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FIKES, Lewis Edgar, 1943- A STUDY OF STBRIC, ELECTRONIC AND ACID- CONCENIRATION EFFECTS IN SCHMIDT REACTIONS OF ARYL M - m KETONES, DIALKYL KETONES, AND CYCLOPROPYL KETONES.
The Ohio State University, Ph.D., 1972 Chemistry, organic
University Microfilms, A XEROX Company, Ann Arbor, Michigan
THIS DISSERTATION HAS BEEN MICROFILMED EXACTLY AS RECEIVED. A STUDY OF STERIO, ELECTRONIC AND-ACID-CONCENTRATION EFFECTS
IN SCHMIDT REACTIONS OF ARYL ALKYL KETONES,
DIALKYL KETONES, AND CYCLOPROPYL KETONES
✓
DISSERTATION
Presented, in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University
By Lewis S, Fikes, B.A., M.A.T,, M.S. *****
The Ohio State University 1972
Approved by
Adviser Department of Chemistry PLEASE NOTE:
Some pages may have
indistinct print.
FiImed as received.
University Microfilms, A X e ro x Education Company DEDICATION
To the memory of my Mother and Father
ii ACKNOWLEDGMENTS
I wish to thank Professor Harold Shechter for suggesting this study and, for his expert assistance in the preparation of this manuscript.
I extend my appreciation and gratitude to ray mother-in-law, Ruth Heisel, for typing the rough draft of this dissertation.
Finally, I am grateful to ray wife, Martha, for typing the final draft of this dissertation with so much care and expertise and for her constant encouragement and support during ray graduate training.
iii TABLE OF CONTENTS
Page DEDICATION...... ii
ACKITOWLEDGîIENTS...... iii
LIST OF T A B L E S ...... v
INTRODUCTION ...... 1
HISTORICAL REVIEW ...... 5
RESULTS AND DISCUSSION...... 35
EXPERIMENTAL ...... 113
APPENDIX A ...... 144
APPENDIX B ...... 146
iv LIST OF TABLES
Table Page
1 Scrirnidt Reactions of para-Substituted Benzophenones...... 17
2 Schniidt Reactions of Alkyl Phenyl Ketones . 19
3 Schr;:idt Reactions of l-Tetralones and 4-Chroraanone 21
4 Schmidt Reactions of Ohromanones ...... 22
5 Schrcidt Reactions of In d a n o n e s ...... 25
6 Schmidt Reactions of Oyclopropyl Ketones . 29
7 Schmidt Reactions of Ethyl Aryl Ketones . . 38
8 Schmidt Reactions of Isopropyl Phenyl K e t o n e ...... 47
9 Schmidt Reactions of Iscprcpyl para-Tolyl K e t o n e ...... 56
10 3chr.iidt Reactions of Isopropyl nara-Anisyl K e t o n e ...... 59
11 Schmidt Reactions of Neopentyl Phenyl K e t o n e ...... 63
12 Schmidt Reactions of Alley 1 Methyl Ketones . 72
13 ScWidt Reactions of Neopentyl Methyl Ketone...... 75
14 Schmidt Reactions of Oyclopropyl Phenyl K e t o n e ...... 83
15 Product Recovery Studies ...... 84
16 Schmidt Reactions of Oyclopropyl Methyl Ketone...... 90
V 17 Schmidt Reactions of Oyclopropyl Ethyl K e t o n e ...... 94
18 Schmidt Reactions of Oyclopropyl Isopropyl Ketone ...... 95
19 Schmidt Reactions of Oyclopropyl Alkyl Ketones ...... 96
20 Product Recovery Studies of Brackenridge's W o r k ...... 145
VI INTRODUCTION
The acid-catalysed reaction of unsyiTUDetrical ketones with hydrogen aside, the Schmidt reaction,^
(l) For reviews see: H. V/olff, Org, Reactions, 3.» Chapter S (1946) and P. A, S. Smith in Mayo, "Molecular Rearrangements," Vol. 1, Interscience Publishers, Inc., New York, 1963. yields as principal products two isomeric amides (Eq 1),
HR^ R-CO-R‘ — R-NH-CO-R' + R-CO-NH-R' (l) the ratio of which is profoundly influenced by the structure of the starting ketone. Early investigations indicated this structural influence was primarily steric in nature, the more bulky R group migrating preferentially.
Accordingly, the early mechanistic formulations for the
Schmidt reaction reflected this steric factor. However, subsequent scattered investigations have shovm additional factors (eg, electrical and acid concentration effects) may be operative in Schmidt reactions of ketones, and thus modifications of earlier proposed mechanisms may be necessary.
The effect of the concentration of the acid
1 catalyst on the course of the Schmidt reaction of ketones 2 has received little study. However, Brackenridge has
(2) B, R, Brackenridge, Ph.D. Thesis, The Ohio State University, Columbus, Ohio, 1966. reported that the concentration of sulfuric acid affects the ratio of isomeric amides produced in Schmidt reactions of meta-substituted benzophenones. At elevated acid concentrations he reported that preferential migration of electron-deficient phenyl groups occurred. This was a surprising result.
Perhaps equally surprising have been the results of the few Schmidt reactions which have been carried % out on oyclopropyl ketones. F o r instance, Bunce and
(5) S. C. Bunce and J. B. Cloke, J. Am. Cham. Soc,, 76, 2244 (1954).
% Cloke^ have reported that in the Schmidt reaction of oyclopropyl methyl ketone (Eq 2), the sterically smaller
[^CO-CH^ - P>-CO-NH-CH^ + [>-NH-CO-CH^ (2) " 77fo methyl group migrates preferentially. Since this was the opposite result one would expect on steric grounds,
Bunce and Cloke concluded that electronic effects must be of importance. However, the nature of such electronic effects was not specified. The initial phase of the present study was con cerned with the investigation of Schinidt reactions of a number of alkyl aryl ketones in order to see;
1. whether in Schmidt reactions of alkyl aryl
ketones there is an acid-concentration effect
on the amide ratios, similar to that observed p by Brackenridge for Schmidt reactions of
meta-substituted benzophenones;
2, whether various electron-withdrawing and -dona
ting substituents on the aryl moiety of these
allcyl aryl ketones might result in amide ratios
indicating the operation of electronic factors
in the Sctoidt reactions of these ketones.
In this initial phase, Schmidt reactions were effected on. the following: ethyl phenyl ketone, ethyl meta-tolyl ketone, ethyl nara-bromophenyl ketone, ethyl meta-nitrophenyl ketone, ethyl para-tolyl ketone, ethyl para-anisyl ketone, isopropyl phenyl ketone, isopropyl para-tolyl ketone, isopropyl para-anisyl ketone, and neopentyl phenyl ketone.
The second phase of the present study involved study of Schmidt reactions of various cyclopropyl ketones to see:
1, whether the amide ratios are a function of acid
concentration; 2, whether the cyclopropyl group gives rise to
any electronic effects in Schmidt reactions
of cyclopropyl ketones.
Accordingly, Schmidt reactions were carried out on the following: cyclopropyl phenyl ketone, cyclopropyl methyl ketone, cyclopropyl ethyl ketone, and cyclopropyl isopropyl ketone.
To assist interpretation of the results of reactions of hydrogen aside with cyclopropyl ketones and allcyl aryl ketones, Schmidt reactions were effected on the following dialley 1 ketones : methyl ethyl ketone, methyl isopropyl ketone, and methyl neopentyl ketone. ■
In summary, the present investigation involves study of steric, electrical, and acid concentration effects on the products and mechanism of Schmidt reactions of alkyl aryl ketones, cyclopropyl ketones, and dialkyl ketones. HISTORICAL REVIEW
The acid-catalyzed reaction of hydrogen azide
(HN^) with ketones and aldehydes was discovered by Karl
Friedrich Schmidt^ while investigating the decomposition
(4) K. P. Schmidt, Z. Angew. Chera., 511 (1923). of hydrogen azide. Observing that aniline v;as produced when hydrogen azide was decomposed by sulfuric acid in the presence of benzene, he postulated that imine (:E-H) was the species responsible. When Sclimidt attempted to capture imine with ketones, amides were obtained^ (Eq 3),
(5) K. P. Schmidt, Ber., 704 (1924).
HLSO. r -CO-R- + HN, ---- -—^ R-NH-CO-R (3)
Schmidt thought that imine was adding to the carbonyl group to form an intermediate which would either rearrange directly or isomerize to an oxirae and undergo
Beckmann rearrangement.^ However, reaction of carbonyl compounds with imine was essentially disproved by
Schmidt's own work because carbonyl compounds react (6) K. R. Schmidt, Ber., 2413 (1925). readily with hydrogen azide at 0°, at which temperature hydrogen azide is stable to sulfuric acid. 7 A more satisfactory proposal by Oliveri-Kandala
(7) E. Oliveri-Mandala, Gaz. Chira. ital., 271 (1925). in 1925 involved addition of hydrogen azide to the car bonyl group, giving an azidohydrin, which then rearranges to the amide with loss of nitrogen (Eq 4).
/OH R-CO-R + HR, — > RgC >- R-CO-l'm-R + lU (4) '3 The Oliveri-Mandala proposal has been elaborated O into reaction mechanisms by Newman and Gildenhorn and by Smith^ (Eq 5 and 6). Each assumes that the initial
(8) M. S. Newman and H. Gildenhorn, J. Am. Chem. Soc., 20, 317 (1948).
(9) P. A. S. Smith, J. Am. Chem. Soc., 70, 320 (1948). step of the Schmidt reaction is addition of hydrogen azide to the protonated carbonyl function. The inter position of the dehydration step by Smith in Eq 6 was prompted by the necessity of an intermediate to explain formation of tetrazoles and ureas in the Schmidt reaction, and to account for the parallel often observed between 8^0=0 + HA ^ R2C=0H + A'
+ .OH R - C ^ + Ng (5) RH-R + HR, RoC=OH — 2^ RgC-OH 2 2|
""'V V -»,o + R,0=N. , ---> R-C=R-R + ïï„ (6) iC HgO
the ratios of isocieric amides produced from ursymmetrical ketones hy the Schmidt reaction and by oximation plus
Beckmann rearrangement.
The principal reaction products of ketones and hydrogen azide are amides, of which a single compound is produced from symmetrical ketones, but a pair of isomers may be produced in unequal amounts from unsymmetrical ketones (Eq 7), In addition, there have been found, to an extent varying greatly with structure and reaction condi tions, nitriles, 1,5-disubstituted tetrazoles, ureas, and
5-arainotetrazoles. Formation of nitriles requires one equivalent of hydrogen azide (Eq 8); two equivalents of 8
hydrogen azide are necessary to give 1,5-disuhstituted
tetrazoles and ureas (Eq 9 and 10), and 5-aininotetrazoles
are obtained from reaction of a ketone with three equiva
lents of hydrogen azide (Eq 11),
R-CO-R• + m L — > R-NH-CO-R' + R-CO-NH-R» (?)
R-CO-R' + HN_ — > R'-CN + R*^ (8)
R-CO-R' + 2 HN„ — > R-N--C-R' + R-C--- N-R' (9) 3 I II II
R-CO-R' + 2 HN^ — > R-ÎIÏÏ-CO-NH-R' (lO)
R-CO-R' + 3 NH, — > R-NH-C N-R' + R-N C-NH-R' (ll) 3 II I I II
An important feature of these reactions is that, with the exception of tetrazoles originating from nitriles, the products derived from reaction of more than
one equivalent of hydrogen azide cannot be obtained from
compounds whose formation consumed less hydrogen azide, under the conditions used in the Schmidt reaction.
