University of the Pacific Scholarly Commons
University of the Pacific Theses and Dissertations Graduate School
1972
Birch reduction of benzenesulfonamide, N,N- dimethylbenzenesulfonamide, N,N-diisobutylbenzenesulfonamide, and 2-mesitylenesulfonamide
Vishnubhai V. Patel University of the Pacific
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Recommended Citation Patel, Vishnubhai V.. (1972). Birch reduction of benzenesulfonamide, N,N-dimethylbenzenesulfonamide, N,N-diisobutylbenzenesulfonamide, and 2-mesitylenesulfonamide. University of the Pacific, Thesis. https://scholarlycommons.pacific.edu/uop_etds/420
This Thesis is brought to you for free and open access by the Graduate School at Scholarly Commons. It has been accepted for inclusion in University of the Pacific Theses and Dissertations by an authorized administrator of Scholarly Commons. For more information, please contact [email protected]. BIRCH REDUCTION OF BENZENESULFONAMIDE, N,N-DIMETHYLBENZENESULFONAMIDE, N,N-DIISOBUTYLBENZENESULFONAMIDE AND 2-MESITYIENESULFONAMIDE.
A Thesis Presented to the Faculty of the Graduate School -1 University of the Pacific I I -i
In Partial Fulfillrnent of
_j the Requirement for the Degree Master of Science
by Vishnubhai V. Patel June 1972 ACKNOWLEDGEMENT
The author wishes to express his sincere gratitude to Dr. Charles
A. Matuszak for his unceasing encouragement and help during the course
of-this research.
My grateful thanks to Dr. Herschel G. Frye and Dr. Donald K.
Wedegaertner for their kind suggestions.
I would like to thank Dr. E.G. Cobb, Chainnan of the Chemistry
Department, for his help and facilities.
Finally, rey sincere appreciation to Mrs. Dawn Mallard for an excellent
job of typing.
--j j TABLE OF CONTENTS ,PAGE
INTRODUC'J1ION . • • • . . I 1 RESULTS AND DISCUSSION . \u I SUMMARY AND CONCLUSION . \25 EXPERTIVIENTAL • • • • • .!27 ! A. Summary of General Experimental Procedure i27 B. Preparation of Benzenesulfonamide ~7 I C. Reduction of Benzenesulfonamide 28 1. First Reduction . 28 2. ·Second Reduction . 29 3. Third Reduction . ~3 4 . Fourth Reduction 33 5. Fifth Reduction • 33 6. Sixth Reduction . 33 7. Seventh Reduction 33 8. Eighth Heduction 34 9. Ninth Reduction . 34 10. Terith Reduction . 34 11. Eleventh Reduction 34 12. Twelfth Reduction • 35 13. Thirteenth Reduction 35 14. Fourteenth Reduction 35 15. Fifteenth Reduction • 36 16. Sixteenth Reduction . 36 17. Seventeenth Reduction 36 D. Preparation of N,N-D:imethylbenzenesulfonamide 38 E. Reduction of N,N-D:imethylbenzenesulfonamide 38 1. First fuduction . 38 2. Second Reduction 39 3. Third Reduction . 39 4. Fourth Reduction 39 5. Fifth Reduction . 40 6. Sixth Reduction . lJO 7. Seventh Reduction .. 40 8. Eighth Reduction 40 PAGE
F. Preparation of N,N-Diisobutylbenzenesulfonamide 41
G. Reduction of N,N-Diisobutylbenzenesulfonamide . i, 41 1. First Reduction ...... ~ . . . .' . . . . : 41 2. Second Reduction :. 42 3. Third Reduction 1'. 43 4. Fourth Reduction . 43 5. Fifth Reduction • 44 6. Sixth Reduction 1i• 44 H. Reduction of 2-Mesitylenesulfonamide i• 45 (2,4,6-Trimethylbenzenesulfonamide) ' 1. First Reduction • 45 2. Second Reduction ~ 46 3. Third Reduction 51 4 , Fourth Reduction 52
BIBLIOGRAPHY 53 LIST OF FIGURES FIGURE NO. PAGE l. Reduction Products of Toluene, Anisole, Dimethylaniline and Benzoic Acid • • • • . · 4 2. Reduction Products of p-Toluenesulfonamide 7 3. Dimerization of Phenylsulfur Radical to Diphenyldisulfide ll 4. Reduction Products of Substituted Benzenesulfonamide 13 5. Reduction Products of 2-Mesitylenesulfonamide • • • . 22 6. IR Spectrum of Thiophenol from First Reduction Product of Benzenesulfonamide . . • . 30 7. IR Spectrum of known Thiophenol • • . . • . • . 31 8. IR Spectrum of known Mixture of Thiophenol and Diphenyldisulfide ••• . . 32 9. IR Spectrum of Mesitylene • • • . . . • . • • . 47 I -,' 10. IR Spectrum of Mesitylene from First Reduction Product of 2-Mesitylenesulfonamide • . • • • . . . . • • • 48 ll. IR Spectrum of 2,4,6-Trimethylthiophenol from First Reduction Product of 2-Mesitylenesulfonamide . . . • • • • . 49
LIST OF SCHEMES SClJEI'IIE NO. PAGE I. Reaction Mechanism of Birch Reduction ...... 2 II. Birch Reduction Cleavage of Supstituted Tosylsulfonamide 7 III. Reaction Mechanism for Sulfonamide Cleavage by Arene Anion 9 IV. Reductive Cleavage of Alkyl Substituted Benzenesulfonamide 12 LIST OF TABLES TABLE NO. PAGE I. Comparative Yield of Reduced N-Alkylated Benzamides 5 II. Comparative Acidity Tabulation ...... 6 III. L~quid Ammonia Cleavage of p-Toluenesulfonamide 8 rr. N-Ethyl-N-Phenyl-p-Toluenesulfonamide Cleavage 8 V. Birch Reduction of Benzenesulfonamide • • • • • 14 VI. Birch Reduction of N,N-Dimethylbenzenesulfonamide 19 VII. Birch Reduction of N,N-Diisobutylbenzenesulfonamide 21 VIII. Birch Reduction of 2-Mesitylenesulfonamide •••• 23
_j' Chapter I INTRODUariON
The use of active metal-liquid ammonia-alcohol reagents in the reduction of aromatic compounds dates from 1937, when Wooster (1) showed
that the presence of alcohol in active metal-liquid ammonia allowed the
reduction of benzene to its dihydro derivative, Whereas~ in· the absence of the alcohol there was no reduction.
He did not examine the reduction product in detail (1). In later - l years Arthur J. Birch (2,4,5,7,12) reexamined the method, improved it
and utilized it extensively in the reduction of a variety of aromatic compounds and this type of reduction often is called "Birch Reduction". The Birch method (2,4,5) has great synthetiq usefulness because it proVides a simple route to 19-nor-analogues of steroidal hormones (37
and in peptide chemistry (19,20) to remove tosyl blocking groups. ·.The extensive modifications of this method by variation of experimental conditions have proven its versatility. The original method used an alkali metal, liquid ammonia and an acid or proton source (1). The most commonly used metal is sodium, although lithium and potassium have also been used. The proton source
is usually an a~cohol (methyl or ethyl) or an amnonium salt e.g. NH Cl. 4 Sometimes cosolvents such as anhydrous tetrahydrofuran and ether are
used when the compounds are not very soluble in liquid anmonia. The
1 primary function of the alcohol is that of a proton donor, but it also facilitates the process by buffering the reaction mixture, thus preventing
the accU!Illllation of strongly basic li!H ion. Thus the base catalysed 2 rearrangements can be minimized. The acidity of the proton source is an important factor in determining the nature of the reduction product ( 6).
If the acidity is very high, the proton donor will react readily with the
alkali metal and gaseous hydrogen will be the main product. Alcohols
have optimum pKa for the reduction of aromatic rings.
The mechanism of Birch reduction (2,15,16,17,18,24) as established
for most benzenoid compounds is depicted in Scheme I.
Scheme I
[A]
(?olvated catio'11 a.md <;,olvcded eleci;to'Yl)
CBJ .. MQ) e + CNH ')------e CNH) " e 0-----M~""Y 3 3 0 -e e(NH~)
( il.+e'l'le "-'1'1 i 01'\ "1'-o.d i ca. I )
2 CCJ .. pKc.;: 16-1~ ------MEFJ +ROH -~ ( NH~)
0• • CNH) e :;
CD]
·•- .. -. Q H H ... -j . !
C.E1
H H
+ROMCNH) 3
3 It can be noted that .ammonia can not furnish proton due to its low
acidity (pKa about 34) . Therefore, more acidic proton sources such as
alcohols (pKa about 16-18) are required. Wilds and Nelson (3) modified
this method by using lithium instead of sodium or potassium and adding
alcohol last. This procedure has improved the yields in many cases and
therefore is widely used.
