions 33 to 38): mp 171-172 °C (1,2-dichloroethane); 1H FT-NMR (acetone-d6) Hz 6 2.6 (s, 3H), 7.29 (m, 4h ), 7.90 (m, 1H), and 8.34 (s, 1H); MS (70 eV), m/e (relative inten sity, M+-fragment) 159.0796 (M+ , 100.00; calcd for CgHgN3 159.07964), 132 (M+-CHN, 8.21), 131 (M+-N2 , 12.81), 118 (M+-CHN2, 36.12), and 117 (M+-CH2N2, 4.42), and (2) 129-8 mg (0.8 mmole) of 3-(£-tolyl)-1H-1,2,4- triazole (isolated from fractions 46 to 65): mp 135-136 °C (1,2-di- chloroethane); 1H FT-NMR (acetone-d6) Hz 6 2.37 (s, 3H), 7.23 (s, 1H), 7-33 (s, 1H), 7.95 (s, 1H), 8.27 (s, 1H), and 8.31 (s, 1H); MS (70 eV), m/e (relative intensity, M+-fragment) 159.0793 (M+ , 16.91; calcd for C9H9N3 159.07964), 158.0735 (M+-H, 5.27), 132.0666 (M+-HCN, 10.25), 131.0597 (M+-N2 , 14.89), and 118.0629 (M+-CHN2 , 5.16). Thermolyses in Toluene, 110 °C Two thermolyses of 3-diazo-3H.-1,2,4-triazole in toluene were performed according to procedure 3 to give 3-(tolyl)-1H-1,2,4-triazoles separable by HPLC as follows: (1) 52.9 mg (0.3 mmole); HPLC peak areas: 66% ortho, 5% meta, and 29°/° para; and (2) 60.3 mg (0.4 mmole); HPLC peak areas: 32% ortho, 20% meta, and 48% para. The average isomer percentages are 49% ortho, 12.5% meta, and 38.5% para. 197 Thermolyses in Anisole, 80 °C Thermolyses of 3-diazo-3H.-1,2,4-triazole, obtained from an aqueous solution having the indicated pH, were performed in anisole four times according to procedure 2 to give 3-(methoxyphenyl)-121-1,2,4-triazoles separable by HPLC as follows: (1) pH 9, 158.9 mg (0.9 mmole); HPLC peak areas: 57% ortho, 6% meta, and 37% para, (2) pH 9, 49.5 mg (0.9 mmole); HPLC peak areas: 50% ortho, 5% meta, and 44% para, (3) pH 9, 158. mg (0.9 mmole); HPLC peak areas: 53% ortho, 5% meta, and 43% para and (4) pH 11, 28. mg (0.2 mmole); HPLC peak areas: 50 % ortho, 5% meta, and 45% para. Averaging the HPLC results from the first three experiments give 53% ortho, 5% meta, and 41% para as isomer percentages. The products from the first three experiments were also examined by GLC (column temp 250 °C, He flow rate 7 ml/min). The meta isomer did not separate from the para isomer under these conditions. The GLC peak area percentages for the products were: (1) 69% ortho and 31% meta and para, (2) 90% ortho and 10% meta and para, and (3) 82% ortho and 18% meta and para. The average GLC peak area percentages are 80% ortho and 20% meta and para. The residues from the first three thermolyses were combined (403 mg) and separated by MPLC to give (1) 162.6 mg (0.9 mmole, ca 4C% yield) of 3-(£-methoxyphenyl)-1FI-1,2,4-triazole (isolated from fractions 27 to 40): mp 182-183 °C (1,2-dichloroethane); ^H FT-NMR (acetone-dg) Hz 6 4.09 (s, 3H), 7.27 (m, 3H), 7.93 (s, 1H), and 8.33 (m, 1H); MS (70 eV), m/e (relative intensity, M+-fragment) 175.0745 (M+, 38.66; calcd for C9H9N30 175.07455), 174.0665 (M+-H, 30.81), 148.0707 (M+-CHN, 1.33), 198 147.0634 (M+-N2 , 5.47), 146.0700 (M+-CH0, 19-48), 145.0621 (M+-CH20, 15.21), 134.0555 (tT*‘-CHN2, 1.45), and 133.0562 (M+-CH2N2 , 2.13), and (2) 101.0 mg (0.6 mmole, ca 25% yield) of 3-(jwnethoxyphenyl)-111-1,2,4- triazole (isolated from fractions 58 to 61): mp 174-175 °C (1,2-dichlo- roethane); FT-NMR (acetone-dg) Hz 6 3.85 (s, 3H), 6.97 (s, 1H), 7.08 (s, 1H), 7.99 (s, 1H), 8.10 (s, 1H), and 8.24 (s, 1H); MS (70 eV), m/e (relative intensity, M+-fragment) 175.0745 (M+ , 53.22; calcd for CgHgNgO 175.07455), 134.0590 (M+-CHN2 , 12.90), and 133.0490 (M+-CH2N2, 9.07). Thermolysis in Anisole, 154 °C Two decompositions of 3-diazo-3H-1,2,4-triazole in anisole performed according to procedure 3 gave 3-(methoxyphenyl)-1H^1,2,4-triazoles separable by HPLC as follows: (1) 135.1 mg (0.8 mmole); HPLC peak area percentages: 79% ortho, 4% meta, and 16% para, (2) 102. mg (0.6 mmole); HPLC peak areas: 62% ortho, 9% meta, and 29% para. The results of averaging give the isomer ratio 70% ortho, 7% meta, and 23% para. The products were examined by GLC (column temp 250 °C, He flow rate 7 ml/min). The meta isomer did not separate from the para isomer under these conditions. The GLC peak area percentages for products are: (1) 80% ortho and 20% meta and para, and (2) 80% ortho and 20% meta and para. 199 Thermolyses in tert-Butylbenzene, 80 °C 3-Diazo-3H.-1,2,4-triazole was thermolyzed 3 times in tert-butyl- benzene according to procedure 2 to give 3-(tert-butylphenyl)-1H-1,2,4- triazoles separable by HPLC as follows: (1) 119.4 mg (0.6 mmole); HPLC peak areas: 5% ortho, 27% meta, and 68% para; (2) 140.7 mg (0.7 mmole); HPLC peak areas: 4% ortho, 21% meta, and 75% para, and (3) 100.5 mg (0.5 mmole); HPLC peak areas: 6% ortho, 24% meta, and 70% para. The average isomer composition is 5% ortho, 21% meta, and 73% para. Thermolyses in tert-Butylbenzene, 169 °C 3-Diazo-3j1-1,2,4-triazole was decomposed 3 times in tert-butylben- zene according to procedure 3 to give 3-(tert-butylphenyl)-1H-1,2,4- triazoles separable by HPLC as follows: (1) 131.4 mg (0.7 mmole); HPLC peak areas: 4% ortho, 29% meta, and 67% para, (2) 127.5 mg (0.6 mmole); HPLC peak areas: 2% ortho, 30% meta, and 65% para and (3) 135.6 mg (0.7 mmole); HPLC peak areas: 2% ortho, 27% meta, and 71% para. Thermolyses in Fluorobenzene, 80 °C 3-Diazo~3H.-1,2,4-triazole was decomposed in fluorobenzene 3 times according to procedure 2 and yielded 3-(fluorophenyl)-1fr-1,2,4-triazoles separable by HPLC as follows: (1) 185.7 mg (1.1 mmole); HPLC peak area percentages: 57% ortho, 14% meta, and 29% para; (2) 146.7 mg (0.9 mmole): HPLC peak areas: 43% ortho, 13% meta, and 43% para; (3) 200 130.4 mg (0.8 mmole); HPLC peak areas: 50% orbho, 15% meta, and 35% para. The results of averaging are 50% ortho, 1*1% meta, and 36% para. Thermolyses in Chlorobenzene, 0 °C Three decompositions of 3-diazo-3,H-1,2,4-triazole in chlorobenzene were effected as in procedure 1. 3-(Chlorophenyl)-1FL-1,2,4-triazoles separable by HPLC were obtained as follows: (1) *10 mg (0.2 mmole, 28% yield); HPLC peak area percentages: *10% ortho, 8% meta, and 52% para, (2) 70 mg (0.*1 mmole, 50% yield); HPLC peak areas: 3*1% ortho, 6% meta, and 60% para, and (3) 50 mg (0.3 mmole, 35% yield); HPLC peak areas: 26% ortho, 6% meta, and 58% para. The average isomer percentage is 31% ortho, 7% meta, and 59% para. Thermolyses in Chlorobenzene, 80 °C 3-Diazo-3.H-1,2,*l-triazole, obtained from an aqueous solution having the indicated pH, was thermolyzed in chlorobenzene *1 times according to procedure 2 to give 3-(chlorophenyl)-1ji-1,2,4-triazoles separable by HPLC as follows: (1) pH 9, 101.3 mg (0.6 mmole, 71% yield); HPLC peak areas: 33% ortho, 6% meta, and 56% para, (2) pH 9, 77.*1 mg (0.*1 mmole, 50% yield); HPLC peak areas: 30% ortho, 8% meta, and 58% para, (3) pH 9, 87.2 mg (0.4 mmole, 50% yield); HPLC peak areas: 26% ortho, 6% meta, and 58% para, and (4) pH 11, 48.8 mg (0.5 mmole, 50% yield); HPLC peak areas: 31% ortho, 7% meta, and 54% para. The average of the HPLC peak areas is 31% ortho, 7% meta, and 61% para. The products were also scanned by GLC (column temp 270 °C, He flow rate 9 ml/min). The meta isomer did not separate from the para isomer 201 under these conditions. The GLC peak areas for the three experiments are: (1) 59% ortho and 41% meta and para, (2) 51% ortho and 49% meta and para, (3) 55% ortho and 45% meta and para and (4) 55% ortho and 45% meta and para. The average isomer peak area percentages are 55% ortho and 45% meta and para. The residues from the first 3 thermolyses were combined (249.8 mg) and separated by MPLC to give (1) 93.8 mg (0.5 mmole, 28% yield) of 3- (o^chlorophenyl)-1H-1,2,4-triazole (isolated from fractions 30 to 34): mp 152-154 °C (1,2-dichloroethane); FT-NMR (acetone-dg) Hz 6 7.50 (m, 3H), 7.92 (m, 1H), and 8.36 (s, 1H); MS (70 eV), m/e (relative intensity, M+-fragment) 181.0220 (M++2, 33.68), 179.0250 (M+ , 100.00; calcd for CgHgNgCl 179.02501), 152.0119 (M+-HCN, 8.48), 151.0152 (M+-N2 , 9.18), 138.0100 (M+-CHN2, 62.89), and 137.0036 (M+-CH2N2, 2.25); and (2) 105.6 mg (0.6 mmole, 32% yield) of 3-(_£-chlorophenyl)-1H-1,2,4-triazole (isolated from fractions 38 to 52): mp 193-194 °C (1,2-dichloroethane); 1H FT-NMR (acetone-dg) Hz 6 7.44 (s, 1H), 7.52 (s, 1H), 8.07 (s, 1H), 8.18 (s, 1H), and 8.45 (s, 1H); MS (70 eV), m/e (relative intensity, M+- fragment) 181.0232 (M++2, 33.17), 179.0253 (M+ , 100.00; calcd for CgHgNgCl 179.02501), 152.0111 (M+-HCN, 24.49), 151.0140 (M+-N2 , 3.49), 138.0086 (M+-CHN2 , 22.79), and 137.0035 (M+-CH2N2, 4.01). Thermolyses in Chlorobenzene, 132 °C Thermolyses of 3-diazo-3H.