(lO) P. A. S. Smith and E, P. Antoniades, Tetrahedron, 9, 210 (1960).
Reactive intermediates must therefore be involved, which under appropriate conditions have the choice of reacting 9
with more hydrogen azide or of reacting in another way
to give terminal products. It was in part to account for
these facts that Smith^ proposed the mechanism shcvm in
Eq 12, Thus, hydrogen azide adds to the protonated car bonyl group to give an azidohydrinium ion (I), which
loses water to form an iminodiazonium ion (II), Migration
of the organic moiety to the imine nitrogen of II with loss of nitrogen gives an iminocarbonium ion (ill), which reacts with water to give the amide (Eq 12),
+ HN, -H-O RgCcOH ---^ R-C-R R_C=N. ^ (12)
I -Eg
■V H„0 + R-CO-RH-R ' 2- R-C=R-R III
Tetrazole could thus be formed by addition of hydrogen azide to the iminocarbonium ion and subsequent oyclization and deprotonation of the conjugate acid of the intermediate imidyl azide (Eq 13), Such a sequence is in agreement with general experience that tetrazoles are formed when imidyl azides are prepared from imidyl chlorides,
(11) F, R, Benson, Chem, Rev,, 41, 1 (1947). 10
+ im_ , EC=N-R --- 2^ R-C=1'I-R — > R-C N-R + ir (15)
Combination of the iminocarhoniun ion with hydrogen azide may lead to ureas as products instead of 12 tetrazoles. This is the result of rearrangement of
(12) P. A. S. Smith, J. Am. Chem. Soc., 76, 436 (1954). the protonated imidyl azide (before it cyclizes) to give a protonated carbodiimide which reacts with water to give the urea (Eq 14). The protonated carbodiimide in Eq 14
+ RrC=N-R -- >• R_NH=C=N-R + (I
HgO w R-NH-CO-NH-R + (14) may react with still more hydrogen azide rather than water, leading to an aminotetrazole (Eq 15). Such a product has
+ HN, R-NH=C=N-R ---2- R-NH-C=N-R i R-NH-C N-R + (15)
15 been reported only for benzophenone. 11
(15) K. P. Schmidt, Priedlander, Fortsor, In der Teerfarb. und Verv/and. Ind., 15, 333 (1930).
Additional evidence that the irainocarbonium ion may be an intermediate in the reaction is provided by 14- Hassner's observation that iminocarbonium ions, formed
(14) A. Hassner, Tet. Lett., 27, 3119 (1966). from reaction of halonium ion intermediates with nitriles
in the presence of silver perchlorate, react with azide
ion to form tetrazoles and with hydroxide ion to form
amides (Eq 16).
Rcw /, + 'N=CR
HO (16)
/ \v
Evidence that an iminodiazonium ion can be gener ated which has properties similar to that postulated by
Smith was provided by Pearson,who found that benzo phenone hydrazone is converted to benzanilide by nitrous 12
(15) D. E. Pearson, J. Am. Chem, Soc., 71, 1895 (1949). acid in concentrated sulfuric acid (Eq 17),
+ /NHp HONO (CgH5)20=H'2 HgSO^
(17) + HpO . CgHcE^O-O^Hc + Ng — ^ CgH^NH-CO-CgH^ + r
Eishel and Wu^^ have observed transient peaks
(16) D. L. Eishel and Yueh-shiou (Huang) V/u, Abstracts of the First Central Regional meeting of the American Chemical Society, May, 1968, Akron, Ohio. in the nmr of mixtures of various acetophenones and hydrogen azide in sulfuric acid solutions over the range
65 to 100^3 sulfuric acid which they claim support the intermediacy of both iminodiazonium ions and iminocar bonium ions in the Schmidt reaction of ketones. Methyl chemical shifts (7^) are listed for the structures thought present during reactions of substituted acetophenones with hydrogen azide at 99^ sulfuric acid; 13
■^OH II + Substituent 0-C-CH, 0-C-CH, 0-N=C-CH, 0NHCOCH, (protonated)
-H 6.74 6.84 5.94 7.34
2“Et 6.82 —— 5.97 7.35
£-Me 6.77 6.87 5.94 —
£-01 6.76 6.84 5.95 7.29
m-EOg 6.60 none none 7.23
£-OMe 6.95 none none 7.33
In Smith’s proposed mechanism (Eq 18), the rate-
+ mi. A R2C=0H ^ R-C-R --- ^ R„C=N I ^ B -N, (18) H„0 + R-GO-EH-R «- -■■■■- R-C=N-R -H+ determining step for release of nitrogen in the Schmidt reaction might conceivably be the addition of (step
A), the dehydration of the azidohydrinium ion (step B), or the rearrangement step (C). With any of these, the position of equilibrium of the initial protonation of the carbonyl group could affect the rate, so that one might expect (ffl'I^), (RgCO), and the acidity function, h^, to appear in the rate expression. The only step that can be 14 assumed to be irreversible is step C, so Smith maintained 17
(17) P. A, S. Smith in Mayo, "Molecular Rearrangements", Vol. 1, Interscience Publishers, Inc., New York, 1963. equation 18 should be written as a series of equilibria as in Eq 19 (shown for an unsymmetrical ketone).
0 ^OH A OH I I II i RCR' ^ RCR' R-C-R' ,'V B (19) + C C + , R-N=CR < — R-C-R' R-p-R' — > RC=N-R
IVa IVb
By analog]' with oximation, which has been shown^^
(18) W. P. Jencks, J. Am, Chem, Soc., 81, 475 (1959). to take place by similar steps of addition and dehydration,
Smith maintains that step B is probably slow and may be 17 rate determining. The reversal of step B provides a path for equilibration between the isomeric iminodiazonium ions IVa and IVb. If the rearrangement (step C) is faster than this equilibration, then the relative populations of
IVa and IVb will determine the product ratios. The relative 15
populations of IVa and IVb were presumed by Smith to be
largely the result of different steric repulsions in
the transition states for step B leading to these con
figurations. In this situation, then, one would predict
the ratio of isomeric amides observed in the Sclimidt
reaction to be sterically controlled; the more bulky
R group migrating to the greater extent.
However, if IVa and IVb isomerize appreciably
faster than they rearrange, then equilibration between
IVa and IVb will be achieved continually while rearrange ment is going on, so that the product amide ratios would
then be determined by the relative rates of rearrangement
of IVa and IVb; that is, migration ratios combining
electronic and steric effects would govern the product ratios. Allcyl migrations to positive centers are gener ally much slower than aryl migrations. Therefore, step
C is expected to be slower with aliphatic ketones than with aromatic ketones, and migration ratios arising from
electronic effects may more likely be observed for ali phatic than for aromatic ketones.
The importance of a steric effect as compared with electronically determined migration aptitudes was
demonstrated by Smith and Horwitz.^^ Reaction of a
series of para-substituted benzophenones with hydrogen azide in fused trichloroacetic acid (with a small amount 16
(19) P. A, S, Smith and J. P, Horv/itz, J, Am, Chem, Soc,, 72, 5718 (1950). of concentrated sulfuric acid added) yielded mixtures of isomeric benzanilides in ratios very close to 1:1, regard less whether the substituent v/as phenyl, methyl, chloro, or nitro, para-Kethoxybenzophenone showed some prefer ence for forming benzanisidide, but £-chloro-> ;^-metho}qy- and £-nitro-p’-methoxybenzophenones gave 1:1 mixtures like the others,Smith and Horwitz's results^^ are
(20) P, A, S, Smith and B, Ashby, J, Am, Chera, Soc,, 72, 2505 (1950), listed in Table 1, together with comparative information on the ratios of isomeric oximes (as determined by an examination of the amides formed from them by Beckmann rearrangement),
Smith and Honvitz^^ place great importance on the parallel between the ratios of isomeric amides obtained from Schmidt reactions and the ratios of geometrically isomeric oximes formed from the same ketones as determined by the ratios of amides produced from the oximes by
Beckmann rearrangement. Since the ratios of the oxime isomers determined in this way are largely in accord with the generalization that the more stable configuration is that in which the bulkier group is anti to the oxime 17
TABLE 1
Comparative Migration of for Schmidt and Beckmann
Rearrangements of Substituted Benzophenones and
Benzophenone Oximes, Respectively
Migration Ratio p-R-C^H^- vs C^H^-
R Schmidt Beckmann
01- 59:41 56:44
NOg- 51:49 50:50
0H%- 54:46 52:48 5 CHgO- 61:39 49:51
52:48 ^6^5- 51:49
pi hydroxyl, and are' not influenced by the electronic
(21) A. B. McLaren and K, E, Schachat, J. Org, Chem., lA, 254 (1949).
effects which control migration aptitudes, Smith and
Horwitz believe that the ratios of amides produced in the
Schmidt reactions have a similar relation to structure and
are thus a result of steric factors.
Effects attributable to steric influence on the
relative stabilities of geometrically isomeric iraino-
diazoniura ions have been observed in a number of other
systems. Schmidt reaction of cyclopentanones and cyclo- hexanones substituted in the 2-position by either 18 electronegative or electropositive substituents give ring-expansion products resulting from nearly exclusive np migration of the tertiary carbon (Eq 20 and 21).
(22) H. Shechter and J. Kirk, J, Am, Chem, Soc,, 73, 3087 (1951).
O HN, / \ ^ ^ I N H (20)
HE. NH (21)
R = methyl, ethyl, propyl, isopropyl, cyano, and carboethoxy
The results of Schmidt rearrangement of certain alkyl phenyl ketones^^ are given in Table 2. In these systems, steric rather than electrical effects were postulated to control the ratio of products, although it was subsequently stated^^ that electrical factors might also explain these results.
Although the methyl group migrates to a smaller extent than other alkyl groups, unsaturation has been 19
TABLE 2
Migration Ratios in Schmidt Reactions of Allcyl Phenyl
Ketones
R Migration Ratio O^Hr- vs R
CH^- 95:5
OHLOHg- 85:15
51:49 H^O
iq found to reverse this result ’ . The Sotoidt reaction of styryl methyl ketone in concentrated hydrochloric
(25) L, H. Briggs. G. C. DeAth and S, R. Ellis, J. Chem, Soc, (London), 1942, 61, acid gave îi-methycinnamide in 75/' yield as the only product^^ (Eq 22), Thus the interposition of the vinylene group between the phenyl and the carbonyl groups
n HIL uH 0CH=CH-C-OH^ ---2-. 0CH=OHCNOH, (22) ^ HCl ^ of acetophenone essentially reverses the extent of methyl migration. Smith and Horv/itz maintained^^ that since the vinylene group is Imown to be a good transmitter of electronic effects, it would seem the major difference between the extent of methyl migration observed in the
Schmidt reaction of acetophenone and that observed in 2 0 the Schmidt reaction of styryl methyl ketone lies in the steric environment of the carbonyl group. This view was substantiated by their observation^^ that in the Schmidt reaction of 1-methylstyryl methyl ketone the only products detected were those arising from migration of the 1-methyl- styryl group.
While some experimental results point to the operation of a "bulk effect" (the sterically larger group migrates preferentially), results from other systems indicate the operation of additional factors and the possibility that Smith's mechanism may not be the only one operating in the Schmidt rearrangement of ketones.