The nature of substituents in a benzene nucleus profoundly effect
the mode of Birch reduction. Substitution of a benzene nucleus with
electron releasing groups (e.g. alkyl and amino) generally decrease ease
of Birch reduction and give 2,5-dihydroderivatives (6) ~ Electron with
drawing groups (COOH, amide) give increased ease of reduction and give -, 1,4-dihydroderivatives as illustrated in Fig. 1.
R. R M r L,[q_ NH3 ---~ ROH - 1--1 0 -N ..- cH, H R= -cH -oc.H . 3 I ~I -.. Gf-3
cooH H cooH M+ Liq NH3 I. 0 :ROH \-\ \-\
Figure 1
4 Kuehne and Lambert (6) reported the reduction of the ring of ben-
zarnide in high yields using :!2_-butanol but not using ethanol. However, Niem (10), Dickson (27) and Qazi ( 36) found that reduction of the ring rather than amide group occurred using either ethanol or :!2_-butanol. The following 1,4-dihydro-3,5-dimethoxybenzarnides (Table I) were obtained from Birch reduction of 3,5-dimethoxybenzamide, 3,4,5-trimethoxy benzarnide or N-alkyl-3,4,5-trimethoxybenzarnides (6).
TABLE I
A B %yield -~ 1\ R2 OCH OCH H H 90* 3 3 OCH OCH H 90 3 3 c2~ 1\ 13 OCH OCH H CH(CH ) 74 d H H 3 3 3 2 OCH OCH CH 6 3 3 CH3 3 OCH OCH H 8 3 3 C(CH3)3
* About the same yield of 1,4-dihydro-3,5-dimethoxybenzamide was obtained from 3,5-dimethoxy benzarnide as from 3,4,5-trimethoxybenzarnide.
The yield of the substituted 1,4-dihydro-N-:!2_-butyl-3,4,5-trimethoxy- benzamide was much lower than that obtained from the other mono-N-substi-
tuted trimethoxybenzamides . Thus, in that compound the amide apparently behaves as one which can not be stabilized by a negative ion (N,N-dimethyl compound). Since methyl, ethyl and isopropyl groups have no similar large effect, the size of the single substituent on the nitrogen may be :important.
5 The acidity factor plays a great role in the protection of amide
groups (6~ 10, 27). A comparative tabulation of the acidities of benzoic
acid, benzamide and benzenesulfonamide showed (Table II) that the order of acidity is ~co 2H) ~S0 2NH 2 ) ~CONH2 , (36) •
TABLE II
-K P a
Benzoic acid 4.5
Benzamide 15-16
Benzenesulfonamide 10 l Ethanol 18 t-Butanol 19
Benzoic acid is highly acldic, so anionic form of carboxyl group
L is protected during Birch reduction. According to Lambert and Kuebne
(6) benzamide is a weak acid so it does not exist in anion form and the
amide group undergoes Birch reduction in presence of ethanol. They found
the use of a weaker proton source (!_-butanol) preferentially led to re-
duction of the ring rather than the amide group.
Benzenesulfonamide is more acidic than benzamide, therefore it is
logical to predict that the ring rather than the sulfonamide group would
be reduced when either !_-butanol or ethanol is used as proton source.
However, it is well known that in the case of p-toluenesulfonamides,
6 the functional group is reduced to thiocresol (19) as shown in Figure 2.
Figure 2.
1~ Na./NH'. Rf!N- -oJ _ S \ CH 11 \\ II ~ RoH 0
Kovacs et al (19) reported that during Birch reduction of the sub-
stituted tosylsulfonamide follows two paths. Cleavage of carbon-sulfur
(a) bond gives sulfur dioxide and toluene whereas cleavage of sulfur-
nitrogen bond (b) yields s ulfinic acid which undergoes further reduction
to both p-thiocresol and toluene, as depicted in Scheme II.
Scheme II. j G..-. b !
b
7 The liquid ammonia cleavage of p-toluenesulfonamide gave 70-80% of sulfite and 10-14% of thiocresol when 3.5 g atoms of sodium was used (19) Table III.
TABlE III Coll'q)ound g. a toms of % sulfite %thiocresol sodium/mole Iodometric
p-Toluenesulfonamide 3.5 70, 81 14, 10 p-Toluenesulfonamide 2.5 59, 65 traces
Later Closson and his coworkers (21) studied the similar reduction
of N-ethyl-N-phenyl-p-toluenesulfonamide in dimethoxyethane with sodium
naphthalenide. The stoichiometric data is provided in Table IV.
TABlE r1 The Products from the Cleavage of N-Ethyl-N-Phenyl-p-Toluenesulfon r amide with Sodium-Naphthalenide in Dimethoxyethane at 25° C*.
%yield **
Exp. No. Molar ratio Toluene Ethyl- Na s Na S 0 *** of arenide aniline 2 2 2 3 to sulfonamide
1 9 85 100 20 29 32 2 7 78 99 23 23 46
* Reaction time = 12 hr ** Yield based on sulfonamide *** Calculated on the basis of sulfur content
8 Closson ( 21) proposed a possible mechanism for N-ethyl-N-phenyl-
p-toluenesulfonamide cleavage by arene anion radical as depicted in
Scheme III.
SCHEME III.
'Sodiww, No.phth~;lide
'D i 'YYl et\-, 0 )( 'f e.tho..m e e 2.C1oHs 'f. C. a:"-e11e AA'I i crY\ "1'-o.d i co. I ) '
1 (Qffll j de, CVYiiO')'))
e e ?.- SOi + C1o Hg• --'>) S 02. + (I o H 8
e 0 • 2.. s :1-
9 It occurred to Dr. C.A. Matuszak and his coworkers to study arene sulfonamide reduction by Birch method var~ing different experimental parameters. They reported in 1965 ( 10) that benzenesulfonamide can be reduced using ethanol or t-butyl alcohol as a proton source and found that the Birch reduction preferentially reduced the sulfonamide group rather than the arene ring. Thus reduction of sulfonamide does not resemble the reduction pattern of aromatic amides or acids.
This thesis is a report on the study of the Birch reduction of benzenesulfonamide and alkyl-substituted sulfonamides. This work was carried out in order to elucidate the role of steric factors, to ex amine the possibility of a large temperature effect (-33° vs ~75° C) and to see the effect of no acidic hydrogen on the sulfonamide nitrogen.
With this objective the Birch reduction of benzenesulfonamide
N,N-dimethylbenzenesulfonamide· and N,N-diisobutylbenzenesulfonemi.de were performed at -33°C and -75°C as well as 2,4,6-trimethylbenzene suJ.foncunide (2-mesitylenesulfonanride) at -33°G.
10 Chapter II DISCUSSION AND RESULTS
The present study involved the Birch reduction of benzenesulfonam1de, N,N-dimethylbenzenesulfonamide, N,N-diisobutylbenzenesulfonamide and 2-mesitylenesulfonamide. It has been previously shown (10) that benzenesulfonamide gives thiophenol and diphenyldisulfide upon Birch reduction. The sulfonamide .group is easily reduced. Probably the electron deficient sulfur atom in sulfonamide can accommodate an electron easily. Diphenyldisulfide could have formed as shown in Figure 3 by dimer ization of thiophenyl radicals possibJy formed during reduction or by direct air oxidation of thiophenol during work-up.
Figure 3.
The reduction follows two competing pathways of reduction (19)
as shown in Scheme DJ. A higher yield of thiophenol would result when pathway (b) is favored over pathway (a).
ll Scheme IV. a.. b R H :1? j /R 5--:-N · II : ...... R 0 . 0 :
No../NH?;, RoH (a.. (j,)
There were several experimental factors which effect the amount
of thiophenol isolated. ~nall amounts of thiophenol were being handled
in the work-up and millor losses affected the yield appreciably. The b .p. of thiophenol is 168°C and some loss by evaporation probably oc-
curred during removal· of ether and ethanol using the rotatory evaporator
12 under vacuum with hot water for heating. Any unx'ellloved ether or ethanol in the san:ple would increase the apparent yield of thiophenol. Mechanical losses undoubtedly also occurred.