-1,2,4-triazole, obtained from an aqueous solution having the indicated pH, were effected 3 times in chlorobenzene according to procedure 3 to give 3-(chlorophenyl)-111-1,2,4-triazoles separable by HPLC. Experiment 1, pH 9, gave 90 mg (0.5 mmole, 63% 202 yield); HPLC peak areas 60% ortho, 6% meta, and 3*1% para. Experiment 2, pH 9, gave 80 mg (0.4 mmole, 56% yield); HPLC peak areas 56% ortho, 9% meta, and 35% para. Experiment 3, pH 11, gave 50 mg (0.3 mmole, 56% yield); HPLC peak areas 57% ortho, 10% meta, and 33% para. The average isomer percentage for these two experiments was 58% ortho, 8% meta, and 34% para. Thermolyses in Bromobenzene, 80 °C 3-Diazo-3H-1,2,4-triazole was thermolyzed in bromobenzene 3 times according to procedure 2. 3-(Bromophenyl)-1H^1,2,4-triazoles were obtained and separated by HPLC as follows: (1) 173.6 mg (0.8 mmole); HPLC peak areas: 30% ortho and meta and 70% para, (2) 122.8 mg (0.5 mmole); HPLC peak areas: 31% ortho and meta and 69% para, and (3) 96.3 mg (0.4 mmole); HPLC peak areas: 28% ortho and meta and 72% para. The average of the HPLC peak areas are 30% ortho and meta and 70% para. Thermolyses in Trifluoromethylbenzene, 80 °C Three thermolyses of 3-diazo-3H.-1,2,4-triazole, obtained from an aqueous solution at pH 9, in trifluoromethylbenzene were effected as in procedure 2 to give 3-(trifluoromethylphenyl)-1I1-1,2,4-triazoles. The ortho and meta isomers could not be separated. The results of the ther molyses are as follows: (1) 92.0 mg (0.4 mmole); HPLC peak area percen tages: 84% ortho and meta and 15% para, (2) 127.0 mg (0.6 mmole); HPLC peak areas: 86% ortho and meta and 14% para, and (3) 106.5 mg (0.5 mmole); HPLC peak areas: 76% ortho and meta and 24% para. The HPLC 203 results showed an average isomer percentage of 82% ortho and meta and 18% para. The above products were also scanned by GLC (column temp 180 °C, He flow rate 7 ml/min). The meta and para isomers did not separate from each other under these conditions. The GLC peak areas for products 1-3 are: (1) 100% meta and para, (2) 100% meta and para, and (3) 100% meta and para. Two thermolyses of 3-diazo~3H-1,2,4-triazole, obtained from an aqueous solution at pH 11, were effected in trifluoromethylbenzene as in procedure 2 to give 3-(trifluoromethylphenyl)-1H-1,2,4-triazoles. The results of the thermolyses are as follows: (1) 60.0 mg (0.3 mmole); HPLC peak area percentages: 82% ortho and meta and 17% para, (2) 117.0 mg (0.2 mmole); HPLC peak areas: 88% ortho and meta and 12% para. The average isomer percentage from the HPLC analyses are 85% ortho and meta and 15% para. Thermolyses in Nitrobenzene, 80 °C A neutral aqueous solution of 3-diazo-3H_-1,2,4-triazole (_1_), prepared from 3-amino-1fl-1,2,4-triazole (0.9558 g, 11.4 mmole) via diazotization with sodium nitrite and tetrafluoroboric acid followed by neutralization with sodium bicarbonate, was extracted with methylene chloride (twelve 100 ml portions). The combined organic extracts were dried (Na2 S0 jj), filtered and concentrated in vacuo until crystals started to form. The vacuum was relieved with nitrogen, nitrobenzene (30 ml) introduced and the mixture concentrated further until degassing ceased. The vacuum was again relieved with nitrogen and the solution was blanketed with nitrogen and heated to and at 80 °C until degassing ceased. The product solution contained 1.5 mmole of nitrosobenzene _1_ by GLC analysis. The results indicate that nitrosobenzene is formed in 13% overall yield from 3-amino- 1_H— 1,2,4-triazole and in 20% yield from the amount of _1_ initially present, as inferred from the previous results for isolation of solid _1_. 3-Diazo-3H-1,2,4-triazole, obtained from an aqueous solution at pH 9, was decomposed in nitrobenzene 3 times according to procedure 2 to give 3-(nitrophenyl)-1H-1,2,4-triazoles. The meta and para isomers could not be separated by HPLC. The results of the thermolyses are as follows: (1) 138.6 mg (0.7 mmole, 61% yield); HPLC peak areas: 42% ortho and 58% meta and para, (2) 175.3 mg (0.9 mmole, 77% yield); HPLC peak areas: 41% ortho and 59% meta and para, and (3) 192.2 mg (1.0 mmole, 84% yield); HPLC peak areas: 43% ortho and 57% meta and para. The average isomer ratio by HPLC is 42% ortho and 58% meta and para. The residues from these thermolyses were combined (406.5 mg) and separated by MPLC to give (1) 130.0 mg (0.7 mmole, 32% yield) of 3-(.o- nitrophenyl)-1F?-1,2,4-triazole (isolated from fractions 37 to 34): mp 171.5-172.5 °C (1,2-dichloroethane); 1H FT-NMR (acetone-dg) Hz 5 7.70 (m, 3H), 8.03 (m, 1H), and 8.54 (s, 1H), (2) 109.0 mg (0.6 mmole, 29% yield) of 3-(m-nitrophenyl)-1H-1,2,4-triazole (isolated from fractions 46 to 52): mp 211.0-211.5 °C (1,2-dichloroethane); 1H FT-NMR (acetone- dg) Hz 6 7.86 (m, 1H), 8.58 (m, 3H), and 8.94 (s, 1H), and (3) 24.2 mg (0.1 mmole, 6% yield) of 3-(j>.-nitrophenyl)-111-1,2,4-triazole (isolated form fractions 59 to 70): MP 216-217 °C (1,2-dichloroethane) 1H FT-NMR (acetone-dg) Hz 6 8.36 (s, 4h ) and 8.59 (s, 1H). 3-Diazo-3H-1,2,4-triazole, obtained from an aqueous solution at pH 11, was decomposed in nitrobenzene three times according to procedure 2 to give 3-(nitrophenyl)-1H^1,2,4-triazoles. The results of the thermolyses are as follows: 1) 40.6 mg (0.2 mmole); HPLC peak areas: 71% ortho and 29% meta and para, (2) 48.6 mg (0.3 mmole); HPLC peak areas: 65% ortho and 35% meta and para, and (3) 34.5 mg (0.1 mmole); HPLC peak areas: 67% ortho and 33% meta and para. The average isomer percentages by HPLC are 65% ortho and 32% meta and para. Thermolyses in Nitrobenzene, 210 °C Two decompositions of 3-diazo-3H.-1,2,4-triazole, obtained from an aqueous solution at pH 9, were conducted in nitrobenzene as in procedure 3 to give 3-(nitrophenyl)-1F[-1,2,4-triazoles as follows: (1) 323 mg (1.7 mmole); HPLC peak areas: 61% ortho and 39% meta and para, and (2) 300 mg (1.6 mmole); HPLC peak areas: 54% ortho and 46% meta and para. Averaging the results of the two experiments gives an isomer ratio of 57% ortho and 43% meta and para. Two decompositions of 3-diazo-3H,-1,2,4-triazole, obtained from an aqueous solution at pH 11, were performed in nitrobenzene as in procedure 3 to give 3-(nitrophenyl)-1H-1,2,4-triazoles as follows: (1) 153 mg (0.8 mmole); HPLC peak areas: 60% ortho and 40% meta and para, and (2) 130 mg (0.7 mmole); HPLC peak areas: 55% ortho and 45% meta and para. Averaging the results of the two experiments gives an isomer percentage of 53% ortho and 47% meta and para. Thermolyses in Benzonitrile, 80 °C 3-Diazo-3H-1,2,4-triazole, obtained from an aqueous solution having a pH of 9, was thermolyzed in benzonitrile 3 times according to proce dure 2 to give a mixture 3-(cyanophenyl)-1j1-1,2,4-triazoles as follows: (1) 122.0 mg (0.7 mmole, 70% yield); HPLC peak areas 29°/° ortho, 32% meta, and 39% para, (2) 130.9 mg (0.8 mmole, 80% yield); HPLC peak areas 30% ortho, 35% meta, and 35% para, and (3) 142.7 mg (0.8 mmole, 80% yield); HPLC peak areas 27% ortho, 36% meta, and 37% para. Averaging gave the isomer percentage 29% ortho, 34% meta and 37% para. The residues from these thermolyses were combined (390 mg) and separated by MPLC to give (1) 64.5 mg (0.4 mmole, 16% yield) of 3-(o- cyanophenyl)-1fr-1,2,4-triazole (isolated from fractions 25 to 29): mp 189-190 °C (1,2-dichloroethane); % FT-NMR (acetone-dg) Hz 6 7.81 (m, 3H), 8.21 (m, 1H), and 8.60 (s, 1H); MS (70 eV), m/e (relative inten sity, M+-fragment) 170.0588 (M+ , 13.68; calcd for CgHgNgCl 170.02501) and 128.0380 (M+-CHN2, 11.41), (2) 83.7 mg (0.5 mmole, 21% yield) of 3- (in-cyanophenyl)-1H—1,2,4-triazole (isolated from fractions 32 to 36): mp 93-94 °C (1,2-dichloroethane); ^H FT-NMR (acetone-dg) Hz 6 7-49 (m, 2H), 7.99 (m, 2H), and 8.54 (m, 1H); MS (70 eV), m/e (relative intensity, PT^-fragment) 170.0602 (M+ , 100.00; calcd for CgHgNgCl 179.02501), 143.0465 (M+-HCN, 39-70), 142.0520 (M+-N2 , 5.32), 129.0443 (M+-CHN2, 24.17), and 128.0386 (M+-CH2N2 , 2.68); UV (water), A[log( )] 193.5 (4.6) and 221.8 (4.1); UV (ethyl acetate), X[log( )] 254 (3-2); and (3) 56.6 mg (0.3 mmole, 15% yield) of 3-(j3-cyanophenyl)-1H-1,2,4- triazole (isolated from fractions 37-45): mp 164-165 °C (1,2-dichloro- 207 ethane); FT-NMR (acetone-dg) Hz 6 7.89 (s, 1H), 7.92 (s, 1H), 8.26 (s, 1H), 8.28 (s, 1H), and 8.56 (s, 1H); MS (70 eV), m/e (relative intensity, M+-fragment) 170.0604 (M+ , 35.19; calcd for CgHgNgCl 179.02501), 143.0478 (M+-HCN, 20.63), 142.0561 (M+-N2 , 1.70), 129.0464 (M+-CHN2, 7.75), and 128.0383 ( M ^ C H ^ , 2.34); UV (water), X[log( )] 259.8 (4.2) and 190.0 (4.2); UV (ethyl acetate), X[log( )] 254 (4.0). 