24 Evans and Lockhart have carried out experiments
(24) I. li. Lockhart and D. Evans, J. Chem. Soc., 4805 (1965). whose results are highly suggestive of the operation of electronic factors in the Schraidt reactions studied.
Schmidt reactions of 1-tetralone (VI), 6-methoxy-l- tetralone (VII), and 4-chromanone (VIII) give the results shown in Table 3. These results were taken to imply that the lone pairs of electrons on ethereal oxygen VII and
VIII were imparting partial unsaturated character to the potentially migrating aryl-alkyl bonds (bond a in Eq 23) and thus retarding such rearrangement. The significance of these results is limited, however, by the failure to 21
TABLE 5
Schmidt Reactions of 1-Tetralones and 4-Chronanone
Ketone Product(s)
VI
o H some VII Me Me o II
w;
(23)
report yields of products and by the method of analysis
(crystallization) which could have resulted in one of the isomeric amides going undetected, even though present in significant amount.
The results of Schmidt reactions of substituted 22
chromanones,25 using concentrated sulfuric acid as the acid
(25) V. T. Bhalerao and G. Thyagarajan, Can, J. Chem,, 46, 5567 (1968).
catalyst are contained in Table 4.
TABLE 4
Migration Ratios in Schmidt Rearrangements of Chromanones*
* Compounds of structure
Chromanone Isomer Ratio
io Aryl io Alkyl Hp ... R fo Yield Migration Migration ■' ' L. % H H HH 78 0 100
H Et- HH 55 0 100
H t—Bu— HH 51 0 100
H Me- H Me- 60 54 46
Me- HH Me- 57 55 45
2,5-Lihydronanhtho 50 60 40 (2,1-b) pyran-l-one
HH H Et- 45 78 22
H t—Bu— H t—Bu— - No reaction
The authors discuss their results as follows. 25
In a chromanone unsubstituted in the 5-position an elec
tronic effect prevails in which conjugation arising out
of the lone pair electrons on the ethereal oxygen atom
stabilizes the potentially migrating arylalkyl bond by
giving it partial double bond character. Since the ben-
zenoid character of the benzene ring is reduced, a phen-
onium type of intermediate which allows aryl migration is not possible. Alkyl bond migration therefore results.
Table 4 shows that as the bulk of the 5-position
increases there is a corresponding increase in the quantity
of the product arising from aryl migration. Models of
chromanones containing substituents in the 5-position
show that if iminodiazonium ions are intermediates, on
the basis of steric repulsion, the population of ion XI
(Scheme 1) would be relatively small at equilibrium. It
is thus possible that the migration (20-40^') of the
sterically non-favored alkyl group arises by direct rearrangement of azidohydrinium ion IX. V/hen R=H dehydra
tion of the azidohydrinium ion to iminodiazonium ions X and XI may be favored, whereas this dehydration will not be sterically favorable when R=He, etc., since in the
iminodiazonium ion the stereochemistry about 0=11 is preferably planar, whereas in the azidohydrinium ion the hydroxyl and azide groups would be above and below the plane of the ring. The increase in migration of the aryl 24
Scheme 1
IX
X
several steps 0 XU XIII
group with increase in bulk of the substituent in the
5-position of the chromanone may be attributed to pre ference by the diazo nitrogens of the azido group (due to non-bonded interaction with the substituent in the 5-posi tion) for a conformation which is trans to the aryl bond.
The dissimilarity in these results from Beckmann rearrangement of corresponding chromanone oximes^^ under
(26) Bhalerao and Thyagarajan report that Beckmann re arrangement of chromanone oximes having methyl or bulkier groups in the 5-position leads exclusively to aryl group migration. 25 similar conditions, and the absence of tetrazoles (even when a 3:1 molar"excess of is employed) further indi cates that intermediates of the azidohydrinium type and not iminodiazonium ions are involved.
Bhalerao and Thyagarajan conclude that the products of their Schmidt reactions could be derived either through the iminodiazonium ion or, when the latter is not steri cally favored, through the azidohydrinium ion. Thus, more than one pathway to products is possible. A similar
27 conclusion was reached by Dimaio and Permutti from their work on the Schmidt reaction of cis-8-methyl-hydrindan-l-
2 8 one and by Sasaki, et. al., from their work on the
Schmidt reaction of adamantan-2-one.
(27) G, Dimaio.and V. Permutti, Tetrahedron, 22, 2059 (1966).
(28) T. Sasaki, S. Eguchi and T. Toru, J. Org. Chem., 15, 4109 (1970).
2Q Lansbury and Mancuso ^ have obtained evidence for yet another mechanism for the Schmidt reaction. They carried out Schnidt reactions on a series of indanones
(29) P. T. lansbury and N. R. Mancuso, Tet. Lett., 29, 2443 (1965). using polyphosphoric acid at 55-60° as the acid catalyst.
These results, together with the results for the Beckmann 26 rearrangement of the corresponding oximes and the anhy drous diazotization of the corresponding hydrazones, are shown in Table 5.
TABLE 5
Migration Ratios in Indanone Rearrangements
io Aryl i Alkyl Ketone Reaction Migration Migration Yield
o Schmidt 76 24 60 Beckmann 90 10 20 f6 r Z) Hydrazone 91 9 77 diazotization
Me 0 Schmidt 57 65 65 // Beckmann 54 66 48
Hydrazone 22 78 56 Ma diazotization i'Bu /? Schmdit (1) 15 85 50 Schmidt (2) 15 87 25
Beckmann (1) 19 81 25 R (1) , R = Br (2) , R = H
Although in the 7-substituted indanones one might attribute the observed predominance of alkyl migration to a preference for the syn-aryl configurations of the imino diazonium ions or oximes, further inspection of the data in Table 5 shows the greatest amount of alkyl migration 27 occurs in those compounds least likely to exist in that configuration. Lansbury and Mancuso conclude, then, that the major products from all three reactions of the inda nones arise either predominantly from cis-rearrangements or, more probably, from non-stereospecific rearrangements of iminium ions, the species previously shovm to be ■ZQ responsible for C-H insertion, a side reaction occurring for these ketones. Equation 24- illustrates this mechanism
(30) P. T, Lansbury, J, G-. Colson and W, R. Mancuso, J, Am, Chem. Soc., 85, 5225 (1964), for the case of the Schmidt reaction of 7-t~butylindanone, *
-N
C-H xalkyl aryl Me insertion migration migration (24) Me NH n
The authors theorized that aryl migration decreases with increasing bulk of the 7-substituent because there is more steric compression generated in the transition state,
' Lansbury and Mancuso thought that one of the 28
driving forces for the production of the iminium ion
in these reactions of indanones was the high ionizing
power of polyphosphoric acid. In support of this view they
noted that in kinetic studies of Beckmann rearrangements
of meta- and para-suhstituted acetophenone oximes where
the solvents were varied, the smallest rho value (-0,25)
observed was for polyphosphoric acid; suggesting little
aryl participation in the rate-determining step and a
non-concerted loss of the leaving group to give an
iminium ion. % Cloke and Bunce have studied Schmidt reactions
of cyclopropyl ketones (Table 6) and believe their
experiments indicate the operation of electronic factors
in these systems. The authors believe, although their
results agree in general with those of Smith and Horwitz^^
in that as the group opposite the cyclopropyl group becomes less bulky it migrates to a lesser extent, that
migration of the cyclopropyl and 1-phenylcyclopropyl groups
is less than would be expected on steric grounds alone.
The ratio (5:95) found for the cyclopropyl aryl ketones
is roughly equivalent to that for methyl phenyl ketone^^
and indicates much lesser migration of the cyclopropyl 29
TABLE 6
Migration Ratios in Schmidt Reactions of Cyclopropyl Ketones
Ketone Migration Ratios
R-CO-R» R : R'
Cyclopropyl p-tolyl
Cyclopropyl o-anisyl ^ 5:95
Cyclopropyl phenyl
Cyclopropyl styryl 9:91
Cyclopropyl methyl 25:77
1-Phenylcyclopropyl phenyl 62:38
1-Phenylcj'-clopropyl methyl 77:23
group than found^^ for the alkyl groups in ethyl phenyl ketone (15/^ ethyl migration) and isopropyl phenyl ketone
(ça,50^0 i-Pr migration). Accordingly, Cloke and Bunce conclude that in some way electrical effects influence the migration ratios in Schmidt rearrangements of cyclopropyl ketones.
They support this conclusion with their further observation that the methyl to cyclopropyl migration ratio in the Schmidt reaction of methyl cyclopropyl ketone is
77:23. Since the steric requirements of the cyclopropyl group apparently are greater than those of methyl (as shown in the Beckmann rearrangement of methyl cyclopropyl 30
ketoximes^^*^^), predominant migration of the methyl
(31) A, D. McLaren and R. E. Schachat, J. Org. Chera., 14, 254 (1949).
(32) J, D, Roberts and V, 0. Chambers, J. k a . Chem. Soc., 73, 3177 (1951).
group is the reverse of what would be expected on steric
grounds.
However, the validity of much of Bunce and Cloke's
data in Table 6 is questionable. They carried out their
Schmidt reactions in concentrated sulfuric acid, and
it has been shov/n in this thesis that under these condi tions H-cyclopropyl amides are hydrolyzed. This would have resulted in Bunce and Cloke underestimating the amount of cyclopropyl migration in the Schmidt reactions
of cyclopropyl ketones. 2 A recent investigation by Brackenridge indicated that acid concentration may play an important role in
Schmidt reactions. Benzophenones containing meta substi
tuents react with hydrozen azide to give isomeric amides,
the proportions of which were functions not only of the
electronic properties of the substituent, but also of acid concentration (Eq 25, 26, and 27). 51
0 II H /? Cl l'laK, eu Cl i: O. CECI,
(25)
99% HgSO^ 75 25
88# HgSO. 58 42 q w ON O CECI
(26) 99% HgSO^ 85 17
88# HgSO. 68 32
(27)
93# H-SO 12 88 2""4 88# H.SO 50 50 2SO4
The observed preferential migration of electron-
deficient phenyl groups at increased acid concentrations p has been explained' in the following manner: 32
Scheme 2
■No ^ X-0-NH-CO-0 + X-0-CO-NH-0 (28)
/N / -HpO i! 1. -Np X-0-.C-0 4 ^ X_0_C_0 ^ X-0-NH-CO-0 (29) ' H,0 2. H,0+
-H_0 n 1. -ÎL ^ ^ X-0-C-0 ^ X-0-CO-EH-0 (30) 2. H_0
X = electronegative substituent
Scheme 2 shows the azidohydrinium ion may (1) rearrange directly to amides (Eq 28) or (2) dehydrate to isomeric iminodiazonium ions which rearrange and hydrate or isomerize, equilibrate, rearrange and hydrate to products
(Eq 29 and 30). The more electron-rich group would be expected to migrate preferentially if every azidohydrinium ion rearranged directly to amides. However, in the presence of sulfuric acid some of these ions may be dehydrated to iminodiazonium ions. Brackenridge argued that the iminodiazonium ion in which the diazonium nitrogen is anti to the more electron-deficient phenyl group is more stable, presumably is formed faster, and is there fore the predominant isomer of the tv;o iminodiazonium 35
ions. Hence, a reaction path through iminodiazonium
ions will favor migration of the more electron-deficient phenyl group. Since such a pathway might he expected to be favored at high acid concentration, the observed preferential migration of the more electron-deficient phenyl group at increased acid concentration seemed reasonable.