Birch Reduction of'Benzenesulfonamide:
Birch reduction of benzenesulfonamide yielded thiophenol and diphenyl~ disulfide. Benzene formation was assumed but no attempt 1<1as made to isolate it , The reaction is shown in Figure 4,
o c. •C Li / li(jl NH3 -33 o-'t -'l5 Abso. EtoH /NH4-c.l CASSLI'YYiecl) + <(1}-s--6-Q
Figure 4
~be reduction was carried out seventeen times under various ex- perimental conditions, (See Table V.) The range of yields of thiophenol ran from 10 to 28% (average 18%) but none of the experimental variations c.aused a :!hange in the yield beyond experimental error. Thiophenol was identifled by comparison of its ir spectrum with the ir spectrum of authentic thiophenol .. A small amount of solid was also often present
13 ! . --~'-
TABLE V
BIRCH P.EDUCTION OF BENZENESULFONAMIDE*
Reduction Reduction• Product ** No. ·Temperature % yield
1 -75°C 22.3% (1.155 g) 2 -75°C 19.9% 3 -75°C 20.7% 4 -33°C 21.6%
1--' 5 -33°C 15. 2% some material was -1=" lost during work-up; 6 -33°C 21.0%
NCJI'E: * In each reduction 7.4 g (0.0471 mole) benzenesulfonawdde, 2.678 g (0.4 mole) lithium, 65 ml absolute ethanol and 21.4 g (0.4 mole) =nium chloride were used
** In each case the isolated reduction product was a mixture of mostly thiophenol and small amount of diphenyldisulfide. The yield calculated as if all the product was thiophenol. Benzene is also assumed to fonn. I , __ ,_ L_ ,--·--- --'"' , --'·~--
TABlE: V -Continued
BIRCH REDUCTION .OF BENZENESULFONAJVIIDE ***
Reduction Lithium Absolute Reaction Product ** - No. Ethanol Temperature % yield
7 2.768 g 65 ml -33°C 16.8% (0.4 role)
8 2.768 g 65 ml -33°C 15.0% (0.4 mole)
9 5-536 g '65 ml -33°C 15.2% (0.8 mole) 1-' \.YI 10 1.384 g 65 ml -33°C 10.1% (0.2 mole)
ll 11.072 g 105 ml -33°C 12.3% (1.6 mole)
12 5.536 g ,65 ml -33°C ll.O% (0.8 mole) 43.77 g (0.8 mole) some material was lost ammonium chloride during work-up
13 5-536 g '65 ml -33°C 23.4% (0 .8 mole)
NOTE: ***In each reduction 7.4 g ~0.0471) benzenesulfonamide and 21.4 g (0.4 mole) ammonium chloride were used. I In reduction 7 and 8 specially dried ammonia was used (see for detail experimental reduction 7). TABLE V - Continued ,
BIRCH REDUCTION OF BENZENESTJLFONAMIDE ***
Reduction Lithium Proton Reaction Product ** No. SoUrce .Temperature % Yield
14 **** 2.768 g 65 ml -33°C 28.2% (0.4 mole) absolute ethanol ' 15 **** 2.768 g 65 ml -75°C 21.4% (0.4 mole) ab~olute
I-' ethanol "' 16 2.768 g 20 ml -33°C 14.0% (0.4 mole) t-butanol 17 2. 768 g 5Q ml -33°C 15.5% Thiophenol (0.4 mole) t-butanol Diff work-up 2.34% Diphenyldisulfide see exp. reduc. 17
NOI'E: **** In reduction 14 and 15, different lithium metal was used (for detail, see experimental reduction 14). and believed to be diphenyldisulfide. In one case (17th reduction) the diphenyldisulfide was isolated and had the same melting point as reported for diphenyldisulfide. The presence of small aiDJunts of diphenyl disulfide did not alter the ir spectrum of thiophenol noticeably (see
figure 8 ) .
Reductions 1,2, and 3 were done at -75°C using dry ice and acetone while 4,5,and 6 were performed at the b.p. of anmonia (-33°C). There was no significant effect of temperature upon the yield.
In reductions 7 and 8, specially dried am:nonia, prepared by first refluxing the liquid ammonia with lithium, was used to see if precluding the possibility of water being a proton source could be important. No
significant effect on the yield of thiophenol occurred.
To examine the effect of moderate changes in the amount of lithium used, exper·iments 9,10,ll,l2 and 13 wen~ perfor·med. In 9 and 13, double the usual arnount of lithium was used. In 10, the amount was half, in
- 11 the amount was four times and in 12, the amounts of both lithium a'1d am:noniurn chloride were double. The yields of the products indicated that within these limits, variations in the amounts of lithium have n:J large effect. Since 6 equivalents of metal are theoretically needed to reduce benzenesulfonamide to thiophenol via benzenesulfinic acid, the 4.25 equiv. used i11 experiment 10 does not seem enough to reduce all the benzenesulfinic acid intermediate. However, since a major part of the
starting material was reduced via path (a) (Scheme IV) to benzene which
requires only 2 equivalents, there is theoretically more than enough.
In experiments 14 and 15,_ the lithium used had been in the department
17 for more than seven years and its origin was unknown. Ne:!m (10) u:sed this lithium and he reported higher yields of thiophenol and diphenyl disulfide than that found in the present investigation. But the present investigation showed that the use of the same lithium had no large effect upon the yields of thiophenol.
In reductions 16 and 17 !_-butanol was used instead of absolute ethanol with no significant effect upon the yield of thiophenol.
Benzenesulfinic acid may be a possible initial product of benzenesul fonamide reduction, but no attempts were made to isolate it.
Reduction of N,N-Dimetnylbenzenesulfonamide:
Reduction of N,N-d:!methylbenzenesulfonamide was performed eight times (see Table V) under different experimental parameters using the sa.'Jle procedure and work-up as with benzenesulfonamide (see Figure 5).
'Ihe yields of thiophenol were much higher ( 55-73% ,average 67%) , than from ben~en~sulfonamide itself (10-28%, average 18%). 'l'hus the presence of the two rr:ethyl groups on nitrogen seems to favor path (b) of Scheme
IV versus path (a), compared to unsubstituted benzenesulfonamide.
The experiments 1 and 2 were done at -33°C, the boiling point of ammonia whereas 3 and 4 were done at -75°C, the dry ice and acetone temperature. In experiments 5 and 6 (-33°C) and 7 and 8 (-75°C) specially dried arrnnonia was used. 'Ihe exper:iinental variables examined did not cause a change in thiophenol yield outside the exper:!mental error.
18 --·"'"'--'--· L - ---~~,~~·~---.:..·--'--~--' _----'..-''---'-·--'---L..LJ-"--";"-----~- ' --- i ' _j~--
TABlE VI
BIRCH REDUCTION OF N ,N-DTIVJETHYLBENZENES\JLFDNAMIDE * Reduction Reduction A111rnonia Product: % Yield No. Temperature, Calculated as all thiophenol
l ** -33°C Approximately 55.4% Some loss during work-up 2 -33°C 600 ml of 61.0% 3 -75°C arihydrous liquid 73.0% 4 -75°C ammonia 73.16%
5 *** -33°C Approximately 69.0% 6 -33°C 600 rnl of 69.69% 1--' \D 7 -75°C specially dried 70.65% 8 -75°C liquid ammonia 68.34%
NOI'E: * In each case 8. 713 g ( 0. OIH mole) of N,N-dimethylbenzenesulfonami.de, 2.768 g (0.4 mole) of lithium, 20 ml of absolute ethanol, and 21.4 g (0.4 mole) of ammonium chloride were used.
** In 1,2,3 and 4 reductions, 600 rnl of ammonia were used. *** In 5,6, 7 and 8 reductions, 600 rnl of specially dried ammonia were used. For specially dried ammonia, see exper:!mental. Reduction. of N,N-Diisobutylbenzenesulfonamide:
To examine the steric effect of bulky alkyl substituents on nitro
gen, six reductions of N,N-dilsobutylbenzenesulfonamide were performed . ., (See Table VII).
The products were thiophenol and diphenyldisulfide as shown in Figure 4.
However, the finding that substantial amounts of starting material were
recovered indicates that isobutyl groups retarded the reduction. 1be
yield of thiophenol (36-53%, average 46% based on consumed starting mater
ial) is somewhat lower than from N,N-dimethylbenzenesulfonamide ( 55-73%,
average 67%), but much higher than from benzenesulfonamide (10-28%,
average 18%) .
. Experiments 1 and 2 were run at - 33°C and 3 and 4 were run at -75°C.
The recovery .of the starting material was higher at -75°C ( V) 70%) than
at -33°C ( <11 30%). J- In reductions 5 and 6 (-33°C) the amounts of lithium and alcohol were doubled but did not appreciably increase the amount of reduction.
In these reductions excess lithium.probably reacted with alcohol. to
form hydrogen.