3-Diazo-3f1-1,2,4-triazole, pH of the aqueous solution was 11, was thermolyzed in benzonitrile twice according to procedure 2 to give a mixture 3-(cyanophenyl)-1H-1,2,4-triazoles as follows: (1) 65.0 mg (0.7 mmole); HPLC peak areas 34% ortho, 36% meta, and 30% para and (2) 50.6 mg (0.8 mmole); HPLC peak areas 30% ortho, 37% meta, and 33% para. The average isomer percentage is 32% ortho, 37% meta, and 31% para. Thermolyses in Benzonitrile, 191 °C 3-Diazo-3H-1,2,4-triazole, obtained from an aqueous solution of pH 9, was thermolyzed in benzonitrile twice according to procedure 3 to give: (1) 160 mg (0.9 mmole) of a mixture of 3-(cyanophenyl)-1H-1,2,4- triazoles. HPLC analysis of the mixture showed the peak areas of the isomers to be 10% ortho, 80% meta, and 10% para and (2) 160 mg (0.9 mmole) of a mixture of 3-(cyanophenyl)-1]1-1,2,4-triazoles. HPLC analy sis of the mixture showed the peak areas of the isomers to be 10% ortho, 80% meta, and 10% para. The average isomer percentage is 10% ortho, 80% meta, and 10% para. 3-Diazo-3H.-1,2,4-triazole, obtained from an aqueous solution of pH 11, was thermolyzed in benzonitrile twice according to procedure 3 to 208 give a mixture of 3-(cyanophenyl)-1JI-1,2,4-triazoles: (1) 70 mg (0.4 mmole); HPLC analysis 10% ortho, 78% meta, and 12% para and (2) 50 mg (0.3 mmole); HPLC analysis 9% ortho, 79% meta, and 12% para. The average isomer percentage is 10% ortho, 78% meta, and 12% para. Thermolyses in Methyl Benzoate, 80 °C Three decompositions of 3-diazo-3H_-1,2,4-triazole, obtained from an aqueous solution of pH 9, were effected in methyl benzoate as in proce dure 2 to give a mixture of 3-(methoxycarbonyl phenyl)-111-1,2,4-tria zoles separable by HPLC as follows: (1) 215.8 mg (1.0 mmole); HPLC 14% ortho and 86% meta, (2) 227.8 mg (1.1 mmole); HPLC peak areas to be 18% ortho and 82% meta, and (3) 175.9 mg (0.9 mmole); HPLC peak areas 5% ortho and 95% meta. The average isomer percentage is 12% 3-(.o-inethoxy- carbonyl phenyl)-1jI-1,2,4-triazole and 87% 3-(m-methoxycarbonyl phenyl)-1 FI-1,2,4-triazole. The residues from these thermolyses were combined (408.5 mg) and separated by MPLC to give (1) 61.1 mg (0.3 mmole, 15% yield) of 3-(.o- methoxycarbonyl phenyl)-1H- 1,2,4-triazole (isolated from fractions 7 to 11): mp oil (1,2-dichloroethane); ^H FT-NMR (acetone-dg) Hz 6 4.1 (s, 3H), 7.61 (m, 1H), 8.3 (m, 3H), and 8.78 (m, 1H); MS (70 eV), m/e (relative intensity, M+-fragment) 203.0659 (M+ , 5.00; calcd for CgHgNgCl 203.02501) and (2) 257.6 mg (1.2 mmole, 63% yield) of 3-(rn-methoxy- carbonylphenyl)-11^-1,2,4-triazole (isolated from fractions 24 to 37): mp 158-159 °C (1,2-dichloroethane); ^H FT-NMR (acetone-dg) Hz 6 4.1 (s, 3H), 7.61 (m, 1H), 8.3 (m, 3H), and 8.78 (m, 1H); MS (70 eV), m/e 209 (relative intensity, ^-fragment) 203.0659 (M*, 5.00; ealcd for CgHgN^Cl 203.02501). Two decompositions of 3-diazo-3H.-1,2,4-triazole, obtained from an aqueous solution of pH 11, were effected in methyl benzoate as in procedure 2 to give a mixture of 3-(methoxycarbonylphenyl)-1j1-1,2,4- triazoles separable by HPLC as follows: (1) 98.8 mg (0.5 mmole); HPLC 16% ortho and 8*1% meta and (2) 106.8 mg (0.5 mmole); HPLC peak areas to be 14% ortho and 86% meta. The average isomer percentage is 15% 3-(o- methoxycarbonylphenyl)-1fr-1,2,4-triazole and 85% 3-(in-methoxycarbonyl- phenyl)-1_H-1,2,4-triazole. Thermolyses in Methyl Benzoate, 198 °C The thermolyses of 3-diazo-3.H-1,2,4-triazole, (the pH of the aqueous solution was 9), were performed twice in methyl benzoate according to procedure 3 to give mixtures of 3-(methoxycarbonyl phenyl)-1H-1,2,4- triazoles as follows: Experiment 1: 320 mg (1.6 mmole); HPLC peak areas: 28% ortho and 71% meta. Experiment 2: 298 mg (1.5 mmole); HPLC peak areas: 30% ortho and 70% meta. The average isomer percentage is 29% ortho and 71% meta. The thermolyses of 3-diazo-3H.-1,2,4-triazole, obtained from an aqueous solution of pH 11, were performed twice in methyl benzoate according to procedure 3 to give mixtures of 3-(methoxycarbonylphenyl)- 1H-1,2,4-triazoles as follows: (1) 42 mg (0.2 mmole); HPLC peak areas: 31% ortho and 69% meta, and (2) 58 mg (0.3 mmole); HPLC peak areas: 30% ortho and 70% meta. The average isomer percentage is 30% ortho and 70% meta. 210 Photolysis of 3-Diazo-3H-1,2,4-triazole in Benzenoid Solvents A freshly prepared aqueous solution of 3-diazo-3H-1,2,4-triazole, of the indicated pH, was extracted with a benzenoid solvent (300 ml) at 0 °C and the resulting organic solution of 3-diazo-3H.-1 ,2,4-triazole was introduced into a photolytic reactor. The mixture was then irradiated for 2 hr between 0-10 °C with a Hanovia 450-W medium pressure mercury lamp placed in a pyrex immersion well. The resulting solution was concentrated in vacuo. The residue was dissolved in methanol (20 ml), adsorbed on silica gel (5 g) and chromatographed over silica gel (25 g) using ethyl acetate (150 ml). The eluent was concentrated in vacuo to a solid. The identities and the ratios of ortho, meta, and para isomers of the 3-(substituted phenyl)-111-1,2,4-triazoles produced were deter mined by the HPLC methods mentioned previously. Some specific examples of photolyses of 3-diazo-3H.-1,2,4-triazole in varied benzenes are presented here and are summarized in Table 21. Photolyses in Benzene Photolysis of 3-diazo-3H-1,2,4-triazole, extracted from an aqueous solution of pH 9, was performed in benzene as described above to give 96 mg (0.7 mmole, 47% yield) of 3-phenyl-1j1-1,2,4-triazole. Photolyses in Anisole Three photolyses of 3-diazo-3F1-1,2,4-triazole, obtained from an aqueous solution of pH 9, in anisole gave 3-(methoxyphenyl)-1H-1,2,4- triazoles as follows: (1) 40.0 mg (0.2 mmole, 28% yield); HPLC peak 211 areas: 63 % ortho, 5% meta, and 32% para, (2) 1)5.0 mg (0.3 mmole, 32% yield); HPLC peak areas: 51% ortho, 7% meta, and *12% para, and (3) 47.0 mg (0.3 mmole, 33% yield); HPLC peak areas: 50% ortho, 6% meta, and 44% para. The average percent peak areas are 55% ortho, 6% meta, and 39% para. Photolyses of 3-diazo-3H.-1,2,4-triazole, obtained from an aqueous solution of pH 11, in anisole gave 3-(methoxyphenyl)-1H- 1.2.4-triazoles in the percentages, by HPLC analysis, 62% ortho, 6% meta, and 32% para. Photolyses in Toluene 3-Diazo-3.H-1,2,4-triazole,(the pH of the aqueous solution was 9), was photolyzed in toluene 3 times to give 3-(tolyl)-IH-l,2,4-triazoles as follows: (1) 55.0 mg (0.3 mmole); HPLC peak areas: 38% ortho, 11% meta, and 51% para, (2) 48.0 mg (0.3 mmole); HPLC peak areas: 38% ortho, 10% meta, and 52% para, and (3) 40.0 mg (0.3 mmole); HPLC peak areas: 39% ortho, 9% meta, and 52% para. Averaging gave the peak area percentages of 38% ortho, 10% meta, and 52% para. 3-Diazo-3H_- 1.2.4-triazole, from an aqueous solution of pH 11, photolyses in toluene to give, by HPLC, 3-(tolyl)-IH-l,2,4-triazoles in the yields 39% ortho, 9% meta, and 52% para. Photolyses in tert-Butylbenzene Photolyses of 3-diazo-3H_-1,2,4-triazole in tert-butylbenzene were effected twice to give 3-(tert-butylphenyl) — 1H—1,2,4-triazoles as follows: (1) 95.0 mg (0.5 mmole); HPLC peak areas: 9% ortho, 25% 212 meta, and 66% para, (2) 80.0 mg (0.4 mmole); HPLC peak areas: 4% ortho, 27% meta, and 69% para, and (3) 80.0 mg (0.4 mmole); HPLC peak areas: 9% ortho, 28% meta, and 62% para. THe average peak area percentages turned out to be 7% ortho, 27% meta, and 66% para. Photolyses in Fluorobenzene 3-Diazo-3.H-1,2,4-triazole was photolyzed in fluorobenzene 3 times to give 3-(fluorophenyl)-1JH-1,2,4-triazoles as follows: (1) 110.0 mg (0.7 mmole); HPLC peak areas: 56% ortho, 10% meta, and 34% para, (2) 115.0 mg (0.7 mmole); HPLC peak areas: 52% ortho, 10% meta, and 38% para, and (3) 45.0 mg (0.4 mmole); HPLC peak areas: 57% ortho, 15% meta, and 30% para.. The average peak area percentages are 55% ortho, 11% meta, and 34% para. Photolyses in Chlorobenzene Three photolyses of 3-diazo-3.H-1,2,4-triazole were effected in chlorobenzene as described above to give 3-(chlorophenyl)-1j1-1,2,4- triazoles as follows: (1) 114.0 mg (0.6 mmole); HPLC peak areas: 67% ortho, 6% meta, and 27% para, (2) 63.0 mg (0.4 mmole); HPLC peak areas: 52% ortho, 10% meta, and 38% para, and (3) 29-0 mg (0.1 mmole); HPLC peak areas: 62% ortho, 8% meta, and 30% para. The average peak area percentages are 60% ortho, 8% meta, and 32% para. 3-Diazo-3JH-1,2,4-triazole, obtained from an aqueous solution of pH 11, was photolyzed in chlorobenzene as described above to give 3-(chloro- phenyD-IH^I ,2,4-triazoles: 61% ortho, 10% meta, and 29% para. 213 Photolyses in Bromobenzene 3-Diazo-3H-1,2,4-triazole was irradiated in bromobenzene twice to give 3-(brorao phenyl )-1F[-1,2,4-triazoles as follows: (1) 134.0 mg (0.6 mmole); HPLC peak areas: 30% ortho and meta and 70% para, (2) 290.0 mg (0.5 mmole); HPLC peak areas: 39% ortho and meta and 61% para. The average peak area percentage is 35% ortho and meta and 65% para. Photolyses in Trifluoromethylbenzene Photolyses of 3-diazo-3H.