There is doubt concerning some of Brackenridge’s results and conclusions, for it has been established in this thesis (Appendix A) that sulfonation of the amide with the more electron-rich aryl group attached to the amide nitrogen, but not its isomer, occurs in 99?^
sulfuric acid.
Kinetic studies of the Schmidt reaction have not permitted the choice of one mechanism to the exclusion of all others. The rate expression d(ll2)/dt = kh^(HK^)
(ketone) has been obtained for both cyclohexanone in
either sulfuric or hydrochloric acid and for acetophenone
in sulfuric acid,^^ for meta- and nara-substituted acetophenones in 68-80^ sulfuric acid,^^ and for 2-hexan-
one in 52-78^ sulfuric acid.^^ However, such kinetic
(33) D. M. Howell, Doctoral thesis. University of Michigan, Ann Arbor, Michigan, 1952.
(34) D. L. Pishel and M. J. Maximovich, private commun ication based upon the M. S. Thesis of M. J. M., 34
Kent State University, Kent, Ohio, 1964.
(55) 0. I. Koldobskii; G. P. Tereshchenko, L. I, Bagal, J. Org. Chem., U.S.S.R., 6 , 2407 (1970). expressions do not distinguish between the mechanism proposed by Smith and that involving rearrangement of the azidohydrinium ion directly to products; the same rate expression (that given above) is expected for both mechanisms.
Tereshchenko and co-workers^^ have measured the activation energies of the Schmidt reaction of 2-hexanone
(55) G, P. Tereshchenko, G. I, Koldobskii and L. I. Bagal, J. Org. Chem., U.S.S.R., 6 , 1157 (1970). at 58^'o and 94^ sulfuric acid and found them to be
10.0 kcal/mole and 12.3 kcal/mole, respectively. The authors believed the closeness of the activation energies at the different sulfuric acid concentrations permitted the conclusion that the mechanism of the reaction does not change in the range 58^ to 94^ sulfuric acid. However, such thermodynamic data is not very definitive since "the thermodynamic parameters of complex reactions are summary values and their interpretation causes certain difficulties without additional information."^^ RESULTS AND DISCUSSION
A study has been made of Schnidt reactions of
meta- and para-substituted ethyl phenyl ketones in acids
of different concentration and strength. The products
of the reactions are the isomeric amides and minor amounts
(5-10^)) of the corresponding ureas (Eq 31),
HN, CO-Et ^ /QVNH-CO-St + / Q Vco-NH-St H-? xrv Any R R NN-CO-NN-Et (31)
R R = H, m-He, p-Br, m-NO^, p- me, £-MeO
Scheme 3 outlines two possible mechanistic path
ways for Schmidt reactions of the ethyl aryl ketones.
The azidohydrinium ion XIV may rearrange directly to the
conjugate acids of the amides (Eq 32), or it may dehy
drate to isomeric iminodiazonium ions XV and XVI which
rearrange stereospecifically (to irninocarbonium ions
XVII and XVIII) and hydrate or isomerize, equilibrate,
rearrange stereospecifically and hydrate to products
(Eq 33 and 34).
There is much evidence^^that ureas in the
35 36
Scheme 3
.W„ ■ y — W Et-C-l'IH~Ar + Et-NH-C-Ar (32)
,^2 -H_o M -n? + ILO Et-C-Ar ^ *"• Et-C-Ar — ^ Et-1T=C-Ar Et-rlH-CO-Ar
H Ng XV XVII
XIV \ -H,0 II -IL + ÎLO — k" Et-C-Ar — 4- Et-C=E-Ar Et-00-ÎIH-Ar + HgO -H XVI XVIII (34)
Schmidt reaction of ketones arise from reaction of hydro gen azide with irninocarbonium ions, so the ureas formed in the Schmidt reaction of the ethyl aryl ketones of the present study must arise by reaction of hydrogen azide with irninocarbonium. ions XVII and XVIII. These ureas cannot be formed if XIV rearranges directly to the con jugate acids of the amides. Thus, dehydration of azidohydrinium ion XIV to isomeric iminodiazonium ions
XV and XVI with subsequent rearrangement and conversion to products better accounts for the reaction products than does direct conversion of XIV to the conjugate acids of the amides.
Such a mechanistic pathway is also consistent 57 with the ethyl to aryl migration ratios observed for
Schmidt reactions of the ethyl aryl ketones in various acid concentrations which are summarised in Table 7.
The data of Table 7 for R = H, m-Me, j^-Br, and
-m-EOg will be discussed first. These data indicate that changing the sulfuric acid concentration from 83-99^ and changing the electronic nature of the aryl substi tuent does not affect the ethyl to aryl migration ratio, which is (within experimental error) 15:85 in every case.
These results are quite different from those of 2 Brackenridge , who reported significant changes in the migration ratios for Schmidt reactions of meta-substituted benzophenones as a function of sulfuric acid concentra tions in the range 88-990.
The absence of any change in the amide ratio over this range (R = H, m-He, £-Br, and m-ITO^) of elec tron-donating and -withdrawing substituents supports the view that the ethyl to aryl migration ratio of 15:85 observed in the Schmidt reactions of these ethyl aryl ketones is a measure of the relative populations of the iminodiazonium ions XV and XVI, assuming that the rear rangement sten is faster than isomerization and equili bration of XV and The relative populations of XV and XVI, in turn, are largely the result of steric repulsions in the transition states leading to their ÎABIE 7 a b Migration Ratios in the Schmidt Reaction of Ethyl Aryl Ketones at Various Acid Concentrations ’ Ethyl : R-CgH^ Migration Ratio® Acid Catalyst R = H R = m-Me R = p-Br R = m-NO^ R = p-Me R = p-MeO 52.6 54 HgSO^ no rxn no rxn ------43:57^
69.4 54 HgSO^ — -- -- 3:97 40:6q S 83.3 54 HgSO^ 15:85 15:85 14:86 -- 4:96 40:60 89.0 54 HgSO^ 16:84 16:84 15:85 -- e e 93.7 54 HgSO^ 15:85 e 14:86 14:86 e e 99.4 54 e e -- 14:86 -- — CCl^COgH 17:83*^ 17:83 -- — --
a. All ScWidt reactions using sulfuric acid as catalyst were run in chloroform at room temperature (22-24 ), and the temperature range was never more than 5 . Schmidt reactions in trichloroacetic acid were run at 61-1 , trichloroacetic acid serving both as solvent and acid catalyst. b. Only one determination was done for each reaction. The yields of solid products (assuming only amides present) were 91-97/4 in all cases. c. Isomer ratios were determined by integration of the methylene protons in the nmr, except in the cases of R=p-Me, £-MeO, where glc using 5' x 1/8" 1554 XF-1150 on Chrom W at 220 was employed. d. Smith and Horwitz^^ report a ratio of 15:85. e. Preferential hydrolysis or sulfonation of the amide mixture was shown to occur under the reaction conditions, so the observed amide ratios are not reported. f. About 9554 (by glc) of the product mixture consisted of unreactedketone. g. About 1554 (by nmr) of the product mixture consisted of unreacted ketone. œ 59 formation. Thus— assuming the transition states leading to XV and XVI resemble XV and XVI— the 15:85 ethyl to aryl migration ratio observed in the Schmidt reaction of the ethyl aryl ketones under discussion would seem to be a measure of the different steric requirements of the ethyl and aryl groups in the iminodiazonium ions
XV and XVI, and the steric requirements of the aryl group apparently are greater than those of the ethyl group in ions XV and XVI,
Molecular models of iminodiazonium ions XV and
XVI indicate that indeed the steric requirements of the aryl group are greater than those of the ethyl group, •
XIX XX
R = H, m-He, £~Br, m-NOg
In ion XIX— from which aryl migration would presir.iably occur~the steric interaction between the methyl group and the diazonium group can be removed by a slight rota tion of the methyl group away from the diazonium group, giving conformer XX of lower ener/^y, (This is not possible when there are two methyl groups, as is the 40 case with the isopropyl aryl ketones.) In iminodia zonium ion XXI— from which ethyl migration would
✓ cII
XXI XXII
R = H, m-Me, n-Br, m-hOg presumably occur— tiio steric hindrance between the diazonium group and can be removed by a- slight rotation of the aryl group from the plane of the carbon-nitrogen double bond (XXII), but this also removes some of the conjugative stabilization which occurs by overlap of the
"p" orbitals of the aryl ring with the carbon-nitrogen pi bond.
It is expected, then, that the transition state leading to conformer XX will be of lower energy than that leading to either XXI or XXII and aryl migration will therefore predominate over ethyl migration, as is observed.
The data of Table 7 show that in the Schmidt reaction of ethyl para-tolyl ketone in 69- 83/0 sulfuric acid the ethyl to -para-tolyl migration ratio is about
3:97; that is, the nara-methyl substituent has resulted 41 in an increase in aryl migration from that seen when the substituent is II, m-Me. n-Br, or m-KO^.
A clue to this apparent electrical effect of a para-methyl group may be the observation-^ that para-
(37) C. R. Hauser and G. Vermillion, J. Am, Chem. Soc,, 1224 (1941). methyl groups promote interconversion of stereoisomeric aldoximes. This suggests that the para-methyl group may be promoting interconversion of iminodiazonium ions
XXIII and XXIV in the Schmidt reaction of ethyl para- tolyl ketone.
XXIII XXIV
The rates of isomerization of XXIII and XXIV may be considered to be dependent upon the single bond character of the carbon-nitrogen group. Single bond resonance forms of the iminodiazonium ion of ethyl phenyl ketone are shown in Eq 35. Substituents in the ring may
N ^ + IC N ^^C-Et ^ ^^C-Et ^^C-Et + ^^C-Et (35) 42 increase or decrease the contributions that such single bond resonance forms make to the structure of the molecule; thus for example, a methyl group in the para position should increase the single bond character of the carbon-nitrogen group and thereby promote isomerization of the iminodiazonium ions XXIII and XXIV.
As the rate of interconversion of XXIII and XXIV becomes comparable to the rate of rearrangement of XXIII and
XXIV, migration aptitudes could make a significant contri bution in determining the amide ratio; and the para- tolyl group would be expected to migrate better than ethyl, as is observed.
This same substituent-promoted isomerization of iminodiazonium ions may also be occurring in the Schmidt reaction of ethyl para-anisyl ketone. However,the data of Table 7 reveal that the para-anisyl to ethyl migration ratio is 60:40, less than what one would expect if isomerization of iminodiazonium ions XXV and XXVI were
f ÎÎC-Et MeO-\^-C-Bt
XXV XXVI occurring and migration aptitudes were making a signi ficant contribution in determining the migration ratio.