Reduction of 2-Mesitylenesulfonamide:
It is well known that benzoic acid (32) can be easily esterified
with alcohol in the presence of acid, whereas mesitoic acid ( 2, 4, 6-
trimethylbenzoic acid) does not undergo this type of esterification due
to the steric effect of the two ortho methyl groups. It interested us
to subject 2-mesitylenesulfonamide (2,4,6-trimethylbenzenesulfonamide)
20 ___ l ,,. ___ .____ !_ -~~-
I TABlE VII
BffiCH REDUCTION OF N1,N-DIISOBUTYI.BENZENESULFONAMIDE *
Reduction Lithium Absolute Reduction Ammonium Product * No. Ethanol Temperature Chloride %Yield
1 2.768 g 20 ml -33°C 21.4 g 32. 8% starting material (0.4 mole) (0.4 mole) (a) 27.8% Thiophenol (b) 41.2% Thiophenol
2 2.768 g 20 ml -33°C 21.4 g 28. O% starting material (0.4 mole) (0.4 mole) (a) 26.0% Thiophenol (b) 35.7% Thiophenol
3 2.768 g 30 ml -7~C 21.4 g 74.8% starting material f-' (0.4 mole) (0.4 mole) (a) 11.0% Thiophenol "' (b) 41.9% Thiophenol
4 2.768 g 30 ml -75°C 21.4 g 67.6% starting material (0.4 mole) (0.4 mole) ·(a) 17.1% Thiophenol (b) 53.0% Thiophenol
5 5.536 45 ml -33°C 42.8 g 24.2% starting material (0.8 mole) (0.8 mole) (a) 39.2% Thiophenol (b) 52.0% Thiophenol
6 5-536 45 ml -33°C 42.8 g 24. 5% starting material (0.8 mole) (0.8 mole) (a) 39.0% Thiophenol (b) 51.5% Thiophenol I NO.I'E: * In each case, 12.688 g (0.0471 moleD of N,N-diisobutylbenzenesulfonamide was used. The %yield of thiophenol was calcu1Lated (a) in relation to all 12.688 g of starting material and (b) in relation to material consumed ( 12. 688 g minus the am:>unt recovered) • I to the Birch reduction in order to find out if .there is a similar retarding
steric effect of the ortho methyl groups on this reduction.
2-Mesitylenesulfonamide was subjected to four reductions (See
Table VIII) and yielded mesitylene, 2,4,6-trimethylthiophenol and mesityl- disulfide as shown in Figure 5, The later two were formed in combined yield (13-37%, average 27%) about the same or slightly more than from benzenesulfonamide. The mesitylene was characterized by comparison with ir spectrum and glc of known sample of mesitylene.
so2_NH2. ""'.:::::: CHJ L.i (li CH3 c,\-13 r-----< ··if ··~······ s ; ~---·-_···-;;.... ~ c Figure 5. ·'· 22 cCC- _1, , '""-~~~- - __ j ;TABLE: VIII BIRCH REDUCTION ,OF' 2-~'IESITl.wENESULFONJ\ll'liDE * Reduction LithiUm Absolute A'llDlonimn T:iJll.e Interval Product No. Ethanol Chloride between reduc- % Yield and tion and work-up Reaction Temperature l 2.768 g 20 rrJ. 21.4 g about 4 hrs. 33.33% Mesitylene (0.4 mole) ~33°C (0.4 mcle) (some material used for IR) 20:27% 2,4,6-Trirnethyl- thiophenol 1\) w 2 2.768 g 20 ml 21.4 g about 16 hrs. 21.27% Mesitylene (0.4 mole) -33°C (0.4 mole) 2.13% 2,4,6-Trimethyl- thiophenol ·21. O% Mesityldisulfide 3 2.768 g 20 ml 21.4 g about 16 hrs .-: 23. O% r1esitylene (0.4 mole) -33°C (0.4 mcle) (some material was lost during work-up) 10.69% 2,4,6-Irimethyl- thiophenol 20.00.% J'fJesityldisUlfide 4 2.768 g 20 ml 21.4 g about 4 hrs. 41.71% !1esitylene (0.4 mole) '-'33°C (0.4 mole) 28.30% 2,4,6-Trimethyl- thiophenol i NOI'E: * In each reduction 9.385 g (0.0471 mel~) of 2-mesitylenesulfonamide and approximately 600 ml of dry liquid ammonia were used. In reductions 1 and 4 the time interval between the reduction and work-up was about 4 hours whereas in 2 and 3 it was 16 hours. The yield of mesityldisulfide versus 2,4,6-trimethylthiophenol was greatly in creased in reductions 2 and 3. This indicates that 2,4,6-trimethylthio phenol air oxidized more easily than did thiophenol. This might be due to increased stability of the thiol radical intermed:iate due to the electron donating ability of methyl group as shown in Figure 5. Thus di-ortho alkyl substitution in the arene ring did not slow down the reduction or change the nature of the reduction products. However, there could be differences in the ease of the reduction of 2- mesitylenesulfonamide compared to benzenesulfonamide that these experiments were not sensitive enough to detect. J - f 24 SUMMARY AND CONCLUSION 1. Birch reduction of benzenesulfonarnide using lithium and absolute ethanol or t-butanol yielded thiophenol (10-28%, avera§e 18.3%, 17 exper:illlents) and small amounts of diphenyldisulfide. Benzene is assumed to also form. Variation in temperature (-33°C vs -75°C), variation in the amounts of lithium from four times to half the usual amount and the use of specially dried ammonia vs undried ammonia did not effect the yield within experimental error. 2 . Reduction of N,N-dimethylbenzenesulfonarnide also yielded thiophenol plus small amounts of diphenyldisulfide but in much higher yield ( 55-73%, average 67%, 8 experiments) than benzenesulfonarnide, The use of' -33°C vs -75°C or specially dried aJm.onia vs undried ammonia did riot effect the yield within experimental error. 3, The reduction of N,N-diisobutylbenzenesulfonarnide resulted in recovery of starting material with more recovered using -75°C than -33°C. This indicated that bulky alkyl substitution in sulfonamide group did retard the reduction. The yield of' diphenyldisulfide and thiophenol ( 36-53%, average 46%, 6 experiments) based on consumed starting material, was not affected by temperature (-33°C vs -·75°C) within experimental error but seems to be somewhat less than the yield from N,N-dimethylbenzenesulfonarnide but substantially is larger than from benzenesulfonarnide. 25 4. 'lhe reduction of 2-mesitylenesulfonamide at -33°C gave 2,11,6-trimethyl thiophenol (20-37%, average 27%, 4 experiments) and mesitylene (21-42%, average 26%) leaving no starting material. Mesitylene was identified by corrparison by :i.r and glc with known mesitylene. Thus di-ortho methyl substitut.i.on did not cause an observable change in reduction within the limits of the experiments perfonred. The 2,4,6-trimethylthiophenol was more readily air oxidized to mesityldisulfide than was thiophenol itself. i I ' 26 SUMMARY OF GENERAL EXPERIMENTAL PROCEDURES In all of the reducUons the arru:nonia was distilled from the gas cylinder and condensed into the reaction flask by a dry ice-acetone condenser but was not dried \mless so indicated. '!he lithium (Foot Mineral Co.) used was cut from llDiform thickness lithium ribbon that was protected by petrolatum. '!he petrolatum was removed by washing the lithium ribbon in a series of baths of low-boiling petrolemn ether and cut into small pieces just before use. A rotatory evaporator with partial vacuum from a water aspirator ··- and a hot v Organic solvents used were, in general, not distilled prior to use. Reductions were performed at either refluxing arru:nonia (-33°C) or at about -75° C using dry ice-acetone bath and Wilds and Nelson's ( 3) pro cedure of adding the alcohol last . 27 EXPERIMENTAL Preparation of Benzenesulfonamide: To 800 ml of concentrated ammonium hydroxide, 314 g (2.00 mole) of benzenesulfonylchloride was slowly added over a period of 20 minutes wlth constant stirring. An additional 400 ml of concentrated ammonium hydroxide was slowly added into the mixture and the mixture was allowed · to stand for four hours. The excess ammonium hydroxide was decanted from the sol:l.d benzenesulfonsmide which was then washed with three 200 ml portions of distilled water. The benzenesulfonamide was recrystallized from water, yielding 240 g (1.53 mole, 76% yield), melting point 1511·-155°C (lit. (10) rn.p. 155ac) and·had an ir spectrum identical to a known sanple of' benzenesulf'onamide. REDUC'l'ION OF BE:NZmESULFONAMIDE: Fi:rst Reduction of' Benzenesulfonamide (-75°C). Benzenesulfonamide, 7.4 g (0.0471 mole) was added to 600 rru of dry Hquid ammonia in a two liter, three-necked flask equipped with a mechan ical stirrer, a dropping furmel and a dry ice condenser. 