-1,2,4-triazole in trifluoromethylbenzene were performed twice at the indicated pHs' to give 3-(trifluoromethyl)- 1H-1,2,4-triazoles as follows: (1) pH = 9, 53.0 mg (0.2 mmole); HPLC peak areas: 84% ortho and meta and 16% para and (2) pH = 11-12, 27.5 mg (0.1 mmol); HPLC peak areas: 79% ortho and meta and 21% para. Averaging gives the peak area percentages: 81% ortho and meta and 19% para. Photolyses in Nitrobenzene Decompositions of 3-diazo-3.H-1,2,4-triazole were performed twice in nitrobenzene at pH = 9 to give 3-(nitrophenyl)-1J3-1,2,4-triazoles as follows: (1) 150.0 mg (0.8 mmole, 66% yield); HPLC peak areas: 60% ortho and 40% meta and para, (2) 163.0 mg (0.9 mmole, 71% yield); HPLC peak areas: 68% ortho and 32% meta and para. The average peak area percentages are 67% ortho and 33% meta and para. The decompositions of 3-diazo-3j1-1,2,4-triazole was performed twice in nitrobenzene at pH = 11-12 to give: (1) 115.0 mg (0.6 mmole); HPLC peak areas: 77% ortho and 23% meta and para, (2) 95.0 mg (0.5 mmole); HPLC peak areas: 81% 214 ortho and 19% meta and para. The average peak area percentages are 79% ortho and 21% meta and para. Photolyses in Methyl Benzoate 3-Diazo-3H-1,2,4-triazole was photolyzed in methyl benzoate three times to give mixtures shown to be 3-(methoxycarbonyl phenyl)-1H-1,2,4- triazoles as follows: (1) 268.0 mg (1.3 mmole); HPLC peak areas: 22% ortho and 78% meta, (2) 296.0 mg (1.4 mmole); HPLC peak areas: 24% ortho and 76% meta, and (3) 212.0 mg (1.0 mmole); HPLC peak areas: 26% ortho and 74% meta. The average peak area percentage is 24% ortho and 76% meta. Photolyses in Benzonitrile Two photolyses of 3-diazo-3.H-1,2,4-triazole in benzonitrile were performed as described above, with the pH of the diazotized solution being 9, to give mixtures of 3-(cyanophenyl)-1H-1,2,4-triazoles as follows: (1) 122.0 mg (0.7 mmole); HPLC peak areas: 43% ortho, 22% meta, and 34% para, (2) 98.0 mg (0.6 mmole); HPLC peak areas: 43% ortho, 21% meta, and 36% para. The average peak area percentages are 44% ortho, 21% meta, and 35% para. Two photolyses of 3-diazo-3H_- 1,2,4-triazole in benzonitrile were performed, with the pH of the diazotized solution being 11-12, as described above to give mixtures of 3-(cyanophenyl)-111-1,2,4-triazoles as follows: (1) 62.0 mg (0.4 mmole); HPLC peak areas: 43% ortho, 22% meta, and 35% para, (2) 98.0 mg (0.6 mmole); HPLC peak areas: 42% ortho, 25% meta, and 33% para. The average peak area percentages are 43% ortho, 24% meta, and 33% para. 215 Thermal Decomposition of 3-Diazo-3H.-1,2,4-triazole in Mixed Solvents General Procedure A freshly prepared aqueous solution of 3-diazo-3H.-1,2,4-triazole was extracted at 0 °C with a mixture of benzene and another organic sub strate (three 70 ml portions). (See the individual experiments for descriptions of the solvent mixtures.) The resulting organic solution of 3-diazo-3j1-1,2,4-triazole was added dropwise, via an ice cooled addition funnel, to more of the solvent mixture heated between 79— 81 °C. The reaction mixture was then heated for 0.5 hr, cooled to room temperature and concentrated in vacuo (2 mm Hg). The residue was dissolved in methanol (20 ml), adsorbed on silica gel (5 g) and chrom atographed over silica gel (25 g) eluting with ethyl acetate (150 ml). The eluent was concentrated in vacuo (20 mm Hg) to a solid. The 3-substituted-1jl-1,2,4-triazoles produced were analyzed by GLC and their ratios determined by application of the standard curves described in Table 10. Each chromatogram was examined for the total product peak area and the percentage each product peak contributed to the total peak area determined. These percentages and the standard curves were used to determine (1) the moles of 3-(substituted)-111-1,2,4- triazole produced per mole of 3-phenyl-1f1-1,2,4-triazole, (2) the isomer ratio of the 3-(substituted phenyl)-1j1-1,2,4-triazoles produced, (3) the molar reactivity, and (4) the relative reactivity reactivity of 3-diazo- 3H.-1,2,4-triazole. Some examples of the thermolyses of 3-diazo~3H.- 1,2,4-triazole in mixed solvents are presented here. An example of 216 the calculations performed is presented in the thermolysis in benzene and anisole at 80 °C. The results are summarized in Table 28. Thermolyses in Benzene and Cyclohexane, 80 °C Thermolyses of 3-diazo-3H.-1,2,4-triazole in a solution of benzene (250 ml, 219 g, 2.8 mole) and cyclohexane (250 ml, 194 g, 2.3 mole) were performed three times to give the following: (1) 14 mg of 3-phenyl-3H.- 1.2.4-triazole and 3-(cyclohexyl)-1H-1,2,4-triazole; GLC peak areas (column temp 200 °C, He flow rate 11 ml/min): 79% 3-phenyl-1H-1,2,4- triazole, 21% 3-(cyclohexyl)-1H-1,2,4-triazole; (2) 13 mg of 3-phenyl- 1H-1,2,4-triazole and 3-(cyclohexyl)-1JH-1,2,4-triazole; GLC peak areas: 80% 3-phenyl-1H-1,2,4-triazole and 20% 3-(cyclohexyl)-1H-1,2,4- triazole; (3) 21 mg of 3-phenyl-1j1-1,2,4-triazole and 3-(cyclohexyl)-111- 1.2.4-triazole; GLC peak areas: 80% 3-phenyl- 1_H— 1,2,4-triazole and 20% 3-(cyclohexyl)-1H-1,2,4-triazole. The results of the calculations gave (1) an average product composi tion (mole cyclohexyltriazole/mole phenyltriazole) of 0.77, (2) an average molar reactivity of 0.93, and (3) an average relative reactivity of 0.46. Thermolyses in Benzene and Anisole (1:1), 80 °C Four thermolyses were performed in solutions of benzene (250 ml, 219 g, 2.8 mole) and anisole (250 ml, 249 g, 2.3 mmole) to give the following: (1) 117 mg of 3-phenyl-111-1,2,4-triazole and 3-(methoxy- phenyl)-111-1,2,4-triazoles; GLC peak areas (column temp 250 °C, He flow rate 7 ml/min): 61% 3-phenyl-1H-1,2,4-triazole, 26% ortho, 13% meta 217 and para 3-(methoxyphenyl )-1j1-1 ,2,4-triazoles, (2) 129 mg of 3-phenyl- 1IL-1,2,4-triazole and 3-(methoxyphenyl)-1H-1,2,4-triazoles; GLC peak areas 64% 3-phenyl-1H-1,2,4-triazole, 24% ortho, 12% meta and para 3- (methoxyphenyl)-1H-1,2,4-triazoles, (3) 115 mg of 3-phenyl-1H-1,2,4- triazole and 3-(methoxyphenyl)-111-1,2,4-triazoles; GLC peak areas 61% 3-phenyl-TH-1,2,4-triazole, 28% ortho, 11% meta and para 3-(methoxy phenyl) — 12L—1,2,4-triazoles, and (4) 99 mg of 3-phenyl-11^-1,2,4-triazole and 3-(methoxyphenyl)-111-1,2,4-triazoles; GLC peak areas 62% 3-phenyl- 1H-1,2,4-triazole, 28% ortho, 1C% meta and para 3-(methoxyphenyl)-1_H- 1.2.4-triazole. These results were interpreted on using the following calculations. The molar composition was determined by dividing the peak area of one of the peaks for the 3-(methoxyphenyl)-1H-1,2,4-triazole by the peak area for 3-phenyl-1H-1,2,4-triazole and application of the appropriate standard curve from Table 10. For example in experiment 1 the amount of 3-(.o-methoxyphenyl)-11L-1,2,4-triazole was determined as follows: Moles0 = {(26/6D-(-0.19)1/1.4 = 0.44 The amount of 3-(m- and ^-methoxyphenyl)-1H-1,2,4-triazoles (moles mp) was determined similarly: Moles^ = {(13/61)-(_0.00)4}/(0.52) = 0.41 Hence the product composition was 0.45 moles of 3-(.o-methoxyphenyl)-1H- 1.2.4-triazole/mole of 3-phenyl-111-1,2,4-triazole and 0.45 mole of 3-(m_- and _g-methoxyphenyl)-1H-1,2,4-triazoles/mole of 3-phenyl-1H-1,2,4- triazole. The o_, in, £ ratio was determined by dividing the moles of one isomer by the total moles of 3-(methoxyphenyl)-111-1,2,4-triazole. % ortho = 0.44/(0.44 + 0.141) = 52% % meta and para = 0.41/(0.44 + 0.41) = 48% The molar reactivity was determined by multiplying the total amount of the 3-(methoxyphenyl)-1H-1,2,4-triazole produced by the ratio of the moles of anisole and benzene used in the reaction solution. Molar reactivity = 0.85 x 1.2 = 1.00 The relative reactivity was determined by multiplying the molar reactivity by thye appropriate statistical factor. Relative reactivity = 1.02 x 6/5 = 1.22 Once these numbers were determined for each experiment they were averaged to give the following results: (1) an average product composition (mole methoxyphenyltriazole/mole phenyltriazole) of 0.46 mole 3-(^-methoxyphenyl)-1H-1,2,4-triazole and 0.40 mole 3-(m- and jD-methyxyphenyl)-111-1,2,4-triazole, (2) an average isomer percentage of 53% ortho and 46% meta and para 3-(methoxy phenyl)-11-1,2,4-triazoles, and (3) an average molar reactivity of 1.10, and (4) an average relative reactivity of 1.32. Thermolyses in Benzene and Anisole (4:1), 80 °C Three decompositions of 3-diazo-3H.