The lower-than-expected migration ratio for para- 43 anisyl to ethyl may he due to resonance contributions to XXV such as XXVII, which increase the double bond
+ / = \ 5 IIeO=( >=0-Et
XXVII character of the migrating bond, thus slowing dovm somewhat the migration of the para-anisyl group. Such an effect has also been postulated in Schmidt reactions of 6-raethoxyl-l-tetralone and 4-chromanones.^^’^^
Another explanation for the surprisingly low para-anisyl to ethyl migration ratio in the Schmidt reaction of ethyl.para-anisyl ketone might be that the ether oxygen is protonated in the acidic medium, resulting in a migrating group which is more electron-poor than a phenyl or para-tolyl group. However if this were the case, it does seem that the para-anisyl to ethyl migration ratio would increase as the sulfuric acid concentration is decreased since fewer of the methoxyl groups would be protonated in the less acidic medium. Such an expectation is contrary to the data of Table 7, which show the ethyl to para-anisyl migration ratio remains constant in sul furic acid concentrations ranging from 52^ to 83/L
Another possible mechanistic pathway for the
Schmidt reaction of the ethyl aryl ketones is sho\ni in
Eq 36, In this mechanism the azidohydrinium ion XXVIII undergoes protonation to XXIX, which concortodly 44
OU ^OHg _H,0+ + + Et-C-Ar^ Et-C-Ar ------^Et-N=C-Ar + Et-C=l'î~Ar (36) J k + A + "^2 \ j H H Ng rearrangement products products
XXVIII XXIX dehydrates and rearranges with loss of nitrogen to give the isomeric iminocarhonium ions leading to the products of the reaction (amides and ureas). While the mechanism of Eq 36 can account for the products of the Schmidt reaction of the ethyl aryl ketones, it does not seem to account in any consistent way for the migration ratios of the Schmidt reactions of ethyl aryl ketones reported in Table 7.
Tv/o further objections can be raised to the concerted mechanism of Eq 36. first, protonation of
XXVIII results in the di-positively charged ion XXIX, which would be expected to be a highly energetic— and therefore highly unlikely— intermediate. However, such an objection must he tempered by the fact that hydrazoic acid undergoes di-protonation in sulfuric acid of 38 elevated concentration. But even so, it does not seem
(38) It has been reported that the i-factor of hydrogen azide in 100/; sulfuric acid is 2.3-2.7 A. Hantzch, Ohem, Ber., 6^, 1702 (1930) , and the pK^ ,r++ has 3 2 been estimated to be 10.1 T. A, Bak and E. L. Praestgaard, Acta. Chem. Scand., 11, 901 (1957) , 45
likely that XXVIII would undergo di-protonation in
trichloroacetic acid. Perhaps, though, the concerted
dehydration and rearrangement of XXVIII does not require
complete protonation to XXIX, but only strong hydrogen bonding to the hydroxyl oxygen, in which case even trichloroacetic acid might promote the concerted dehy dration and rearrangement of XXVIII,
Perhaps an even more serious objection to the concerted mechanism of Eq 36 is that it requires molecule
XXIX to undergo a great deal of simultaneous atomic rearrangement and motion, in opposition to the Principle of Least Motion,Since there is evidence^^ that imino-
(39) J. Hine, J. Am. Chem Soc., 93, 3701 (1971). diazonium ions— such as would be formed from the stenwise dehydration and rearrangement of the azidohydrinium ion XXVIII— are not intermediates of inordinately high energy, there seems no reason to assume that the con certed mechanism of Eq 36 operates in the Schmidt reaction, except possibly in those cases where the intermediate iminodiazonium ions are of inordinately high energy.
(Por example, see the discussion of the results for the
Schmidt reaction of neopentyl phenyl ketone.)
In conclusion, the data of Table 7 for the Sclimidt reaction of ethyl aryl ketones seem most consistent with 46 the mechanism of Eq 32 and 35 in which an azidohydrinium ion: (1) dehydrates to isomeric iminodiazonium ions which rearrange stereospecifically much faster than they isomerize or equilibrate, resulting in steric factors determining the migration ratio; (2) dehydrates to isomeric iminodiazonium ions which— due to electron- donating substituents on the phenyl ring— do not rear range appreciably faster than they isomerize or equilibrate, resulting in both electrical and steric factors determining the migration ratio.
The products from the Schmidt reaction of iso propyl phenyl ketone in the present study are îî-isopro- pylbenzamide, isobutyranilide, and E-isopropyl-h'- phenylurea (Eq 37). The isopropyl to phenyl migration
HIT, i-Pr-CO-0 — i-Pr-IIH-CO-0 + i-Pr-CO-IIH-0 H" - (57) + i-Pr-IIH-CO-lIH-0 ratios determined for the Schmidt reaction of isopropyl phenyl ketone at various acid concentrations are summarized in Table 8,
Systems 3-7 in Table 8 show that the isopropyl to phenyl migration ratio is 65:35 in 830 to 990 sulfuric acid and in molten trichloroacetic acid. This figure is significantly different from the 49:51 migration TABLE 8 Migration Ratios in Schmidt Reactions of Isopropyl Phenyl Ketone at Various Acid Concentrations® i-Prop ; Ph Migration Ratio Number Reaction column System Acid Catalyst # Yield^ of Expts Time (hr) nmr^ chromatography glc 1 52.6 # HgSO^ 95' 2 168 -- — 46:54 2 69.4 # HgSO^ 92® 2 144 60:40 60:40 3 83.3 # HgSO^ 93 2 15 65:35 65:35 65:35 4 89.0 # HgSO^ 90 2 4 65:35 67:33 65:35 5 93.7 # HgSO^ 92 2 24 65:35 65:35 -- 6 99.4 # HgSO^ 90 1 2.2 65:35 65:35 -- 7 CGlgCOgH 90 1 9 65:35 65:35 -- a. See footnote a, Table 7 h. The yield is based upon the weight of crude product which includes the small amounts (5-10#) of side products (ureas and/or tetrazoles) as well as the isomeric amides. Those systems in which starting ketone was present in the reaction product are footnoted, and the amount of unreacted ketone (estimated by nmr) was substracted out in calculating the product yield. c. The migration ratios are considered accurate to i 1# and are not in error as a result of selective hydrolysis or selective sulfonation of the amides after their formation in the reaction mixture, as shown by product-recovery studies discussed in the Experimental part of this thesis. d. The carbinyl proton of N-isopropylbenzamide appears as a multiplet from 5.4T to 6.17*, The carbinyl proton of isobutyranilide appears as a multiplet from 7.17" to 7.97* .
The column used was 5 ' x 1/8" 15# XF—1150 on Chrora W at 175°. Retention times of the indi vidual amides in the mixture were verified by comparison with those of authentic samples of the amides. •N f. In these experiments, on the basis of nmr, approximately 90# of the ketone was unreaoted. -a About 37# unreacted ketone (by nmr) was present in the reaction product. 48
ratio Smith and Horwitz^^ reported using molten tri
chloroacetic acid at 61-62° as the acid catalyst and
solvent. In their work the migration ratio was
determined hy hydrolysing the crude reaction mixture in
methanolic potassium hydroxide and analyzing for
aniline (as acctanilide) and benzoic acid. The present
methods of direct analysis of the amides by nmr,
column chromatography, and glc are superior and the
excellent agreement among the three methods of analyses
attests to the accuracy of the 65 to 55 isopropyl to
phenyl migration ratio found in the present work.
Part of the discrepancy between the present find
ings and those of Smith and Horwitz may be related to
the K-isopropyl-N'-phenylurea found using column chro matography for analysis of the reaction mixtures of this
study. The P-isopropyl-h’-phenylurea constitutes 5-10
of the reaction product in those Schmidt reactions using 85-99# sulfuric acid; the greatest percent of urea results from reaction at the highest acid concentration,^®
(40) With 52# sulfuric acid as the catalyst, no urea v/as detected by column chromatography. This may have been the result of the low conversion of the ketone to products at this acid concentration and an increased probability of water rather than hydrogen azide attacking the iminocarhonium ions at this low acid (high water) concentration.
With molten trichloroacetic acid as both the solvent and 49 acid catalyst the urea constitutes 10^? of the reaction product. Thus, hydrolysis and analysis of the product from Schmidt reaction of isopropyl phenyl ketone in molten trichloroacetic acid which Smith and Horv/itz carried out to determine the extent of isopropyl and phenyl migration would have underestimated the isopropyl migration, because the isopropylamine resulting from hydrolysis of the urea was not analyzed but the aniline was.
Systems 3 through 7 in Table 8 show that the isopropyl to phenyl migration ratio of 65:35 in. the
Schmidt reaction of isopropyl phenyl ketone is unaffected by changing from sulfuric acid to trichloroacetic acid.
However, the ratio of phenyl to isopropyl migration increases from 35:65 to 54:46 as the sulfuric acid concentration decreases from 83^ to 52^^, as shown by comparing systems 1 and 3 in Table 8. These results for the Schmidt reaction of isopropyl phenyl ketone at var ious acid concentrations are relevant, to an understanding of the mechanism of the Schmidt reaction.
Both the presence of H-isopropyl-N’-phcnylurea and the isopropyl to phenyl migration ratio of 65:35 observed in the Schmidt reaction of isopropyl phenyl ketone in 83-99^' sulfuric acid and in trichloroacetic acid, are most easily explained (Scheme 4) by dehydration of azidohydrinium ion XXX to non-equilibrating isomeric 50
Scheme 4
i-Pr-C-0'C ----"2^ i-Pr-.N=C~0 XXXI I OH I i-Pr-C-0 products - I -H_0 i-Pr-C-0 ---^ i-Pr-C=H-0 XXX XXXII
iminodiazonium ions XXXI and XXXII, whose relative
populations are largely the result of steric repulsions
in the transition states leading to their formation.
The ions XXXI and XXXII then undergo stereospecific trans
rearrangement to isomeric iminocarhonium ions, leading to
the products of the reaction (the isomeric amides and
N- i s opr opyl-lT ’ -phenylurea ).
Such a mechanistic interpretation implies that
the steric requirements of the isopropyl group are greater
than those of the phenyl group in the transition states
leading from the azidohydrinium ion XXX to the isomeric
iminodiazonium ions XXXI and XXXII, so that isomer XXXI
predominates in the mixture of iminodiazoniuin ions. If
it is assumed that the transition state leading from XXX
to XXXI and XXXII resembles the products XXXI and XXXII,
then one can approximate the relative steric requirements
of isopropyl and phenyl groups in the transition states by examining the relative steric requirements of these 51 groups in the ions XXXI and XXXII,
Conformons of iminodiazonium ion XXXI are shovm in XXXIII and XXXIV. If the methyl groups are in any
C M II H i
XXXIII other conformation, molecular models shov/ that the hydrogens of the methyl, groups overlap with the ortho hydrogen, Hg, on the phenyl ring causing steric strain.
In XXXIII the phenyl ring is in the same plane as the carhon-nitrogen double bone, and there is steric inter action between and the diazonium group. In XXXIV the phenyl ring is twisted slightly (20-50°) out of the plane of the carbon-nitrogen double bond, thus removing steric involvement between and the diazonium group at the expense of some conjugative overlap between the
"p” orbitals of the phenyl ring and the carbon-nitrogen pi bond.
The least sterically hindered conformer of imino diazonium ion XXXII appears from molecular models to be
XXXV. If the methyl groups are in any other conformation there is severe steric interaction between their hydrogens 52
CHq CH. II
I H
XXXV and H^. But even in XXXV there is steric strain, for the hydrogens of the methyl groups overlap somewhat with the diazonium nitrogens.
Therefore, molecular models are consistent with the view that the steric requirements of the isopropyl group in XXXV are greater than those of the phenyl group in XXXIV. Hence— if the transition state for dehydration resembles the products— the energy of acti vation leading from the azidohydrinium ion to XXXIV is expected to be less than the energy of activation leading from the azidohydrinium ion to XXXV, resulting in preferential migration of isopropyl rather than phenyl in the Schmidt reaction of isopropyl phenyl ketone in
83~99/^ sulfuric acid and in trichloroacetic acid.