'lhen 2.768 g (0.400 mole) of lithium ribbon, after being cleaned of 1.ts protective coating of petrolatum in a series of baths of low boiling petroleum ether, was added in small pieces over a period of 15 --~ minutes with stirring, to the mixture of benzenesulfonsmide and liquid 28 amnonia. While the solution was stirred, 65 ml of absolute ethanol was added over a period of 30 minutes. The reaction was held at -75°C, the temperature of dry ice and acetone. After the blue color of the rrd,xture had disappeared, 21.4 g (0.4 mole) of amnonium chloride was added very slowly to reduce the basicity, and the Jlli.xture was stirred an additional hour. The amnonia was allowed to evaporate overnight at ambient temperature and pressure. The residual material was dissolved in 200 ml of ice cold distilled water. After acidification with 10% hydrochloric acid to pH 1 to 2, the solution was extracted with four 100 ml portions of ether. The com- bined ether solution was dried over 3 g of anhydrous magnesium sulfate. The ether and ethanol was removed by using a rotatory evaporator under reduced pressure. The remaining light yellow liquid weighed 1.155 g (22. 3% yield). The ir spectrum of the reduction product (Figure 6) was identical to the spectrum of known thiophenol (Figure 7). The ------ir spectrum of known thiophenol was not affected appreciably by the addition of .small amounts of diphenyldisulfide (Figure 8). Second Reduction of Benzenesulfonaw~de (-75°C). Tne experimental conditions (equipment, quantities of reagents and reaction temperature) were the same as the first reduction of ben- zenesulfonsmide. The isolated light yellow liquid weighed l. 032 g (19.9% yield) and its ir spectrum was the same as the .ir spectrum of thiophenol. 29 , --·--·' - --'---- '- ---~ '· ·--·~--- .. L__ , ___ ,.. -~~-----'-,___.,___ -- __.____1______~-_ ___ ,, ------_, ~----~~-- _, -·'"----'--'-'-"--'--~"----~--.. ·-·--- I , I 4000 3000 2000 1500 . cM-l 1000 900 800 700 .0 .10 .lO• J.J J 20r• z· -=; •.L "0 <( "'"""' 30 ~'i-·__ ,_,~ -, ::!:: • H ..i [!L _ .30 ::> ~.40 '.40 ~.50 -·50' .60f::i_ .70- . '• ; i\ i -, --- --rr T - -. .. ______• i . =·ki~~ J!s_, ... ~- "1 1 ~~ ' ~-- L-~- ~ ~- ~~ __ , ~ +- _ _ ~.. -~. 60. .: eg&JT ,, '-" · ~ · ,_, - I - I 70 c 1 I ' " " • , i 'i! " i 1II , ' ' i iI 1 , 1= 0 ' " Ir Spectrum of Thiophenol from First Reduction Product of Benzenesulfonarnide (Neat) Figure 6 w 0 '-~--~--"· --·· .. J I 4000 3000 2000 1500 CM·1 1000 900 800 700 I' I _j I 0.0 -&rti:: + il In' I ! .10~ .10 I . ±' c[c·'f't .. lu !I-I--· ··I il! ~~~~~~~~~~~+--·'-J..._J_ J=i:cffcffl I . ~ IJF ·1'-.. rl·.'t}1 ~f:fi'.' X, r::c.l ~c·•. -~ . =~=t=t" + .. ·- e: "': - cc=Rcl=i= . · + · .. _ = ..o;c+• -i'it~:·ooc-lc -Lf.4' 1 ft 1- 11 I · I • ~~-~ '"'t.c.cLcL· • -• ·•-1-•- 1 ; I 1 I 1-\-- 1 • I I i I I • I lo 11 ll 1 00 • -+- . i I ' _[I i I I I ~ i I . 00 '· II ! I 15 3 4 5 6 7 8 9 10 11 12 13 14 W AVE~ENGTH (MICRONS) Ir Spectrum of known Thiophenol (Neat) (Eastman Kodak) LV 1-' ' Ffca:ure 7 , ______---- ______,______.., ______,, ___ ,_---'-..,.C .. _ -.LC...J•~·-"·''""---'-~- ····------ I 4000 3000 2000 1500 I cM-1 1000 900 800 ;700 .10 10 ;_u ~.20 a <( ~.30 '.30 0 fj)ca· 40R-r <( H, .50 .60 -- .7 Q -::- r:-,.::··· _:;::_--'~ _ .--:.-. .•. -· __ ,- ·== ·1=1- =1-1=-" ,_ 1 1·- :.J=.:l=l :::r: ·:t::;:::t:.: ~ - ·-,:::c:-· - =t= - ;::;r___:;);::=-t- ·:::::r_:::.. ·· :--:·=r-. 8=E: .. : _-,-1 -l---- . -- ·~..:..:7::r: •.tJ:__ :-::.;-_.:::_ ' I i ! I 1 I I I I I I ! I "' ! i ,,, 1( 10• I I , • I I I 00 00 3 4 5 6 7 8 9 10 11 12 13 4 15 WAVELENGTH (MICRONS) Ir Spectrum of !mown mixture of Thiophenol and Diphenyldisulfide. (98% Thiophenbl and 2% Diphenyldisulfide) (Neat) Figure 8 w 1\) Third Reduction of Benzenesulfonamide. The factors were the same as the first reduction (-75°C). 'rhe isolated yellow liquid weighed 1.07 g (20.7% yield). Their spectrum was identical with the spectra of the first and second reduction product. Fourth Reduction of Benzenesulfonamide. The exper:ilnental conditions, equipment, quantities of reagents and wor·k-up were the same as in the first reduction except that the reaction temperature was -33°C. The isolated light yellow liquid weighed 1.2 g (21.6% yield). Fifth Reduction of Benzenesulfonamide. The conditions were the same as the fourth reduction (-33°C). There was an accidental loss of some compound during I'Otatory evaporation i l to remove the ether. The isolated light yellow liquid weighed 0. 787 g ( 15. 2% yield) . Sixth. Reduction of Benzenesulfonamide. 'l'he set-up, exper:ilnental conditions, ·quantities of reagents and work-up were the same as the fourth reduction of benzenesulfonanrl.de (-33°C). The isolated light yellow liquid weighed 1.09 g (2l.O%_yield). Seventh Reduction of Benzenesulfonamide. The procedure was the same as the first reduction except for the arrnnonia used and the reaction temperature. The liquid ammonia was first 33 dried by being refluxed for two hours with 5 g of lithium in a two liter, three-necked flask with stirring. It was then distilled into another two-liter, three-necked flask for the reduction. 'Ihe reduction reaction temperature was -33°C, the boiling point of arrnnonia. 'Ihe light yellow liquid weighed 0.868 g (16.8% yield). Eighth Reduction of Benzenesulfonamide. 'Ihe same experimental conditions, quantities of reagents and work-, up were used as ih the.sevehth reduction (-33°C). TI1e isolated light yellow liquid weighed 0.797 g (15.0% yield). Nineth Reduction of Benzenesulfonamide. 'Ihe factors were the same as the fourth reduction (-33°C) except that double the aT!JOunt (5.536 g, 0.8 mole) of lithium was used. 'Ihe isolated light yellow crude liquid 0.789 g (15.2% yield). Tenth Reduction of Benzenesulfonamide. Here the procedure, the reagents and the reaction were the same as the fourth reduction (-33°C) except that one half the amount (1.384 g, 0.2 mole) of lithium was used. 'Ihe extracted li@1t yellow crude liquid weighed 0.526 g (10.1% yield). Eleventh Reduction of Benzenesulfonamide. 'Ihe parameters were the same as the fourth reduction (-33°C) except that four times the amount (11.07 g, 1.6 moles) of lithium and 105 ml 34 of absolute ethanol were used. The isolated light yellow liquid weighed 0.636 g (12.3% yield). Twelfth Reduction of Benzenesulfonamide. Everything was the same as in the fourth reduction (-33°C) except that double the amount ( 5 . 536 g, 0. 8 mole) of lithium and 4 3. 77 g ( 0. 85 mole) of ammonium chloride were used, yielding 0.568 g (11.0% yield) light yellow liquid product; the ir spectrum was identical to the ir spectrum of the previous reduction products. Thirteenth Reduction of Benzenesulfonamide. The factors·(-75°C) were the same as in the first reduction except that double the amount (5.536 g, 0.8 mole) of lithium was used, yielding 1.212 g (23.4% yleld) of light yellow liquid. ------Fourteenth Reduction of Benzenesulfon8inide. ·· In this reduction the major change was that the 2. 768 g ( 0. 40 mole) of lithium used was in large pieces which had been in the department for years and whose origin is unlmown and which Neim (10) used. It was cleaned using low boiling petroleum ether, flattened, and cut into small pieces. The amounts of benzenesulfonamide, absolute ethanol and arrmonium chloride, the reaction temperature (-33°C) and the isolation procedure were the same as the fourth reduction. The light yellow liquid weighed 1.46 g (28.2% yield). 