-1,2,4-triazole were effected in solutions of benzene (400 ml, 350 g, 4.4 mole) and anisole (100 ml, 100 g, 0.9 mole) to give the following: (1) 148 mg of 3-phenyl-11^-1,2,4- triazole and 3-(methoxyphenyl)-111-1,2,4-triazoles; GLC peak areas (column temp 250 °C, He flow rate 7 ml/min): 79% 3-phenyl-111-1,2,4-triazole, 14% ortho, 8% meta and para 3- (methoxyphenyl)-111-1,2,4-triazoles, (2) 127 mg of 219 3-phenyl-1H-1,2,4-triazole and 3-(methoxyphenyl)-1H-1,2,4-triazoles; GLC peak areas: 69% 3-phenyl-111-1,2,4-triazole, 26% ortho, 6% meta and para 3-(methoxyphenyl)-1H-1,2,4-triazoles, and (3) 131 mg of 3-phenyl- 1H-1,2,4-triazole and 3-(methoxyphenyl)-1H-1,2,4-triazoles; GLC peak areas: 72% 3-phenyl-111-1,2,4-triazole, 19% ortho, 9% meta and para 3- (methoxyphenyl)-111-1,2,4-triazoles. The results of the calculations gave (1) an average product composi tion (mole methoxyphenyltriazole/mole phenyl triazole) of 0.35 mole 3-(.o- methoxyphenyl)-1H-1,2,4-triazole and 0.24 mole 3—(nv— and j3-methoxy- phenyl)-1H-1,2,4-triazoles, (2) an average isomer percentage of 59% ortho and 41% meta and para 3-(methoxy phenyl)-111-1,2,4-triazole, (3) an average molar reactivity of 2.88, and (4) an average relative reac tivity of 3.46. Thermolyses in Benzene and Toluene (1:1), 80 °C 3-Diazo-3H.-1,2,4-triazole was thermolyzed in solutions of benzene (250 ml, 219 g, 2.8 mmole) and toluene (250 ml, 217 g, 2.4 mmole) 3 times to give the following: (1) 67 mg of 3-phenyl-1H-1,2,4-triazole and 3-(tolyl)-111-1,2,4-triazoles; GLC peak areas (column temp 220 °C, He flow rate 7 ml/min): 54% 3-phenyl-1H-1,2,4-triazole, 27% ortho, 19% meta and para 3-(tolyl)-1H-1,2,4-triazoles, (2) 41 mg of 3-phenyl-1H- 1.2.4-triazole and 3-(tolyl)-1j1-1,2,4-triazoles; GLC peak areas: 55% 3-phenyl-1H-1,2,4-triazole, 28% ortho, 17% meta and para 3-(tolyl)-TH- 1.2.4-triazoles, and (3) 31 mg of 3-phenyl-111-1,2,4-triazole and 3- (tolyl)-1H-1,2,4-triazoles; GLC peak areas: 55% 3-phenyl-1H-1,2,4- triazole, 27% ortho, 18% meta and para 3-(tolyl)-1H-1,2,4-triazoles. 220 The results of the calculations gave (1) an average product composition (mole tolyltriazole mole phenyltriazole) of 0.48 mole 3-(o- tolyl)-111-1,2,4-triazole and 0.30 mole 3-Cm- and jj-tolyl)-1JH-1,2,4- triazoles, (2) an average isomer percentage of 61% ortho and 39% meta and para 3-(tolyl)-111-1,2,4-triazoles, (3) an average molar reactivity of 0.91, and (4) an average relative reactivity of 1.09. Thermolyses in Benzene and Chlorobenzene (1:1), 80 °C Three decompositions of 3-diazo-3H.-1,2,4-triazole in a solution of benzene (250 ml, 219 g, 2.3 mole) and chlorobenzene (250 ml, 277 g, 2.4 mole) were affected to give the following: (1) 74 mg of 3-phenyl-1H- 1,2,4-triazole and 3-(chlorophenyl)-1H-1,2,4-triazoles; GLC peak areas (column temp 270 °C, He flow rate 9 ml/min): 60% 3-phenyl-1J1-1,2,4- triazole, 27% ortho, 12% meta and para 3-(chlorophenyl)-111-1,2,4- triazoles, (2) 25 mg of 3-phenyl-1H-1,2,4-triazole and 3-(chlorophenyl)- 111-1,2,4-triazoles; GLC peak areas: 78% 3-phenyl-111-1,2,4-triazole, 10% ortho, 12% meta and para 3-(chloropheny)-1H-1,2,4-triazoles, and (3) 32 mg of 3-phenyl-1H-1,2,4-triazole and 3-(chlorophenyl)-1ji-1,2,4- triazoles; GLC peak areas: 7^% 3-phenyl-111-1,2,4-triazole, 11% ortho, 15% meta and para 3-(chloropheny)-111-1,2,4-triazoles. The results of the calculations gave (1) an average product composi tion (mole chlorophenyltriazole mole phenyltriazole) of 0.25 mole 3-(o- chlorophenyl)-111-1,2,4-triazole and 0.33 mole 3-(m- and jj-chlorophenyl)- 1H-1,2,4-triazoles, (2) an average percent isomer percentage of 42% ortho and 58% meta and para 3-(chlorophenyl)-IH-l ,2,4-triazoles, (3) an 221 average molar reactivity of 0.56, and (4) an average relative reactivity of 0.67. Thermolyses in Benzene and Chlorobenzene (1:4), 80 °C 3-Diazo-3H-1,2,4-triazole was thermolyzed in a solution of benzene (100 ml, 87 g, 1.1 mole) and chlorobenzene (400 ml, 442 g, 3-9 mole) 3 times to give the following: (1) 27 mg of 3-phenyl-1H-1,2,4-triazole and 3-(chlorophenyl)-111-1,2,4-triazoles; GLC peak area (column temp 270 °C, He flow rate 9 ml/min): 27% 3-phenyl-1JH-1,2,4-triazole, 45% ortho, 28% meta and para 3-(chlorophenyl)-111-1,2,4-triazoles, (2) 20 mg of 3-phenyl-111-1,2,4-triazole and 3-(chlorophenyl)-1H-1,2,4-triazoles; GLC peak areas: 27% 3-phenyl-111-1,2,4-triazole, 44% ortho, 29% meta and para 3-(chloropheny)-1H-1,2,4-triazoles, and (3) 21 mg of 3-phenyl- 1H-1,2,4-triazole and 3-(chloropheny)-1H-1,2,4-triazoles; GLC peak areas: 33% 3-phenyl-1H_-1,2,4-triazole, 36% ortho, 30% meta and para 3- (chloropheny) - 1_H-1,2,4-triazoles. The results of the calculations gave (1) an average product composi tion (mole chlorophenyltriazole/mole phenyltriazole) of 0.89 mole 3-(o- chlorophenyl)-111-1,2,4-triazole and 0.97 mole 3-(m- and ]3-chlorophenyl)- 111-1,2,4-triazoles, (2) an average isomer percentage of 47% ortho and 53% meta and para 3-(chlorophenyl)-1H-1,2,4-triazoles, (3) an average molar reactivity of 0.52, and (4) an average relative reactivity of 0.63. 222 Thermolyses in Benzene and Trifluoromethylbenzene (1:1), 80 °C The thermolyses of 3-diazo-3H-1,2,4-triazole in a solution of benzene (250 ml, 219 g, 2.8 mmole) and trifluoromethylbenzene (250 ml, 300 g, 2.1 mole) were effected three times to give the following: (1) 56 mg of 3-phenyl-1H-1,2,4-triazole and 3-(trifluoromethylphenyl)-1H- 1.2.4-triazoles; GLC peak areas (column temp 180 °C, He flow rate 7 ml/min): 73% 3-phenyl-1H-1,2,4-triazole, 4% ortho, 22% meta and para 3-(trifluoromethylphenyl)-1IF-1,2,4-triazole, (2) 32 mg of 3- phenyl-1H-1,2,4-triazole and 3-(trifluoromethylphenyl)-1H-1,2,4- triazoles; GLC peak areas: 67% 3-phenyl-1 FI-1,2,4-triazole, 9% ortho, 24% meta and para 3-(trifluoromethylphenyl)-1H-1,2,4-triazole, and (3) 37 mg of 3-phenyl-1IF-1,2,4-triazole and 3-(trifluoromethylphenyl)-1F[- 1.2.4-triazoles; GLC peak areas: 69% 3-phenyl-1H-1,2,4-triazole, 5% ortho, 26% meta and para 3-(trifluoromethylphenyl)-1H-1,2,4-triazoles. The results of the calculations gave (1) an average product composition (mole trifluoromethylphenyltriazole/mole phenyltriazole) of 0.05 mole 3-(.o-trifluoromethylphenyl)-1F1-1,2,4-triazole and 0.34 mole 3- Cm- and £-trifluoromethylphenyl)-1FF-1,2,4-triazoles, (2) an average isomer percentage of 11% ortho and 89% meta and para 3-(trifluoro- methylphenyl)-1H-1,2,4-triazoles, (3) an average molar reactivity of 0.52, and (4) an average relative reactivity of 0.62. Thermolyses in Benzene and Nitrobenzene, 80 °C The thermolyses of 3-diazo-3FF-1,2,4-triazole in a solution of benzene (250 ml, 219 g> 2.8 mole) and nitrobenzene (250 ml, 301 g, 2.4 mole) were preformed 3 times to give the following: (1) 52 mg of 223 3-phenyl-111-1,2,4-triazole and 3-(nitrophenyl)-1H-1,2,4-triazoles; GLC peak areas (column temp 280 °C, He flow rate 18 ml/min): 58% 3-phenyl- 1H-1,2,4-triazole, 42% meta and para 3-(nitrophenyl)-1tl-1,2,4-triazole, (2) 75 mg of 3-phenyl-111-1,2,4-triazole and 3-(nitrophenyl)-1JH-1,2,4- triazoles; GLC peak areas: 71% 3-phenyl-111-1,2,4-triazole, 29% meta and para 3-(nitrophenyl)-111-1,2,4-triazoles, and (3) 86 mg of 3-phenyl- 111-1,2,4-triazole and 3-(nitrophenyl)-111-1,2,4-triazoles; GLC peak areas: 80% 3-phenyl-1H-1,2,4-triazole, 20% meta and para 3-(nitro- phenyl)-1H-1,2,4-triazoles. The results of the calculations gave (1) an average product composi tion (mole nitrophenyltriazole/mole phenyltriazole) of 0.82 mole of 3- (m- and ^-nitrophenyl)-111-1,2,4-triazoles, (2) an average isomer percentage of 100% meta and para 3-(nitrophenyl)-1H-1,2,4-triazoles, (3) an average molar reactivity of 0.93, and (4) an average relative reactivity of 1.11. Kinetic Deuterium Isotope Study Thermolyses in Benzene-Hg and Benzene-Dg A freshly prepared aqueous solution of 3-diazo-3H.