: The observed decrease in isopropyl migration from 65^ to 46;», in reducing the sulfuric acid from
83-99/' to 52fjf can be explained in either of tv/o ways.
One, the rearrangement may still be occurring exclusively via iminodiazonium ions XXXI and XXXII, but at this 55 relatively low acid (relatively high water) concentration the iminodiazonium ions XXXI and XXXII are equilibrating somewhat (via the azidohydrinium ion XXXjat a rate com parable to their rearrangement. Since complete or partial equilibration between XXXI and XXXII would be achieved continually during the rearrangement, the amide ratio would then be determined by the relative rates of rear rangement of XXXI and XXXII; that is, the migration aptitudes of phenyl and isopropyl could in some measure determine the amide ratio. Since alkyl groups exhibit a lower migratory aptitude than phenyl in most rearrange ments to positive sites^^, isopropyl would be expected to
(41) H. 0. House, E, J, Grubbs and W. F. Gannon, J. Am. Chem. Soc., 82, 1099 (i960). migrate to a lesser extent than phenyl at this lower acid concentration, as is observed.
Alternatively, the observed decrease in isopropyl migration in decreasing the sulfuric acid concentration from 85-99^ to 52^ may be explained by assuming that at
52^3 sulfuric acid part of the rearrangement is proceeding directly from azidohydrinium ion XXX. In 52^ sulfuric acid the reaction medium contains a relatively high concentration of water, so the driving force for dehydra tion of the azidohydrinium ion to the iminodiazonium 54
ions is not as great as it is at higher acid concentra
tions. In this situation the concentration of the
azidohydrinium ion may build up and rearrangement may
proceed directly from it, allowing migratory aptitudes
to determine the ratios of amides produced. However
this latter process, if it is occurring at all in 52^
sulfuric acid may be only a minor process, for one would
expect that if this were the predominant mechanism of
rearrangement phenyl migration might occur to a greater
extent than 54^^since phenyl is expected to exhibit a much higher migration aptitude than isopropyl in rear
rangement to positive sites,inasmuch as phenyl can
(42) However, this is not true in the Baeyer-Villiger oxidation of isopropyl phenyl ketone where the migration ratio of i.“?r to phenyl is 66:54. M. P. Hawthorne, VJ. D.“Emmons and K. S. EcCallum, J. Am. Chem. Soc,, 80, 6393 (1958).
form a stable phenonium ion during the rearrangement
process.
Prom the data of Table 8 it is not possible to
decide which of these alternatives may be the correct
explanation for the observed decrease in isopropyl migra
tion in decreasing the sulfuric acid concentration from
83-99^ to 52/b. However, there is good evidence (forma
tion of the urea) that the Schmidt reaction of isopropyl phenyl ketone does proceed, at least in part, through 55
rearrangement of iminodiazonium ions. This, and mechan
istic economy, would indicate it is not necessary to
assume that direct rearrangement of the azidohydrinium
ion XXX to isomeric amides occurs in the Schmidt reaction
of .isopropyl phenyl ketone.
The products of the Sclimidt reaction of isopropyl
para-tolyl ketone in the present study are (Eq 38)
PEL i-Pr-CO-^^— cn^ — i-Pr-Iffi-CO-^^— CH^
+ i-Pr-GO-EH— + iPr-NH-CO-IEICi
IT-isopropyl-para-toluamide, II(para-tolyl )-isobutyra:nide,
and a minor amount (5-10^) of a third component presumed
to he H(para-tolyl)-]I*-isopropylurea, since ureas were
isolated in Schmidt reactions of isopropyl phenyl ketone,
cyclopropyl phenyl ketone, and ethyl meta-hromophenyl ketone.
The isopropyl to para-tolyl migration ratios for
Schmidt reactions of isopropyl para-tolyl ketone at various acid concentrations are shown in Table 9, These
data reveal that in the Schmidt reactions of the respec
tive ketones the para-tolyl group of isopropyl para-
tolyl ketone migrates less readily than the phenyl group
of isopropyl phenyl ketone (see Table 8), and much less
readily than the para-tolyl group of ethyl para-tolyl TABLE 9 Migration Ratios in Schmidt Reactions of Isopropyl nara-Tolyl Ketone at Various Acid Concentrations Prop : -para—Tolyl Migration Ratio Number Reaction System Acid Catalyst Yield nmr
1 52.6 % HgSO^ 1 2 168 No detectable reaction 2 69.4 7Î HgSO^ 96^ 1 192 60 ; 40 60 : 40 3 83.3 f» HgSO^ 95 2 4, 17 67 : 33 67 ; 33
4 89.0 % HgSO^ 96 2 4, 17 74 : 26 74 ; 26 5 93.7 ^ HgSO^ 96 2 4, 17 79 : 21 79 : 21 a. Reaction conditions are described in footnote a, Table 7 b. See footnote b, Table 8 c. The migration ratios are considered accurate to i 27^ and are not in error as a result of selectïye hydrolysis or selectiye sulfonation of the amides after their formation in the reaction mixture, as shown by product—recovery studies of the amides. Howeyer, some selec— tiye destniction of amides does occur at 99^y HpSO., and for that reason the results of the Schmidt reaction of isopropyl para-tolyl ketone in 99^ H^SO^ are not reported. d. The relatiye heak heights of the methyl substituent were used as a measure of isomer ratio. The methyl substituent of N-isopropyl-g^^-methylbenzamide -appears at 7.65 T, while that of M-(para-tolyl)-isobutyramide appears at 7.75 7". e. See footnote e, Table 8 f. About 377» unreacted ketone (by nmr) was present in the reaction product. vn o\ 57 ketone (See Tabel 7). This fact would seem to be con
sistent with the view that the substituent-promoted
isomerization of iminodiazonium ions XXXVI and XXXVII
.U'T+ +T "Ik N ^ Me— Ke—<^)~C-i-Pr
XXXVI XXXVII results in both electrical and steric factors determining the isopropyl to para-tolyl migration ratio, and for this system the balance of these factors favors isopropyl migration.
The other point of interest about the data in
Table 9 is that as the concentration of the acid catalyst
is decreased in the Schmidt reaction of isopropyl para- tolyl ketone the aryl group migrates to a greater extent.
Recall this was also true for the Schmidt reaction of
isopropyl phenyl ketone, and it was stated that it was unclear whether this fact resulted simply from increased
isomerization of the isomeric iminodiazonium ions as the sulfuric acid was decreased or from part (or all)
of the reaction occurring by the rearrangement of the azidohydrinium ion directly to the conjugate acids of the isomeric amides. Since in the Schmidt reaction of
isopropyl para-tolyl ketone isomerization of the isomeric
iminodiazonium ions is presumably occurring throughout the range of sulfuric acid concentration (69-93/^), and 50 the migration ratio of the aryl group still increases as the sulfuric acid concentration is decreased, this might indicate that the increased aryl migration ratio with decreased acid concentration observed in the Schmidt reactions of isopropyl phenyl ketone and isopropyl para- tolyl ketone is due to some rearrangement of the azidohydrinium ion directly to the conjugate acids of the isomeric amides, rather than isomerization of the isomeric iminodiazonium ions.
It is noteworthy that this increased aryl migration with decreased acid concentration observed in the
Schmidt reactions of isopropyl phenyl ketone and isopro pyl nara-tolyl ketone might also have been observed in the Schmidt reactions of the ethyl aryl ketones (Table 7) had the reactions been more extensively investigated in the very low range (52-69^) of sulfuric acid concentration,
The products of the Sclimidt reaction of isopropyl para-anisyl ketone are (Eq 39) the isomeric amides and a
HN. MeO-)—^^CO-i-?r MeO—<^^T!H-CO-i-Pr +
(39)
CO-NH-i-Pr + K e O - ^ ^ NH-CO-1'JÎI-i-Pr minor amount (5-10^) of a third component, again assumed to be the urea.
The data of Table 10 show that the isopropyl to TABLE 10 Migration Ratios in the Schmidt Reaction of Isopropyl nara-Anisyl Ketone at Various Acid Concentrations i»-Prop ; para-Aniayl Migration Ratio Rumher Reaction nmr 1 52.6 ^ HgSO^ 1 1 72 No detectable reaction
2 69.4 fo HgSO^ 96^ 1 156 44:: 56 3 83.3 HgSO^ 98 1 22 45 : 55 44 : 56
4 89.0 io HgSO^ 83 1 9 44 : 56 44 : 56 5 OGl^COgH 80 1 21 44 : 56 -- a. Reaction conditions are described in footnote a. Table 7. b. See footnote b, Table 8 c. The migration ratios are considered accurate to ~ 2^ and are not in error as a result of selective hydrolysis or sulfonation of the amides after their formation in the reaction mixture, as shown by product-recovery studies of the amides. However, some selective destruction of the amide mixture does occur at 93.75^ HpSO. and 99.45^ HgSO., and for that reason the results for the Schmidt reaction at these acid concentrations Sre not reported, d. The carbinyl proton of N—isopropyl—p^-methoxybenzamide appears as a multiplet at 5.5—6.0 T". The carbinyl proton of R-Cp-anisyl)-isobutyramide appears as a multiplet at 7.15-7.65V. e. The column used was 5' x 1/8" 5/^ XT'-1150 on Chrom P at 220°. f . About S Z f o (by nmr) of unreacted ketone was present in the reaction product. VJ3-Wl 60 para-anisyl migration ratio in the Schmidt reaction of isopropyl para-anisyl ketone is 44:56, and does not change when the acid catalyst is changed from 69 to 89m sulfuric acid or to molten trichloroacetic acid. It is thought significant that this isopropyl to para-anisyl migration ratio of 44:56 is essentially the same as the ethyl to para-anisyl migration ratio of 40:60 observed in the Schmidt reaction of ethyl para-anisyl ketone
(Table 7).
This latter fact and the data of Table 10 are explicable in terms of those factors which were thought to operate in the Sclimidt reaction of ethyl para-anisyl ketone. Thus the azidohydrinium ion XXXVIII of Eq 40
Me G—f— Pr
XXXIX OH MeO-^^-C-i-?r (40)
XXXVIII MeO-(C ;^C-i-Pr
XL dehydrates in all of the acid catalysts studied to form 61 the iminodiazonium ions XXXIX and XL whose isomerization or equilibration is promoted by the para-methoxyl sub stituent, allowing electrical factors to operate in determining the migration ratio. The para-anisyl migrates less readily than perhaps what we expect,due to the contribution to isomer XL of resonance form XLI which
+_ / = V MeO=< )=C-i-Pr
XLI increases the double bond character of the migrating aryl-to-carbon bond, resulting in less-facile para-anisyl migration than might otherwise be expected.
The fact that the para-anisyl group migrates nearly the same extent whether the group competing with it is isopropyl or ethyl tends to support the above explanation and to indicate that the major determinant in the migration ratios observed in the Schmidt reactions of alkyl para-anisyl ketones are the electrical factors arising from the para-methoxyl substituent. This suggests that were the Schmidt reaction of methyl para-anisyl ketone to be effected, the methyl to para-anisyl migration ratio might very well be about 40:60,
Products of the Schmidt reaction of neopentyl phenyl ketone are the isomeric amides,small amount;
(2-4/0 of tetrazoles,and small amounts (1-2/) of a 62 purple poljrmer^^ (Eq 41).