35 Fifteenth Reduction of Benzenesulfonamide. Everything was the same as the fourteenth reduction except that the reaction temperature was -·75°C. The light yellow liquid weighed ., 1.11 g (21.4% yield). Sixteenth Reduction of Benzenesulfoncurrl.de. The set-up, work-up, quantities of reagents and experimental con ditions were the same as the fourth reduction (-33°C) except that 40 rol of t-butanol was used instead of absolute ethanol. The isolated liquid weighed 0.726 g (14.0% yield). The product's ir spectrum was not sig nificantly different from the ir spectrum of the products of the previous reductions. Seventeenth Reduction of Benzenesulfonamide. Ir1 this_re(j_uctlon the major ch§Ilge .was the work-up. 'I'he quantities of reagents, reaction temperature and procedure were the same as in the six teenth reduction ( -33°C). The residual material was dissolved in 200 ml of ice cold distilled water and acidified with 10% hydrochloric acid to pH l to 2; the solution was extracted wlth four 100 ml portions of ether. The ether extract was again extracted with four 100 ml portions of 10% sodium hydroxide. The ether solution was dried over 3 g of anhydrous magnesium sulfate and was concentrated using the rotatory evaporator. The remaining di phenyldisulfide weighed 0.12 g (2. 34% yield), m.p. 66-68°C [lit. (3'7) m.p. 68°C]. 36 The above basic solution was acidified with .10% hydrochloric acid to pH 1 to 2 and was extracted with four lOO rnl portions of ether. The ether solutions were combined and dried over anhydrous magnesium sulfate. The ether and ethanol were removed using a vacuum rotatory evaporator. The remaining light yellow liquid weighed 0 .804 g (15. 5% yield), n~5 l. 5260, [lit. (37), n65 l. 5893] and was identified from its ir spectrum as thiophenol by comparison with ir spectrum of an authentic sample. The refractive index is lower than the literature value. This is probably due to presence of some diphenyldisulfide and/or solvent. 37 Preparation of N,N-Dimethylbenzenesulfonamide: One hundred grams ( 2. 5 mole) of sodium hydroxide was dissolved in 200 ml of distilled water, and the solution was allowed to cool. Then 100 g (1.1 mole) of dimethylamine hydrochloride was slowly added followed by 200 ml of ether. The solution was constantly stirred by a magnetic stirrer for 30 minutes, while 80 g (0.46 mole) of benzenesulfonylchloride was slowly added. The ether layer was decanted and evaporated at room temperature yielding 85 g (0.40 mole~ 80% yield) of solid N,N-dimethyl benzenesulfonamide white needle crystals, m.p. 47-48°C [lit. (ll) m.p. 48°C]. REDUCTION OF N,N-DIMETHYLBENZENESULFONAMIDE. First Reduction of N,N-Dimethylbenzenesulfonamide (-33°C). In a three-necked, round-bottomed, two liter flask, equipped with a mechanical stirrer and dry ice condenser, was placed 8. 7155 g ( 0. 04'(1 mole) of N,N-dimethylbenzenesulfonamide and approximately 600 ml of anhydrous liquid ammonia. Then 2.768 g (0.4 mole) of lithium ribbon was cleaned of its pro~ tective coating of petrolatum in a series of baths of low boiling petro- leum ether and was added in small pieces over a ·period of 15 minutes with stirring at -33°C (boiling point of amnonta). While the soluUon was sti.rred, 20 ml of absolute ethanol was added over a period of 30 minutes. After the blue color of the mixture had disappeared, 21.4 g (0.4 mole) of amrr.on:tum chloride was added very slowly to reduce the basicity. and the mixture was stirred an additional hour. The amnon:ta was allowed .i to evaporate overnight at ambient temperature and pressure • j ' 38 The residual material was dissolved in 200 ml of ice cold distilled ·water. After acidification with 10% hydrochloric acid to pH 1 to 2, the solution was extracted with four 100 ml portions of ether. The. combined ether extracts were dried over 3 g of anhydrous magnesium sulfate and the ether and ethanol were removed using a rotatory evaporator under vacuum. The remaining light yellow liquid weighed 2. 87 g (55. 4% yield) • i I Second Reduction of N,N-Dimethylbenzenesulfonamide, The experimental conditions, equipment, quantities of reagents, reaction temperature (-33°C) and work-up were the same· as in the first reduction of N,N-dimethylbenzenesulfonamide. The extracted light yellow liquid weighed 3.16 g (61.0% yield). Third Reduction of N~-Dimethylbenzenesulfonamide. The factors were the same as in the first reduction of N,N-dimethyl- benzenesulfonamide except that the reaction temperature was -75°C. Reaction work-up yielded 3.79 g (73.0% yield) of light yellow liquid whose ir spectrum was identical to the spectrum of the product of the first reduction. Fourth Reduction of N,N-Dimeth.ylbenzenesulfonamide, 'Ihis reduction was the same as the third (-75°C), yielding 3. 79 g (73.16% yield) of product. 39 Fifth Reduction of N,N-Dimethylbenzenesulfonamide. The parameters were the same as the first reduction of N,N-dimethyl benzenesulfonamide (-33°C). The major change being that the arrmonia was dried prior to use in the reduction by refluxing with 5 g of lithium for an hour in a two liter, three-necked flask with stirring. It was then distilled into another two liter, three-necked, round-bottorr.ed flask for the reduction. The isolated light yellow liquid weighed 3.73 g (69.0% yield). Sixth Redu~tion of N,N-Dimethylbenzenesulfonamide. The parameters were the same as the fifth reduction (-33°C), yielding 3.61 g (69.69% yield) of light yellow liquid. Seventh Reduction of N1 N--Dimethylbenzenesulfonamide. The set-up, work-up and quantities of reagents were the same as the- -- -- fifth reduction except that the reaction temperature was -75°C. The isolated light yellow liquid weighed 3.66 g (70.65% yield). Eighth Reduction of N,N-Dimethylbenzenesulfonanrl.de. The factors were the same as the seventh reduction (-75°C). The isolated lig.ht yellow liquid weighed 3.54 g (68.34% yield). 40 Preparation of N,N-Diisobutylbenzenesulfonamide: To a solution of 40 g of sodium hydroxide in 300 ml of distilled water, 100 g (0.7 mole) of diisobutylamine was slowly added followed by adQition of 85 g (0.49 mole) of benzenesulfonylchloride. While the solution was stirred with a magnetic stirrer for 15 minutes, 200 ml of ether was added. The ether portion was decanted and evaporated at am bient temperature and pressure .. The N,N-diisobutylbenzenesulfonamide was recrystallized in low boiling petroleum ether giving 95 g (0.35 mole, 70% yield), m.p. 54-55°0 {lit. (8) m.p. 55°C). REDUCTION OF N,N-DIISOBUTYLBENZENESULFONAMIDE. First Attempt of R~duction of N,N~Diisobutylbenzenesulfonamide. To a three-necked, round-"bottom flask equipped with a dry ice condenser ~"ld mechanical stirrer was added 12.6888 g (O,Oij7l mole) of N,N-diisobutylbenzenesulfonamide and approximately 600 ml of .anhydrous - - -- liquid ammonia. Then 2.768 g (0.4 mole) of lithium ribbon (after being cleaned of its protective coating of petrolatum in a series of baths of low boiling petroleum ether) was added in small pieces to the reaction Jrj_xture over a period of 15 minutes with stirring at the boiling polnt of a'lllllonia (-33°C). While the solution was being stirred, 20 ml of absolute ethanol was added over a period. of 30 minutes . After the 15lue color of the mixture had disappeared, 21. lj g ( 0. 