-1,2,4-triazole was extracted with a solution of benzene-Hg and benzene-Dg (9.2 ml of a solution with m/e 78.00:84.00 = 90.42:100.00) at 0 °C. The resulting organic solution of 3-diazo-3H.-1,2,4-triazole was heated between 79 and 81 °C for 0.5 hr. The solvent was distilled. Methanol (10 ml) was added to the reaction vessel and distilled. The residue weighed 4.1 mg 224 and consisted of a mixture of 3-phenyl-1H-1,2,4-triazole-Hy and -D5-H2 ; m/e 145.00:150.00 = 86.76:100.00. Thermolysis in Nitrobenzene-H^ and Nitrobenzene-D^ A freshly prepared aqueous solution of 3-diazo-111-1,2,4-triazole was extracted with a solution of nitrobenzene-H^ and nitrobenzene-D^ (10.0 ml of a solution with m/e 123.00:128.00 = 95.40:100.00) at 0 °C. The resulting organic solution of 3-diazo-3.H-1,2,4-triazole was heated between 79 and 81 °C for 0.5 hr and worked up as described above to give 4.1 mg of a mixture of 3-(nitrophenyl)-1H-1,2,4-triazoles H6 and D4-H2; m/e 190.00:194.00 = 96.91:100.00. General Procedure for Thermal Decomposition of 3-Diazo-3H.-1,2,4- triazole in Benzenoid/Wafcer Emulsions Freshly prepared aqueous solutions of 3-diazo-3.H-1,2,4-triazole (_1_) at 0 °C and pH = 9 were added to rapidly stirred monosubstituted ben zenes (300 ml) at 80 °C. The degassing emulsions were heated at 80 °C for 1 hr. The solutions were cooled to room temperature and con centrated in vacuo (2mm Hg). The solid residue was dissolved in methanol (20 ml), adsorbed on silica gel (5 g) and then chromatographed over silica gel (25 g) with ethyl acetate (150 ml). The eluent was concentrated in vacuo to a solid. The existence and identity of the ortho, meta, and para 3-(substi- tuted phenyl)-1J3-1,2,4-triazoles produced in all reactions were estab lished by comparison with authentic samples. The ratios of the isomeric 225 3-(substituted phenyl)-1f1-1,2,4-triazoles produced were determined by HPLC analysis and application of the standard curves described on page 54. Each chromatogram was examined for total peak area and the percentage each product peak contributed to the total peak area. The ratios of the peak areas of the 3-(substituted phenyl)-1H-1,2,4- triazoles were used in conjunction with the standard curves to determine the moles and the percent isomer ratio of the substituted triazoles produced. Specific examples of thermolysis of aqueous 3-diazo-3H_-1,2,4- triazole (_1_) in various organic solvents are now presented. Thermolyses in Toluene, 80 °C Thermolyses of aqueous solutions of 3-diazo-3,H-1,2,4-triazole (_1_, pH = 9) in toluene were performed 5 times to give 3-(tolyl)-111-1,2,4- triazoles separable by HPLC as follows: (1) 412.6 mg (2.5 mmole); HPLC peak areas: 37% ortho, 9% meta, and 54% para, (2) 210 mg (1.2 mmole); HPLC peak areas: 37% ortho, 12% meta, and 51% para, (3) l80mg (1.1 mmole); HPLC peak areas: 37% ortho, 14% meta, and 49% para, (4) 88.4 mg (0.6 mmole); HPLC peak areas: 38% ortho, 12% meta, and 49% para, and (5) 126.2 mg (0.8 mmole); HPLC peak areas: 38% ortho, 12% meta, and 50% para. The average peak area percentages by HPLC are 37% ortho, 12% meta, and 51% para. The results of conversion of the average peak area percentages to isomer percentages give 58% ortho, 12% meta, and 30% para. 226 Thermolyses in Chlorobenzene, 80 °C Thermolyses of aqueous solutions of 3-diazo-3H.-1,2,4-triazole (pH = 9) in chlorobenzene were performed 2 times to give 3-(chlorophenyl)-1H- 1.2.4-triazole separable by HPLC as follows: (1) 276.5 rag (1.5 mmole); HPLC peak areas: 33% ortho, 9% meta, and 58% para, (2) 180 mg (1.0 mmole) HPLC peak areas: 32% ortho, 9% meta, and 59% para. The average peak area percentages by HPLC were 32% ortho, 9% meta, and 59% para. Conversion of the peak area percentages to isomer percentages gives 52% ortho, 11% meta, and 37% para. Thermolysis in Bromobenzene, 80 °C Thermolysis of an aqueous solution of 3-diazo-3H.-1 >2,4-triazole (pH = 9) in bromobenzene gave 624.4 mg (2.8 mmole) of 3-(bromophenyl)-1H- 1.2.4-triazoles separable by HPLC as follows: 36% ortho and meta and 64% para (percentages are in peak area percentages). Conversion of the peak area percentages gives 64% 3-(.o and rn-bromophenyl)- 1H-1,2,4- triazoles and 36% 3-(j>-bromophenyl)-1H-1,2,4-triazole. APPENDIX I General Procedure for the Preparation of Standard Curves for GLC Analysis of Mixed Solvent Experiments Solutions containing weighed amounts of 3-phenyl-1H-1,2,4-triazole and a 3-substituted-111-1,2,4-triazole were analyzed by GLC (15% SE 30, 1/8" x 12', see the individual experiments for the column temperatures and helium flow rates used). The ratios of peak areas (substituted phenyltriazole/phenyltriazole) were plotted against the ratios of moles of compounds (substitutedphenyl triazole/phenyltriazole). Assuming a linear relationship, a least squares fit was performed to determine the best straight line through the data points. Some specific examples of the weights and peak areas of the compounds used to create the standard curves, and the results of the least squares fit are given here and are summarized in Table 10. 3-Cyclohexyl-111-1,2,4-triazole The following solutions of 3-phenyl-1H-1,2,4-triazole and 3-cyclo- hexyl-1H-1,2,4-triazole were analyzed by GLC (column temp of 220 °C and a flow rate of 11 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 0.27 and 0.04. 227 228 sample phenyltriazole eyelohexyltriazole weight,mg area,% weight,mg area,% 1 16.1 65 30.9 35 2 13.3 76 12.4 24 3 21.9 87 10.3 13 3-(^-Methoxyphenyl)-1H-1,2,4-triazole The following solutions of 3-phenyl-1H-1,2,4-triazole and 3-(£-meth- oxyphenyl)-1jl-1,2,4-triazole were analyzed by GLC (column temp of 250 °C and a flow rate of 7 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 1.398 and -0.21. sample phenyltriazole aryltriazole weight,rag area,% weight,mg area,' 1 8.3 32 16.7 68 2 10.4 55 9.4 45 3 11.3 62 7.7 37 3- (rn-Methoxyphenyl) - 1H.-1,2,4-triazole The following solutions of 3-phenyl-1H-1,2,4-triazole and 3-(nwneth- oxyphenylJ-IH^I,2,4-triazole were analyzed by GLC (column temp of 250 °C and a flow rate of 7 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 1.00 and -0.11. 229 sample phenyltriazole aryltriazole weight,mg area,% weight,rag area,% 1 9.9 38 20.7 62 2 9.8 59 9.5 41 3 8.7 82 3.4 18 3- (^-Methoxyphenyl) - 1_H-1,2,4-triazole The following solutions of 3-phenyl-1H.-1,2,4-triazole and 3-(j3-meth- oxyphenyl)-1H-1,2,4-triazole were analyzed by GLC (column temp of 250 °C and a flow rate of 7 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 0.52 and -.02. sample phenyltriazole aryltriazole weight,mg area,% weight,mg area,% 1 12.5 55 24.4 45 2 14.2 73 11.6 27 3 12.6 85 6.6 15 3- (£-Tolyl)-1H-1,2,4-triazole The following solutions of 3-phenyl-1J1-1,2,4-triazole and 3-(o-tol- yl)-1H-1,2,4-triazole were analyzed by GLC (column temp of 220 °C and a flow rate of 7 ml/min) and the indicated percent area each peak contri buted to the total peak area determined. The slope and intercept of the best fit line are 1.11 and -0.03. 230 sample phenyltriazole aryltriazole weight,mg area,% weight,mg area,% 1 10.0 72 05.0 28 2 11.3 50 10.2 50 3 10.0 32 21.6 68 3-(m-Tolyl)-1H-1,2,4-triazole The following solutions of 3-phenyl-1t!-1,2,4-triazole and 3-(rn-tol- yl)-1H-1,2,4-triazole were analyzed by GLC (column temp of 220 °C and a flow rate of 7 ml/min) and the indicated percent area each peak contri buted to the total peak area determined. The slope and intercept of the best fit line are 0.81 and 0.00. sample phenyltriazole aryltriazole weight,mg area,% weight,mg area,% 1 15.8 38 29.5 52 2 13.1 58 12.4 42 3 34.6 72 18.3 27 3-(j3-Tolyl )-1H-1,2,4-triazole The following solutions of 3-phenyl- 1JT-1,2,4-triazole and 3-(j3-tol- yl)-1]L-1,2,4-triazole were analyzed by GLC (column temp of 220 °C and a flow rate of 7 ml/min) and the indicated percent area each peak contri buted to the total peak area determined. The slope and intercept of the best fit line are 1.24 and -0.04. 231 sample phenyltriazole aryltriazole weight,mg area,% weight,mg area,% 1 11.8 32 22.8 68 2 11.6 50 10.0 50 3 10.0 67 5.2 33 3- (o-Trif luoromethylphenyl) -11!