(43) The amides were isolated by preparative glc and identified by elemental analysis and by ir, nmr, and mass spectral analysis.
(44) The tetrazoles were not isolated but their presence was inferred from thin layer chromatography and mass spectra of the crude mixtures.
(45) This polymer was isolated by column chromatography.
m e tBuCH2-CO-0 — ^ t-BuCIl2-HH-CO-0 + j^Bu CH2-CO-IIH-0 (41 )
+ tetrazoles + purple polymer
(minor) (minor)
The neopentyl to phenyl migration ratios for the
Schmidt reaction of neopentyl phenyl ketone at various acid concentrations are summarized in Table 11. The percent phenyl migration changes from 61 at 930 sulfuric acid to 93 at 830 and 690 sulfuric acid,^^ The per cent
(46) This fact has synthetic implications. If the amide due to phenyl migration is desired, conducting the Schmidt reaction in 830 sulfuric acid results in about a 900 pure crystalline product, whereas effecting the reaction in 930 sulfuric acid results in incomplete conversion of ketone to a mixture of amides, only 630 of which is the desired amide. phenyl migration in trichloroacetic acid is about the same as in 69-830 sulfuric acid. The most striking thing TABLE 11
Migration Ratios in the Schmidt Reaction of Neopentyl Phenyl Ketone at Various Acid Concentrations Neopentyl : Phenyl Number Reaction Acid Catalyst ^ Yield^ of Expts Time (hr) Migration Ratio^
69,4 0 HgSO^ 95^ 1 24 7 : 93 83,5 # HgSO, 92 1 24 7 : 93 89.0 # HgSO^ 81 1 24 18 : 82
93.7 ^ H2SO4 96® 3 24 39 : 61 CCl^COgH 95^ 1 24 11 : 89 a. See footnote a, Table 7. h. See footnote h, Table 8. c. The amide ratios were determined by glc using 5* x 1/8" 2.io PFAP on Chrom W at 172 and 5* x 1/8" 15^ XP 1150 on Chrom ¥ at 175 . Ratios are probably accurate to + 2^. d. About 60^ (by nmr) unreacted ketone was present in the reaction product. e. About 50‘/ (by nmr) unreacted ketone was present in the reaction product. f. About 5^ (by nmr) unreacted ketone was present in the reaction product. 64
about the data in Table 11 is the very low per cent of
neopentyl migration, especially at 69-85^ sulfuric acid
and in trichloroacetic acid. If steric effects alone were determining the migration ratio in the Schmidt
reaction of neopentyl phenyl ketone, certainly one would expect a greater per cent of migration by the bulky neopentyl group than is observed.
Molecular models show that the azidohydrinium ion
XLII suffers steric strain in whatever conformation it
OH, OH I 5 I H^C-Ç-CHg-Ç
il i'2
ILII
assuines. Furthermore, this steric strain is not removed
during dehydration of XLII, Thus the least sterically
strained conformer of the anti-uhenyl iminodiazonium
ion appears to be XLIV which derives from XLIII by
^3 V\
, \^i I ' Cf 11 (42)
XLIII XLIV 65 dehydration (Eq 42). But dehydration from XLIII to XLIV is not an effective means of reducing steric strain, for there is considerable steric strain in XLIV resulting from interaction between the diazonium group and the nine methyl hydrogens of the neopentyl group.
The syn-phenyl iminodiazonium ions XLVI and XLVII derive from XLV by dehydration (Eq 45). Again, dehydration
t-Bu OH o H
H (45)
XLV XLVI XLVII is not an effective means of releaving steric strain.
In XLVI there is severe steric strain arising from inter action of the diazonium group and ïï-, which can be removed by slight rotation of the phenyl group from the plane of the carbon-nigrogen bond to give XLVII. However, in
XLVII there is also considerable steric strain, for the hydrogens on the methyls of the neopentyl group can now interact with carbons 2 and 5 of the phenyl ring.
Since dehydration to form iminodiazonium ions
XLIV and XLVI or XLVII will have a high energy of activa tion due to steric strain in the transition states leading 66 to them, the rearrangement may occur by alternative routes having lower activation energies. Recall that steric hindrance to dehydration of azidohydrinium ions was also postulated by Thyagarajan and Bhalerao in the 25 Schmidt reaction of chronanones.
One of these routes of lower activation energy might be direct rearrangement of the azidohydrinium ion to the conjugate acids of the amides. Structure XIYIII
phenyl
migration \__ / (44) t-B u CH,
'OH XLYIII
(45) is, according to molecular models, the least sterically conjested azidohydriniumi ion which can lead to phenyl migration, either by direct phenyl migration (mq 4-5) or by dehydration and subsequent phenyl migration (Eq 44).
The phenyl group in XLVITI lies in the plane of the paper. 67 and dehydration would lead to IL in which— not only is there no conjugation between the phenyl ring and the inline group— there is steric strain arising from inter action of the methyl hydrogens with ring carbons and hydrogens. The alternative pathway (Eq 45) of direct phenyl migration would seem to be the reaction pathway
of lower activation energy, since it can reduce steric strain and proceed via a phenonium ion,
heopentyl migration might also occur by rearrange ment of the azidohydrinium ion L directly to the conju gate acid of the amide (Eq 47), rather than by dehydra tion and subsequent neopentyl migration (Eq 46). If the
OH
CH ^'^3 H \neopentyl 3 Migration
+ 0H (46)
(47)
neopentyl and phenyl migrations do occur at the azidohydrinium ion stage, then one would expect phenyl to migrate much better than neopentyl since phenyl migrates 68
to positive sites much more readily than primary alkyl
groups,The high percent (89-93/^0 of phenyl
(47) It is noteworthy that in the Baeyer-Villiger oxida tion of neopentyl phenyl ketone— where electrical factors are believed to be the major factor con trolling migration ratiosj^the phenyl to neopentyl migration ratio is 90:10.''' migration reported in Table 11 for the Schmidt reaction of neopentyl phenyl ketone in 69-83# sulfuric acid and in molten trichloroacetic acid is consistent then with the view that in these acid catalysts neopentyl and phenyl migrations are occurring directly from the azido- ^ . . 48 hydrinium aon.
(48) It is of interest to study how the neopentyl to phenyl migration ratio is affected by substituents on the phenyl ring.
Another rearrangement process may be occurring to a minor extent in 69-83# sulfuric acid and in tri chloroacetic acid. The azidohydrinium ions II and LII are in equilibrium with their protonated forms, LIII and LIT (Eq 48 and 49), which may undergo simultaneous
(or near simultaneous) dehydration and rearrangement to give irainocarbonium ions IV and LVI, It is expected that the activation energies accompanying the near simultaneous dehydration and rearrangement of IIII and 69
t-8u 9^2 -H-0 - 4 *- (^)-N=CCH-t-Bu ri.-arrancjjement\__y (48) IV
II LUI
t-By °»T + t-Bu : & o
J / & N Î ^ />Klt IVI I I H H
III IIV
IIV might he less than the activation energies accom panying dehydration, of LIII and IIV and subsequent
rearrangement, since the former process apparently results
in less sterically strained transition states than the
latter process. Thus as dehydration of LIII and IIV
begins to occur, the accompanying steric strain is
relieved by the early migration to nitrogen.
In 69-83^ sulfuric acid and in trichloroacetic
acid probably little of the rearrangement is proceeding 70
by the simultaneous dehydration and rearrangement of
IIII and LIV, since protonation of LI and LII to give
LIII and LIV may not result in a high concentration of
these ions. But if some of the rearrangement occurs hy this process, then the iminocarbonium ions LV and LVI produced therefrom may react with hydrogen aside to produce the small amounts of tetrazoles observed using
69-85/3 sulfuric acid and trichloroacetic acid.
As the sulfuric acid concentration is increased from 85/3 to 93/3 more of the azidohydrinium ions LI and
LII become "tied up" in their protonated forms LIII and LIV, which means that more of the rearrangement will be occurring by near simultaneous dehydration and rearrangement from LIII and LIV and less by direct rearrangement of LI and LII, In this case the phenyl to neopentyl migration ratio might decrease, since as dehydration from LIII and LIV begins to occur the positive charge accumulating on the central carbon atom may better be stabilized by phenyl than by the neopentyl group, resulting in neopentyl rather than phenyl migration to nitrogen. Such an expectation is consistent with the increase in neopentyl to phenyl migration ratio from 7:93 iu 85^ sulfuric acid to 59:61 in 93/3 sulfuric acid reported in Table 11,
The migration ratios observed in the Schmidt 71 reaction of ethyl methyl ketone and isopropyl methyl ketone are shovm in Table 12. For both ketones the similarity in migration ratios in 49/^ sulfuric acid and in trichloroacetic acid, and the fact that there were no ureas or tetrazoles formed in trichloroacetic acid using a ten-fold excess of hydrogen aside, suggests the rearrangement in these acid catalysts may be occurring directly from the azidohydrinium ions LVII and
LVIII, so that migration aptitudes determine the ratio
OH OH I I Et—C—i:c i—Pr—C—iie
LYII IVIII of amides. This view is consistent with the migration ratios observed for each ketone in these catalysts; ethyl to methyl 74:26 and isopropyl to methyl ca. 85:15.
However, such migration ratios are also consistent with the idea that the'reaction is proceeding through isomeric ininodiazoniura ions LIE and IX and steric
H ^ ^ N II II R-0-îIe R-O-Ke
IIX LX
R = Et, i-Pr effects are determining the ratio of amides products. TABLE 12
Migration Ratios in the Schmidt Reaction of Alkyl Methyl Ketones at Various Acid Concentrations^’^ Alley 1 : Me Migration Ratio‘S Acid Catalyst Alkyl = Ft Alkrv'-l = i—
49.4 # H2SO4 74 : 26 84 : 16 69.4 2 HgSO^ 70 : 30 -
83.5 ^ H2S04 66 : 34 85 : 15
89.0 # HgSO^ 66 : 34 78 : 22 95.7 2 HgSO^ 65 : 35 82 ; 18
99.4 2 HgSO^ 66 : 34 80 : 20
CCl^COpH 73 : 27 87 : 13 a. See footnote a, Table 7 b. Reaction times were 16-24 hr. The yields of product were 80-90^. The data are for only one determination at each acid concentration. c. The amide ratio was determined hy glc using 10’ x 1/8” 10^ FFAP on Chrom V.’ at 175 . The data are considered accurate to withing + 2/5.
ro 73
This fact, the relatively snail difference in migration ratios at the different acid concentrations, and the fact that tetrazoles v/ere produced (as shovm by glc and mass spectral analyses of the product mixture ) in the reaction of ethyl methyl ketone at 83^ sulfuric acid in excess hydrogen azide, make the postulation of rearrangement directly from the azidohydrinium ions more tenuous than in the Schmidt reaction of some of the previous ketones of this study.
If indeed the Schmidt reactions of ethyl methyl ketone and isopropyl methyl ketone are proceeding through iminodiazoniujn ions LIX and LX, it is not possible to decide from the alkyl:methyl migration ratios given in
Table 12 whether or not the iminodiazonium ions LIX and LX are isonerizing to one another during the reaction.