4 mole) of ammonium chloride was added very slowly to reduce basicity and the mixture was stirred an additional hour. The ammo11ia M>s allowed to evaporate overnight at 41 ambient teJlllerature and pressure. The residual material was dissolved in 200 ml of ice cold distilled water. After acidification with 10% hydrochloric acid to pH 1 to 2, the solution was extracted with four 100 ml portions of ether. Then the combined ether extracts were extracted with four 100 ml portions of 10% sodium hydroxide. The ether was dried with 3 g of anhydrous mag- nesium sulfate and was allowed to evaporate at ambient temperature and pressure. The remaining solid material weighed 4.16 g ( 32.8% recovery) . After recrystallization in petroleum ether it had m.p. 54-55°C and was identified as starting material, N,N-diisobutylbenzenesulfonamide, from its ir spectrum. The basic portion.was acidified with 10% hydrochloric acid to pH l to 2 . The solution was extracted with four 100 ml portions of ether. The cornbined ether extracts were dried with 3 g of anhydrous magnesium. su~fate, and the ether solution was concentrated by distillation under ------vacuum to- :remove -etner-and tEe ethanoL 'ihe r6naining pale yellow liquid weighed 1.44 .g (27.8% y~eld). It was identified as thiophenol from the ir spectrum which was identical to the ir spectrum of known thiophenol. Second Reduction of N,N-Diisobutylbenzenesulfonamide. The experimental conditions, equipment, .quantities of reagents,, reaction temperature (-33°C), and work-up were the same as in the first reduction of N,N-diisobutylbenzenesulfonamide. The extracted solid material weighed 3.61 g (28.5% recovery). It was identified as the 42 starting material, N,N-diisobutylbenzenesulfonamide. The extracted light yellow liquid weighed 1.39 g (26.83% yield) and was identified as thio- phenol from its ir spectrum, which was identical to the spectrum of known thiophenol. Third Reduction of N,N-Diisobutylbenzenesulfonamide. The set-up, quantities of reagents and work-up were the same as the first reduction except that 30 ml of absolute ethanol was used and the reaction temperature was -75°C. The isolated solid material weighed 9.49 g (74.8% recovery) and the liquid 0.54 g (10.9% yield), The solid material was identified as starting material (m.p. 53-55°C), l ! N,N-diisobutylbenzenesulfonamide,from its ir spectrum. The light yellow liquid was identified as thiophenol from its ir spectrum which was identical to the ir spectrum of known thiophenol. -Fourth- Reduction-er-N ,N-'Diisobutyltrenzenesulfonamide ;- - The factors were the same as in the third reaction (-75°C). The isolated solid rraterial weighed 8.58 g (67.62% recovery) and liquid 0. 89 g (17 .18% yield) . The solid material was identified as starting material (m.p. 53-55°Ch N,N-diisobutylbenzenesulfonamid~ w~th small amounts of diphenyldisulfide from ir spectrum. The light yellow liquid was identified as thiophenol from its ir spectrum which was identical to the spectrum of known thiophenol. Fifth Reduction of N,N-Diisobutylbenzenesulfonamide. 'Ihe experimental apparatus, conditions and reaction temperature were the same as in the first reduction of N,N-diisobutylbenzenesulfonamide (-33°C) except that double the amount (5.536 g, 0.8 mole) of lithium ribbon was used followed by 45 ml of absolute ethanol and 42.8 g (0.8 mole) of arrnmnium chloride , 'Ihe isolated solid and liquid material weighed 3.07 g (24.2% recovery) and 2.04 g (39.0% yield) respectively. The solid material was identified as the starting material (m.p. 52-55°C),N,N-diisobutylbenzenesulfonamide,with small amounts of di phenyldisulfide from iT spectrum. The liquid was identified as thiophenol from its ir spectrum which was identical to the spectrum of known thiopheno1. Sixth Reduction of N ,N-Diisobutylbenzenesulfonamide. 'Ihe factors were the same as the fifth reduction (-33°C) of N,N- - diisooutylbehzenesulTonalnide. The -isolated solid-and-liqUid material weigheo 3.108 g (24.,5% recovery) and 2,02 g (39.0% yield) respectively. The solid material was identified as the starting material (m.p. 53-55°C),N,N-diisobutylbenzenesulfonamide,with small amounts of di- phenylsulfide from ir spectrum. 'Ihe light yellow liquid was identified as thiophenol from its ir spect1~ which was identical with the ir spectrum of known thiophenol. 44 REDUCTION OF 2-MESITYLENESULFONAMIDE. First Reduction of 2..;.Mesi tylenesulforuimide. ( 2 , 4 , 6..;.Tr:i.Jilethylberizene sulfonamide) : 2-Mesitylenesulfonamide (Aldrich Chemical Co.)(9.3856 g, 0.0471 mole) was added to 600 ml of dry liquid ammonia in a two liter, three-necked flask equipped with a mechanical stirrer, a dropping funnel and a dry ice condenser. Then 2.768 g (0.4 mole) of lithium ribbon, after being cleaned of its protective coating of petrolatum in a series of baths of low boiling petroleum ether, was added in small pieces over a period of 15 minutes with stirring to the mixture at the boiling point of ammonia (-33°C). · While the solution was stirred,· 20 ml absolute ethanol was added over a period of 20 minutes. After the blue color of the mixture had dis- appeared, 21.4 g (0.4 mole) of anmonium chloride was added very slowly to reduce the basicity, and the mixture was stirred an additional hour. Then the anmonia was allowed to evaporate over a warm water bath for four hours. When the ammonia evaporated, the residual material was dissolved in 200. ml of ice cold distilled water. After acidification with 10% hydrochloric acid to pH 1 to 2, the solution was extracted with four 100 ml portions of ether. The combined ether extracts were extracted with four 100 ml portions of 10% sodium hydroxide. Thus an ether solution (A) and a basic solution (B) were obtained. The ether portion (A) was dried over 3 g of anhydrous magnesium sulfate. The ether and ethanol were removed using a vacuum rotatory .evaporator. The remaining light 45 yellow liquid weighed 1.88 g (33.33% yield), ~ 5 1.5135, [lit.(37), ~ 5 l. 5155]. This was identified as mesitylene by corrlJarison with known mesitylene by glc and ir (Figure 9 and 10). The g_lc analysis was done by comparison of retention time of the reduction product with known samples of mesitylene. The analysis wa'3 performed on Carle Instrument Model 6500, 5 ft. x 1/8 .inch columns, l38°C. On a Polar Colurrm (8% CaT'bowax 15liO on 90-100 mesh anala'om ABC) the retention time was 1.5 minutes. On a nonj:Jolar column (8% di-n-nonyl phthalate on 90-100 mesh anakron ABC) the retention time was 0. 5 minutes. The basic portion (B) was acidined with 10% hydrochloric acid to pH l to 2 and extracted with four 100 ml portions of ether. The combined ether extract was dried over 3 g of anhydrou'3 magnesiurr1 sulfate. 'I'he ether and ethanol were removed using a rotatory evaporator;· The rer:].aining crt.::.de matsr:tal was mostly liquid with a s;naJ.l arrnunt of solid, J -- wej£Shed 1.5 g (2ci .27%yie1d), n~5 1.565~, and was assLl!lled to be mostly . 2,4,6-trimethylthiophenol (major product) and small amount of mesityl d~sulfide. (For ir spectrum see Figure 11). Second Reduction of 2-Mesitylenesulfonamide. The experimental conditions (equipment, quantities of reagents and reaction temperature (-33°C) were the same as the first reduction of' 2..:.mesitylenesulfo[lamide, except that after the reaction, the ammonia was allowed to evaporate overnight (approximately 15 hours) at ambient terr~erature and pressure. 'l'he residual material was dissolved in 200. ml ice cold distilled 46 I 4000 3000 2000 1500 CM·1 1000 900 800 700 ,,,1 I ' 00 '' LLt' i i . ~~,,~1' r-HH t--1--1~~' _[ l-r't'l r-Ltt_ ,-.. n-i --·-1 r .