-1,2, *4-triazole The following solutions of 3-phenyl-1j!-1,2,4-triazole and 3-(o-tri- fluoromethyphenyl)-11!-1,2,4-triazole were analyzed by GLC (column temp of 180 °C and a flow rate of 7 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 1.18 and 0.03. sample phenyltriazole aryltriazole weight,mg area,% weight,mg area,% 1 10.3 36 22.9 65 2 12.1 55 10.7 45 3 11.4 74 5.3 26 3- (m-Trif luoromethylphenyl) -1!!-1,2,4-triazole The following solutions of 3-phenyl-1H-1,2,4-triazole and 3-(in-tri- flouromethylphenyl)-1f!-1,2,4-triazole were analyzed by GLC (column temp of 180 °C and a flow rate of 7 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 0.85 and 0.03. 232 sample phenyltriazole aryltriazole weight,mg area,% weight,mg area,% 1 9-4 44 20.5 56 2 10.7 60 10.4 40 3 12.5 81 5.4 19 3- (^-Trifluoromethylphenyl)-1H-1,2,4-triazole The following solutions of 3-phenyl- 1_Hj— 1,2,4-triazole and 3-(£-tri- fluoromethylphenyl)-1H-1,2,4-triazole were analyzed by GLC (column temp of 180 °C and a flow rate of 7 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 1.18 and 0.06. sample phenyltriazole aryltriazole weight,mg area,% weight,mg area,% 1 10.0 37 20.7 63 2 10.9 53 10.0 47 3 11.1 76 4.3 24 3-(o-Chlorophenyl)-1H-1,2,4-triazole The following solutions of 3-phenyl-111-1,2,4-triazole and 3- (o^chlorophenyl)-111-1,2,4-triazole were analyzed by GLC (column temp of 270 °C and a flow rate of 9 ml/min) and the indicated percent areaeach peak contributed to the total peak area determined. The slope and intercept of the best fit line are 1.93 and -0.24. 233 sample phenyltriazole aryltriazole weight,mg area,% weight,mg area,% 1 12.6 64 4.8 36 2 12.0 52 11.3 48 3 11.1 24 23.5 76 3- (m-Chlorophenyl) -11I-1,2,4-triazole The following solutions of 3-phenyl-1JI-1,2,4-triazole and 3- (rn-chlorophenyl)-TH-1,2,4-triazole were analyzed by GLC (column temp of 270 °C and a flow rate of 9 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 0.61 and 0.21. sample phenyltriazole aryltriazole weight,mg area,% weight,mg area,% 1 12.9 55 15.5 45 2 9.5 64 4.0 36 3 12.7 77 6.3 23 3- (^-Chlorophenyl) -11I-1,2,4-triazole The following solutions of 3-phenyl-1_H-1,2,4-triazole and 3- (jD-chlorophenyl)-111-1,2,4-triazole were analyzed by GLC (column temp of 270 °C and a flow rate of 9 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 1.28 and -0.24. 234 sample phenyltriazole aryltriazole weight,mg area,% weight,mg area,% 1 10.2 36 19.7 64 2 10.4 76 5.1 24 3 13.2 64 11.0 36 3-(o-Nitrophenyl)-1H-1,2,4-triazole The following solutions of 3-phenyl-111-1,2,4-triazole and 3-(orni- trophenyl)-1H-1,2,4-triazole were analyzed by GLC (column temp of 280 °C and a flow rate of 18 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line were undetermined due to the poor response. sample phenyltriazole aryltriazole weight,mg area,% weight,mg area,% 1 11.5 100 10.6 2 8.2 100 3.9 3 11.7 100 21.2 3- (m-Nitrophenyl) - 1J3-1,2,4-triazole The following solutions of 3-phenyl-1H-1,2,4-triazole and 3-(m-ni- trophenyl)-1H-1,2,4-triazole were analyzed by GLC (column temp of 280 °C and a flow rate of 18 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 0.74 and -0.14. 235 sample phenyltriazole aryltriazole weight,mg area,% weight,mg area,°/> 1 10.4 68 11.0 32 2 10.5 87 5.6 13 3 6.5 57 10.4 43 3- (^-Nitrophenyl)-1J1-1,2,4-triazole The following solutions of 3-phenyl-1J8-1,2,4-triazole and 3-(j>-ni- trophenyl)-1f1-1,2,4-triazole were analyzed by GLC (column temp of 280 °C and a flow rate of 18 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 0.47 and 0.03. sample phenyltriazole aryltriazole weight,mg area,% weight,mg area 1 11.3 89 5.0 11 2 9.9 57 20.8 43 3 12.9 68 12.2 32 3- (o^/£-Bromophenyl) -1 H_-1,2,4-triazoles The following solutions of 3-(o-bromophenyl)-IH-l,2,4-triazole and 3-(j3-bromophenyl)-1fr-1,2,4-triazole were analyzed by GLC (column temp of 270 °C and a flow rate of 9 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 0.81 and 0.10. 236 sample jo-bromophenyltriazole j)-bromophenyltriazole weight,mg area,% weight,mg area,% 1 13.2 38 25.9 62 2 11.1 75 5.2 25 3 10.7 53 8.1 47 3- (o-/^-Chlorophenyl) -111-1,2, 4-triazoles The following solutions of 3-(o-chlorophenyl)-11i~1 ,2,4-triazole and 3-(j>-chlorophenyl)-1jL-1,2,4-triazole were analyzed by GLC (column temp of 270 °C and a flow rate of 9 ml/min) and the indicated percent area each peak contributed to the total peak area determined. The slope and intercept of the best fit line are 0.85 and -0.20. sample o-chlorophenyltriazole £-chlorophenyltriazole weight,mg area,% weight,mg area,% 1 5.2 38 10.1 62 2 11.1 55 11.1 45 3 20.9 72 10.0 28 APPENDIX II 237 OCH 8 7 8 7 6 Aromatic Region of the 'H-FT NMR(acetone-d ) of 3 -I0-MethoxyphenylHH-l^^-triazole 8 3 2 6 ” OCH OCH 8 7 ©239 Aromatic Region of the 'H-FT NMR(acetone-d6) of 3-(m-Methoxypheny!)-IH-l,2,4-triazol Aromatic Region of the ‘H-FT NMR(acetone-d6) of 3-(pMethoxyphenyl)-lH-i,2,4-triazoie - ro o 8 7 — r ~ 9 Aromatic Region of the ‘H-FT NMR(acetone 1,2,4- triazole CH CH 9 8 7 8 7 Aromatic Region of the 'H-FT NMR(acetone-dg) of 3-(m-Tolyl)-IH-l,2,4-Iriazole CH J ~ T ~ T" ~ r 9 8 7 Aromatic Region of the 'H-FT NMR(acetone-dg) of 3-(p-Tolyl)-IH-l,2,4-triazole 243 8.5 8.0 7.5 9 8 7 44 24 Aromatic Region of the 'H-FT NMR(acetone-d ) of 3-(o-Chlorophenyi)-IH-l,2,4 -triazole 6 " 1 r t i i------r 8 7 9 8 7 Aromatic Region of the 'H-FT NMR(acetone-d ) of 3-(m - Chlorophenyl)-lH-1,2,4 -triazole £ 6 Ol 8.0 7.2 Aromatic Region of the H -FT NMR(acetone-dof 3 -(p - Chlorophenyl)-IH-l,2,4 -triazole Aromatic Region of the *H-FT NMR(acetone-dg) of of NMR(acetone-dg) *H-FT the of Region Aromatic 5 . 8 /=z 8.0 7.5 3 (- tohnl l24ti2l ^ -l,2,4-tria2ole H itrophenylH -(o-N - n I T T T T T T T TT T TT T r TT 9 8 7 Aromatic Regionof the 'H-FT NMRCacetone-d^}of 3-(m- NitrophenylHH- l,2,4-triaiol^0 CO 9 8 7 249 Aromatic Region of the 'H-FT NMR(acetone-dg) of 3-(p-NVtrophenyl)-lH-l,2,4-friazole CN CN w T 8.58-0 7.5 9 8 7 250 Aromatic Region of the 'H-FT NMR(acetone-d ) of 3-Co- Cyanophenyl)-lH-l,2,4-triazole 6 ~ CN CN u T TTT TT T T 85 8.0 75 9 8 7 Aromatic Region of the 'H-FT NMR(acetone-d6) of 3-(m- Cyanophenyl)-IH-l,2,4-triazole 251 CN T r T T T T &5 a o Aromatic Region of the 'H -FT NMR(acetone d6) of 3-(p- CyanophenyD-I1riazoie T T T T 8.5 8-0 T 5 Aromatic Region of the lH -FT NMR(acetone-d of 3 5 2 3-(o- M e thoxycarbonyl phenyl)-1 H-l,2,4-triaz ole T 9 8.0 7.5 Aromatic Region of the ‘H-FT NMR(acetone-d ) 0f 6 3-(m- Methoxycarbonyiphenyl)-! H-l,2,4-tria2ole 4 5 2 APPENDIX III Preparation of 3-Diazo-3H.-1,2,4-triazole To stirred solutions of 3-amino-1H-1>2,4-triazole (0.84 g, 10 mmole) in 48% tetrafluoroboric acid (15 ml) between -30 and -20 °C and under nitrogen were added dropwise solutions of sodium nitrite (1.0 g, 15 mmole) in water (2 ml). The resulting heterogeneous mixtures were stirred for 5 to 10 min and then neutralized with solid sodium bicarbonate. Throughout this process the temperatures of the mixtures/solutions were maintained between -10 and -5 °C. The solutions were supersaturated with sodium bicarbonate and extracted with cold (0 °C) dichloromethane (five 80 ml portions). The combined extracts were dried (MgSOjj) and vacuum filtered through magnesium sulfate (~5 g) into weighed cold flasks. The solutions were concentrated to 200 ml (0 °C, house vacuum), then to moist solids on a rotary evaporator (0 to 10 °C, water aspiration) and finally to dryness (room temperature, house vacuum). This procedure consistently affords solid white 3-diazo-3H.-1,2,4-triazole (0.6 g, 6.4 mmole, 64% yield): IR (CH2 CI2 ) cm"^ 2180 (s), no absorption for NH or OH. The yield of 3-diazo-3H.-1,2,4-triazole is increased to 88% by modifying the above isolation procedure as follows. After neutralization of freshly diazotized solutions of 255 256 3-amino-1H-1,2,4-triazole, the mixtures were poured into methylene chloride (200 ml) and sodium bicarbonate (1 to 2 g) and magnesium sulfate (enought to absorb all the water) were added sequentially and in small portions. The organic phases were decanted and the solids washed with methylene chloride (three 100 ml portions). The organic phases were combined, dried (MgSOij), filtered and concentrated as above to 3- diazo-311-1,2,4-triazole (0.84 g (8.8 mmole, 88% yield). General Procedure for Thermolysis of 3-Diazole-3H.-1,2,4-triazole (_1) in Benzenoid Solvents Solid 3-diazo-3H.-1,2,4-triazole (_1_) was dissolved in an aromatic solvent (the volume of which depended upon the solubility of the diazo compound, see the individual experiments for the quantity of solvent required). These solutions were blanketed with nitrogen and then added rapidly to additional solvent (80 ml) at 80 °C and heated there for 1.5 hr. Thermolysis of nitrobenzene was also effected at 185 °C. The solutions were concentrated in vacuo (2 mm Hg) to solids. For the thermolyses in nitrobenzene the solutions were fractionated prior to concentration. The residues, after chromatographic purification if required, were analyzed using GLC or HPLC methods. Thermolysis in Anisole, 80 °C 3-Diazo-3H.-1,2,4-triazole (0.29 g, 3 mmole) was dissolved in anisole (200 ml) and thermolyzed and concentrated as described above. 257 The product was chromatographed over silica gel eluting with 50% chloroform:acetone. HPLC analysis (using 6% MeOH:CHCl^ as the developing solvent and methyl benzoate as an internal standard) of the product showed it to be 50% 3-(o-methoxyphenyl)-1_H-1 ,2,4-triazole and 50% 3-(m- and ]D-methoxyphenyl)-111-1, 2,4-triazoles. Thermolysis in Toluene, 80 °C 3-Diazo-3.H-1 >2,4-triazole (0.6 g, 6.3 mmole) in toluene (250 ml) was thermolyzed and worked up as described above without chromatographic purification to give a 3-(tolyl)-1_H-1,2,4-triazoles (1.0057 g, 6.2 mmole, 98% yield). The mixture was shown by GLC to be 66% 3-(o- and m- tolyl)-1H-1,2,4-triazoles and 33% 3-(jD-tolyl)- 111-1,2,4-triazole. Thermolysis in Chlorobenzene, 80 °C Solid 3-diazo-3H.-1,2,4-triazole (0.6 g, 6.3 mmole) was suspended in chlorobenzene (200 ml) and the slurry thermolyzed and worked up as described above, without chromatographic purification. The residue ws found to be 57% 3-(_o-chlorophenyl)-111-1,2,4-triazole and 43% 3-(in- and j)-chlorophenyl)-111-1,2,4-triazoles by GLC analysis. Thermolyses in Nitrobenzene, 80 and 185 °C 3-Diazo-3j1-1,2,4-triazole (0.6 g, 6.3 mmole) was dissolved in nitrobenzene (100 ml) and then thermolyzed at 80 °C, fractionated and worked up as described above. GLC analysis of the fractionated nitrobenzene solution showed nitrosobenzene to be present (1.3 mmole, 258 22% yield). Chromatographic purification (silica gel; 4% MeOH:CHCl^) of the reaction residue provided 3-(m-nitrophenyl)-1_H-1 ,2,4-triazole (0.2505 g, 1.3 mmole, 22% yield), by NMR analysis (see accompanying spectra). 3-Diazo-3_H-1,2,4-triazole (0.84 g) was dissolved in nitrobenzene (120 ml). The solution was thermolyzed at 185 °C, fractionated and worked up as described in the previous experiment. GLC analysis showed nitrosobenzene (0.3784 g, 3.5 mmole, 40% yield) to be formed while chromatography as described above provided 3-(m_-nitrophenyl)-1H-1,2,4- triazole (0.4040 g, 2.1 mmole, 24% yield). LIST OF REFERENCES 1) (a) J. Thiele and Manehot, VJ., Ann., 30?i 41-56 (1898): (b) 3- Amino-1,2,4-triazole is a white water-soluble solid with mp 121 °C, bp 260 °C/760 mm, dipole moment 3.17 (dioxane) and pKa = 11.1 [R. C. Elderfield, "Heterocyclic Compounds" Vol. 7, John Wiley and Sons, Inc., New York, N. Y., 1961 and C. F. Kroger and W. Freiberg, Z_. Chem., _5, 381-2 (1965)]. (c) The triazole is an effective herbicide for control of perennial weeds such as poison ivy, poison oak, Canada thistle, quack grass and aquatic weeds {A. J. Tafuro, R. H. Beatty and R. T. Guest, Proc. Northeast. Weed Control Conf., 31 (1955) [Chem. Abstr., 49, 6527f (1955)]}. (d) The amine decreases rat liver and kidney, but not blood, catalase activity within 3 hr after intraperitoneal or intravenous injec tion. {G. Heim, D. Appelman and H. T. Pyfrom, Am. J_. Physiol., 186, 19 (1956) [Chem. Abstr., 50, 15665d (1956)]}. (e) The current method of synthesizing _1_ is described by C. Ainsworthin Org. Syn., 40, 99 (1960) and L. F. Fieser and M. Fieser in "Reagents for Organic Synthesis", John Wiley and Sons, Inc., 1967, p406. (f) Although they give no experimental details, J. Vilarrasa, E. Melendez and J. Elguero report the pKa of 3- diazonium-1j1-1,2,4-triazoles cations to be 0.3 {Tetrahedron Lett., 1609-10 (1974)}. This value is NOT surprising since the pKa of 1,2,4-triazole is 10.0. {L. D. Hansen, E. J. Baca, and P. Scheiner, J_. Heterocyclic Chem., 991-6 (1970)}. 2) W. Manehot, Chem. Ber., 31, 2444-7 (1898); W. Manehot and G. Cipens, Methody Poluch. Khim. Reaktivov Prep., No 14, 119-21 (1966) [Chem. Abstr., 67, 64307w (1967)]J T. J. Schawn and R. L. 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Eftimescu, and R. J. Schip, Rom. Patent 50,786 (Cl. C096), 06 Apr 1968, Appl 09 Jul 1965 [Chem. Abstr., 70, 4114h (1969)]; (b) I. L. Shegal, K. V. Stanovkina, N. G. Kovalenko, and L. M. Shegal, Khim. Geoterosikl. Soedin., 422-4 (1974) [Chem. Abstr., 8l_, 25609r (1975)]; (c) J. F. Morgan and H. W. Gruninel, U. S. Patent 2,515,728 (1950) [Chem. Abstr., 45, P1773e (1951)]; (d) S. Castillon, E. Melendez, and J. Vilarrassa, J^. Heterocyclic Chem., 19, 61-4 (1982); (e) J. Vilarrassa and R. Grandos, J^. Heterocyclic Chem., 867-72 (1974). 12) M. H. Alnagde, M. R. H. Almoghayar, S. M. Fahmy, M. K. A. Ibraheim, and H. H. Alnima, Z_. Naturforsch., B33, 216-9 (1978). 13) G. Tennant and R. J. S. Vevers, J_. C^. J3. Perkin' I, 421-8 (1976). 14) E. J. Gray and M. F. G. Stevens, _J. C_. S_. Perkin I, 1496-1504 (1976). 15) J. Glinka, Ph. D. Thesis, The Ohio State University, Columbus Ohio, 1980. 16) A. Padwa, T. Kumagai, and A. D. Woolhouse, J^. Org. Chem., 48, 2330-6 (1983). 17) (a) G. Ege, K. Gilbert, and H. Franz, Synthesis, 556-9 (1977). (b) N-Phenyl-6-amino-7-methyl[1,2,4]triazolo[5,1-c_][1,2,4]triazine has been prepared by coupling alpha-chloroacetylacetone with 2_ to give 1-chloro-1-(1,2,4-triazol-3-yl-hydrazono)propan-2-one (8^, Eq 6) followed by cyclization and condensation with aniline [M. H. Elnagdi, M. R. H. Elmoghaver, H. A. Elfaham, and M. M. Sallam, ^J. Heterocyclic Chem., 17, 209-12 (1980)}. 18) (a) Diazoazoles are versatile reagents and their synthetic poten tials have received considerable attention. See C. Temple, Jr., "Triazoles 1,2,4" in "The Chemistry of Heterocyclic Compounds", A. Weissberger and E. C. Taylor, Ed., John Wiley and Sons, Inc., New York, N. Y. 1981; E. J. Gray, M. F. G. Stevens, G. Tennant, and R. J. S. Vevers, _J. Chem. Soc. Perkin I, 1496 (1976); G. Tennant and R. J. S. Vevers, J^. Chem. Soc. Perkin I, 421 (1976); 261 J. Solouka, V. Bekarek, and J. Kubato, Monatsh. Chem., 105, 535 (197^)» H. Magie and G. Tennant, Tetrahedron Lett., 4719 (1972); M. Tisler and B. Stanovink, Heterocycles, _4, 1115-1166 (1976); M. Koeevar, D. Kolman, H. Krajne, S. Polanc, B. Porovne, B. Stanovnik, and M. Tisler, Tetrahedron, 32, 725 (1976); D. Tortuna, B. Stanovnik, and M. Tisler, J_. Org. Chem., 39, 1833 (1974); G. Tennant and R. J. S. Vevers, J_. Chem. Soc. (C), 421 (1976). (b) Despite their ready accessibility by diazotization of the corresponding amino-heterocycles, the chemical reactivity of five- membered ring heterocyclic diazo compounds has, in comparison with their benzenoid counterparts, been little investigated. [See J. M. Tedder, Adv. Heterocyclic Chem., j), 1 (1967) and R. N. Butler, Chem. Rev., 75, 241 (1975)]. (c) Many heterocyclic diazo compounds have antimicrobial properties and a broad spectrum of pharmacological properties have been demonstrated for the triazole nucleus [See G. Pellizzari and C. Massa, _J. Chem. Soc., 80, 488 (1901); C. Ainsworth, N. R. Easton, M. Livezey, D. E. 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Triazole rings decompose giving mass spectral peaks corresponding to fragments arising from cleavage of the C ^-^2 and C^-N^ bonds and the Cg-Nij and C^-N^ bonds. 77) I thank Dr. C.B. Rao for conducting the experiments described in Appendix III while this dissertation was being completed. 78) In addition to the C-H substitution products (124 to 129) formed in the reactions of _1_with bromo- and chlorobenzene there are some minor products from these reactions which need to be addressed. In the HPLC chromatograms of the reaction products formed in the reactions of _1_ with chlorobenzene there are three peaks which have the same retention times (1.9 min to 2.1 min) as 3-chloro-1- phenyl-1.H-1,2,4-triazole (198, X = Cl), 5-chloro-1-phenyl-1H- 1,2,4-triazole (199, X = Cl) and 3-chloro-4-phenyl-421-1,2,4- triazole (200, X = Cl). 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