•... :. n -LY+ '-~l=r!I! I I I , n r"'" ' 1- .10[ifl:q~m '+ ~t- .1+++-fl·:iS-!__,. i--L-· ·ii!ft~~· +-t-' it-EEIHH," ,--~, U!1' ..J l_V l++t± 'J tt1 t:!: .I l:__._L_.j_ •• :1 I i'Tl J = -~1-:..i ·i @t:U:tJ:t:t .J.20H-i- ; t.:l [:£ .i \tic[ Ift=fi=f- 7 :!=!=, : ~ l:£i :tl ~ ""' lt++' -~n:J -m -~. :t· :.! '"" 8?=tt- ·:t- ~:-r-I ~~ t=t=~ --~--·--~--·- ~n~~ j! r.~.!=!::- ~.30f+t-~g··~lf ww )n 40 rTf,,. ~, ..~-~ , 1-H·rf· ,- r " 9~ .. -~·Hi '"'-BI~miMfit¥ -f.-Ul. ["'.-" n · rill r : ':± ±l ·~r.~ .. n -+ .. ~ .. t::+~ ::[. -}-rr--r ··t· 50 ·. ~r t:i R= ·H• :·±ti·7·t • ~'::!:±:""'f=E· -'-+-;.=t ;---~ ~1-:::l .i 60 '~+;-~~- 't:p~ - ·-~ c:r•. 1 :t.:r.c!.cj 'I -::::r=l=l--''·t-! .. co '--~-T ·, ___,__,_"_ ·~='F£b I j·H·! tt b-:t~ --~-~~::t::~::£_; t- j: fl· _::f::EF::Et::::t:c )o~~fl C: '~~~i~,fao nxtJJ -::. :I=- -~-:t-· I II I I I! 'I I :I I I :I I I I 111 ' ! I I I I I! iIi I! i 1. 0 ' I'" =t±+~ tw_::o:~_1.0 ~__,.. 1 !fTTT[ I II [_L 00 ULL_j__l II II IJ.UJoo 3 4 5 6 7 8 9 10 11 12 13 14 15 WAVEL.ENGTH (MICRONS) Ir Spectrum of lm~ Mesitylene (Eastman Kodak) (Neat) -1=" Figure 9 -'I --~--'--' . :"'------'~---"-·--~---· -"------"-~------. ------__ ., ______ ! 4000 3000 2000 1500 ·cM-1 1000 900 800 700 0.0 .10 .10 u ~.20 .20 ;( 1 1 ~.30fl i~f+lf1l~TI_____ II.,m ctfff'tffff+r+fj-fffff-t¥FlJ4Ijo f __ 1111 _.II ffltlffRifH'fffFFFFFft1frtfl4'ffffilf/fffffffimtfFffffWtHII I I I _ I. t _ I. I Tftf¥tt-'=fH=r_ttfff'T!ilJ~J Ci 1J1J WWl..lLLL 3 0 ) l) -t+t+ 1\ r-t i-ti , ,-1-+t+ •lj- - I --- -+I ------t-H · +-· -t-+ -• >+ t-f-j- 4Q :a· 40 -n_'';'-+--:f-J':_r_tH- - , - '-' . __j '------H+_ --_~--+'-t_· ,.,. =-+ :p 1 ctlt :J , -- t= 1 ", - +tf - +> ""' t::..Q - _· '•·-+H+ . --H- 50 •.., ~t-+=1=$ :-' : -- H ~ti:: • ' 60 . . • -·=! • . -+ +:tct.- •t+= A() ~ :7og~-~:~g~~~~~:,~=t=~-~ >- .J .:: ___ ~. - " - - -- -~~: -~- I I I I I ,\ I I I ' 10 ,1 '' !I 'I li_+ • I ! I ~ * ,__. ' - ~:r, I I I I' I' t I I I I I I I I I I 00 I 1!-' II 11 11 11 ~~~~~~~~~· 00 3 4 5 6 7 8 9 10 11 12 13 14 15 W AVHENGTH (N\ICRONS) .. I Ir Spectrum of Mesitylene from First Reduction Product of 2-M<:isitylenesulfonamide (Neat) -"'" 00 Figure 10 - --•--'---' '- ~~ ·-·'--'~---- - "~~----·"-"'""-'' i 4000 3000 2000 1500 I (ll/\-1 1000 900 800 700 .10 .10 J..J {20 0 <{ ~.30· 30 ) :2.40 40 <{.50 50 .6olf. 60 .70~~ .____,._.- _-;-:-:r_~ ~·~·...:"'1:: ..... +=---~·_,_··---= --.-:..T;:;~:::t.- >= ,_r-··:~·:::r:> ~:J;:::f:::-·:. .. ,· · .. :::1~-Tnz-·~..":l-- ···::: -~-- ~:- -~ = ...:;.;. ):_..' ___,__ -"-ct.- 70 i! i Ill hi I i II ii Ill I 1. I i I i II 1 · . I I I I 0,,...., I I . I I 1 I I I ' 1 I· 1 1 1• 0 . r •. , ~ II l++ . -r .- ::.-H- • 0 - . CO I I I I i II HTI= 3 4 5 6 7 8 9 10 11 12 13 14 15 W A YELENGTH (MICRONS) Ir Spectrum of 2,4,6-Trimethylthiophenol from First Reduction Product of 2-l"!~sitylenesulfonamide (Neat) .I= \!) Figw:>e 11 water and extracted with four 100 ml portions of ether. The combined ether extracts were extracted with four 100 ml portions of 10% NaOH. Thus an ether portion (A) and a basic portion (B) were obtained. The ether portion (A) was dried over 3 g anhydrous magnesium sulfate. The ether and ethanol were removed using a rotatory evaporator. The light yellow residual material (mostly solid) weighed 4. 22 g (59. 67% yield calculated as if all mesityldisulfide; 76% yield calculated as if all mesitylene). This was washed with low boiling petroleum ether and filtered. The mesityldisulfide was recrystallized from petroleum ether and weighed 1.5 g (21.0% yield) m.p. 124-l25°C [lit, (8) m.p. l25°C]. The above petroleum ether filtrate was concentrated using a rota- tory evaporator. The residual crude liquid was decanted and weighed l. 2 g (.21. 27% yield) . Its ir spectrum was the same as the ir spectrum of the product of the first reduction and appears to be mostly mesitylene and a small amount of mesityldisulfide. -- -- - The basic portion (B) was acidified with -10% hydrochloric aCid and extracted with four 100 ml portions of ether. The combined ether solution was dried over 3 g of anhydrous magnesium sulfate. The ether and ethanol were removed using a rotatory evaporator. The light yellow liquid weighed 0.158 g (2.13% yield) and was considered to be 2,4,6-trimethyl- thiopehnol. Its ir spectrum was consistent with that assignment and it easily air oxidized to material with the same m.p. as that reported for mesityldisulfide (8). ·'· 50 Third Reduction of 2-Mesitylenesulfonamide. The conditions were the same as the second reduction including evaporation of armnonia over 15 hours. The residual material was dis- solved in 200 rnl ice cold distilled water . After acidification, the solution was extracted with four 100 rnl portions of ether. The com bined ether extracts were extracted with four 100 rnl portions of 10% NaOH. Thus an ether portion (!\) and a basic portion (B) were obtained. The ether portion (A) was dried over 3 g of anhydrous magpesium sulfate. The ether and ethanol were removed using the rotatory evap- , orator. The residual crude material (A) was a mixture of liquid and solid and weighed 4.766 g (67.22% yield, calculated as if all mesityl disulfide; 78% yield calculated as if all mesitylene). The liquid was decanted from the solid. The solid was washed with small amount of low boiling petroleum ether to give 1.47 g (20% yield) of mesity1disulfide, m.p. 124-125°C [lit. (8) m.p. 125°C). The liquid weighed 1.1 g (23% yield) and was identified from its ir spectrum as mesitylene. The basic portion (B) was acidified and extracted with four 100 ral portions of ether. The combined ether solution was dried over 3 g of anhydrous magpesium sulfate. The ether and ethanol were removed using the rotatory evaporator. The light yellow liquid weighed 0.79 g (10.69% yield) and assumed to be a mixture of 2,4 ,6-trimethylthiophenol· with':. trace amounts of mesityldisulfide. Fourth Reduction of 2-Mesitylenesulfonamide. Everything was the same as in the first reduction of 2-mesitylene- 51 sulfonamide (-33°C) including evaporation of ammonia over a period of 4 hours. The residual material was dissolved in 200 ml ice cold dis tilled water. After acidification with 10% HCl, the solution was ex tracted with four 100 ml portions of ether. The combined ehter extracts were extracted with four 100 ml portions of 10% NaOH. Thus an ether portion (A) and a basic portion (B) were obtained. After removal of ether and alcohol from ether portion (A) , 'there was obtained 2.36 g (41.71% yield) of a ligpt yellow liquid, n65 1.5020. This was identified as mesitylene with trace amounts of mesityldisulfide by comparison of ir spectrum with the ir spectrum of !mown mesitylene. The basic portion (B) was acidified and extracted with four 100 ml portions of ether. The combined ether extracts were dried over anhydrous magnesium sulfate. The ether and alcohol were removed using the rotatory evaporator. The ligpt.yellow liquid weigped 2.09 g (28.30% yield) and was assumed to be 2,4 ,6-trimethylthiophenol with small amount of rnesityl disulfide. The ir spectrum was the same as the first reduction product • 52 BIBLIOGRAPHY 'f 1. G.B. Wooster, U.S. Patent 2,182,242 (1938). ~· Amer. Chern. Soc., 59' 596 (1937). >( 2. A.J. Birch,~· Chern. Soc., 430 (1944). L 3. A.L. Wilqs and N.A. Nelson, ~· Amer. Chern. Soc., 75, 5366 (1953). '{ 4. A.J. Birch, Nature, 158, 585 (1946). V5. A.J. Birch, Quart. Revs.,~, 69 (1950). i. 6. M.E. Kuehne and B.F. Lanbert, ~· Amer. Chern. Soc., 81, 4278 (1959). ;(7. A.J. Birch and J. 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