IIov;ever, based upon the results of Schmidt reactions for aryl allcyl ketones— where it v/as presumably found that isomerization of iminodiazonium ions occurred only when there were electron donating substituents on the phenyl ring— one might expect that the ions LIX and LX are not isonerizing, and the migration ratios reported in Table 12 would then be a result of steric differences in the transition states leading from the azidohydrinium ions LVII and LVIII to the iminodiazonium ions LIX and LX.
The Schmidt reaction of neopentyl methyl ketone 74
(Eq 50) is much more sensitive to acid concentration
t-BuCI-LCOCIL — t~BuCH„miCOCIL + t-BuCH.COBHCH% (50) - 2 ^ H 2 5 - 2 5 effects than are the Schmidt reactions of ethyl methyl ketone and isopropyl methyl ketone. Table 13 shows the neopentyl to methyl migration ratio is 53:47 in 99/4 sulfuric acid but steadily increases with decreased sulfuric acid concentration until the ratio is 72:28 in
69/4 sulfuric acid. The neopentyl to methyl migration ratio of 74:26 observed in molten trichloroacetic acid is similar to that in 69^ sulfuric acid.
It appears that the factors operating to determine the migration ratios in the Schmidt reaction of neopentyl methyl ketone are similar to those which determined the migration ratios in the Schmidt reaction of neopentyl phenyl ketone (vide supra). î-'olecular models show that the azidohydrinium ion IXI of Eq 51 is sterically crowded and suffers steric strain. But this steric strain becomes even worse if LXI undergoes dehydration to either the anti-neonentyl iminodiazonium ion LXII or the syn- nedpentyl diazonium ion LXIII, in whatever conformation these ions assume. Schemes 5 and 6 show the sources of the steric strain in each conformation of the iminodia zonium ions.
As a result, then, of this steric inhibition to TABLE 13
Eeopentyl to î'ethyl Migration Ratio ig the Solimidt Reaction of l'Ieopentyl Methyl Ketone at Various Acid Concentrations Keopentyl:Methyl Migration Ratio Kur.ib er Reaction Acid Catalyst Yield^ of Ibcots Time (hr) n-lc° nnr^ 52.6 > HgSO^ —— 1 72 No det eatable reaction
69.4 ^ HgSO. 95 2 22 72 : 28 —
85.5 2 n2S04 95 1 5.7 67 : 33
89.0 ^ 90 1 3 65 : 35 65 : 57
95.7 2 H2S04 99 2 3, 14 57 : 43 56 : 44 99.4 ^ HgSO^ 90 1 3 55 : 47 55 : 47 OOl^COgH 93 1 18 74 : 26 71.: 29 a. See footnote a, Table 7. b. See footnote b, Table S. c. The colurnn used was 10 > X 1/8" 55- FFAP on Chrom W at 172°.
VJ1 Integrations were perforned on the nethyl peaks and on the t-butyl peaks o f the two ajT;ides, The methyl group of IT-neopentylacetexiide appears as a singlet at 8,00 r. The methyl group of R-nethyl-t—butylacctanide appears as a double t at 7.25 7". The t-butyl group of R-neopentylacetamide appears as a singlet at 9.10 T, and the t—butyl group of R—methyl-t-butylacotamide appears s a singlet at 9.00 f. The njtr ïïata are considered accurate to + 2y>, 76
Scheme 5
Anti-neopentyl:
t-su H r " ' - . H II "c H I t-Bu
steric interference be steric interference be tween the t-hutyl hydro tween t-butyl hydrogens gens and the methyl and methyl hydrogens hydrogens
z t -Bo II i -Bu ^ 'CH, CM, I H H steric interference be steric interference be tween t-butyl hydrogens tween t-butyl hydrogens and methyl hydrogens and nitrogen 77
Scheme 6
Syn-nep-pentyl :
M 2^ t -Bu H " \ h . "-'A 'CH. I H % -Bu
steric interference be steric interference tween t-bntyl hydrogens between t-butyl hydro and the diazonium nitrogens gens and~the methyl as well as the methyl hydrogens hydrogens
\ w N II CH. H H
steric interference be severe steric interfer tween t-butyl hydrogens ence between the t-butyl and the methyl hydrogens group and the dia'sonium group 78
N II t-BuCHgC-CH.
LXII
OH t-BuOH.C-Cn= (51) - 2 1 3
LXI If """Ngx ^
II t-BuCHgC-CH^
LXIII
dehydration, the azidohydrinium ion LXI may rearrange
directly to the conjugate acids of the isomeric amides
(Eq 52). This may he the predominant mechanism of reac
tion in 69/'o sulfuric acid and in trichloroacetic acid,
OH ■^OH ■^OH I -H2 I' t-BuCIUC-CH, ^ t-BuCH„CHKCH., + t-BuCH^HH&CH, (52) — 2 1 3 — 2 , 3 — + H I-Ç
LXI where neopentyl to methyl migration ratio of about 75:27
follows the "inductive order" of these groups indicating
that inductive effects may determine the migration ratio when the azidohydrinium ion LXI rearranges directly to
amides. 79
With increased sulfuric acid concentration
protonation of LXI promotes dehydration of LXI, hut
the dehydration may he accompanied hy the simultaneous
(or nearly simultaneous) migration of neopentyl or methyl
to nitrogen in order to minimize the steric strain
accompanying dehydration (Eq 53). If such is the case,
t-BuCIUIT=CCIU products 2 3 -H^O -IL rearrangement \
on .+ I H t-BuCH_C-CH? “ 2 1 3 t^BuCHgC-Cn^ (53)
LXI LXII / -ILO
-1-2 rearrangement t-BuCH_0=h-0H% products - 2 3 then the decrease in the neopentyl to methyl migration ratio accompanying the increase in sulfuric acid concen tration becomes understandable. As LXII begins to dehy drate, the neopentyl group— having greater inductive electron release than methyl— can better stabilize the positive charge accumulating on the carbon from which water is leaving than can the methyl group, resulting 8 0 in more facile methyl migration.
It is interesting to note that no ureas or tetra zoles were found in the product mixtures for the Schmidt reaction of neopentyl methyl ketone when these product mixtures were subjected to mass spectral analysis. The same observation was made for the Schmidt reactions of ethyl methyl ketone and isopropyl methyl ketone. In the latter cases, tetrazoles were observed in Sclimidt reactions in 85/^ sulfuric acid, but only when the reaction was carried out in a ten-fold excess (with respect to ketone) of hydrazoic acid. Apparently, then, the absence of any tetrazoles or ureas in the product • mixtures of Schmidt reactions of these dialkyl ketones is due to the instability of the iminocarbonimn ions formed in the reaction; the labile iminocarbonium ions react with water to form amides before they have time to react with the small amount of hydrogen azide present to give ureas or tetrazoles. In Schmidt reactions of aryl alkyl ketones, apparently the iminocarbonium ions are stable enough that they have the opportunity to react with hydrogen azide rather than water, even when, hydrogen azide was not added in a ten-fold excess with respect to ketone.
The products from Schmidt reaction of cyclopropyl phenyl ketone (Eq 54) in the present study are 81
cyclopropanecarboxanilide, IT-cyclopropylbenzarnide,
N-cyclopropyl-N-phenylurea, benzarnide, and an unidentified
brovm polymer. As found for isopropyl phenyl ketone,
O-CO-0 — >-CO-lT-0 + O-IT-CO-0 + O-N-CO-U-0 H 75-800 6-80 5-100
(54) + 0OONH2 + bro\vn polymer
1-50 2-50
the amount of urea produced in Schmidt reaction of cyclo propyl phenyl ketone is a function of acid concentration.
At relatively low acid concentration the urea constitutes
4-50 of the reaction product, but in 99;’ sulfuric acid the urea comprises 100 of the product.
The 1-50 of benzamide produced in these reactions apparently arises via acid-catalyzed ring opening of
K-cyclopropylbenzanide according to the mechanism in Eq 55.
This hypothesis was verified when N-cyclopropylbenzarnide was subjected to the reaction conditions for 24 hr and benzamide v/as recovered in 850 yield (see Experimental).
Furthermore, the propanal produced in the acid-catalyzed hydrolysis of IT-cyclopropylbenzamide was trapped with
2,4-dinitrophenylhydrazine to yield propanal 2,4- dinitrophenylhydrazone.
The results for the Schmidt reaction of cyclo propyl phenyl ketone are summarized in Table 14. A
j(tV. 82
H H If IL .0 ILO O-il-CO-0 CH, OH T ^ -H"'" 5 g -HgO
H H (55) _^0H ^0 / C H _ +î\ /0 CIL ‘^^CII C^ 1— ^ ni-L ^ CH ' c 3 . I u ^ 3 I H 1, *0%, 0 0^ 0 1 -if CH-CHgCHO + ^COHHg possible source of error in the data lies in reaction of
the catalysing acid with the amides produced to give products which are soluble in the aqueous phase of the reaction mixture and thus would not be isolated in the workup. Such consecutive reactions are of particular
interest with the present amides in view of the well knovm^^ reactions of cyclopropane rings with acids. To
(49) A, Bhati, Perfumery and Bssent. Oil Rec., 15 (1962), and references therein. test the possibility that the amides react with the
catalyzing acids, product-recovery studies were carried
out on the isomeric amides at various acid concentrations.
The results of these studies are shown in Table 15.
Table 15 reveals that there is very little, if TABLE 14 Migration Ratios in Schmidt Reactions of Cyclopropyl Phenyl Ketone at Various Acid Concentrations Cyclopropyl : Phenyl Number Reaction Acid Catalvst Yield^ of Exnts Time (hr) Migration Ratio® 52.6 ^ HgSO^ -- 1 84 No detectable reactic
69.4 fo HgSO^ d 1 22 5 : 95° 83.3 ^ HgSO^ 92 2 16 5 : 95° 89.0 ^ HgSO^ 90 2 5 8 : 92 93.7 ^ 89 2 7, 23 9 ; 91 99.4 ^ 89 1 2.2 9 ; 91 CCl^OOgH 95 1 16 8 ; 92 a. See footnote a. Table 7 b. See footnote b. Table 8 c. Unless othenfise noted, column chromatography was used for the analyses. The amount of cyclopropyl migration was calculated by adding the mass of IJ-cyclo- propylbenzamide to that of benzamide produced by the acid-catalyzed brealtdown of îl-cyclopropylbenzamide. The migration ratios thus calculated are probably accurate to only + 3-4^. d. The product was almost entirely unreacted ketone. ,8. The amides were analyzed by glc using 5’ x 1/8" 15^ XF-1150 on Chrom W at 175°. It was assumed that at this acid concentration the acid-catalyzed breakdown of H-cyclopropylbcnzamide to benzamide and propanal was not significant. No attempt was made to confirm the presence of N-cyolopropyl-N’-phenylurea in the reaction product at this acid concentration. TABLE 15
Summary of Prodxiot-Recovery Studies on N-CyclopropylLenzamide and Cyclopropanecarboxanilide
Amide(s) Reaction Conditions Results
Cyclopropanecarboxanilide 0C1_C0?H, 64 , Recovered 100^ of initial amide 20 hr
Cyclopropanecarboxanilide 95.7/^ HgSO^, CHC1„ Recovered 100/j of initial amide 24", 15 hr l'î-cyclopropylbenzamide CCl^CO.H, îTaîI-, Recovered 91# of initial mass, which consisted of initial amide 61°, 20 hr and a minor amount of benzamide
N-cyclopropylbenzaraide 95.7# %2S°4' CHCl- Recovered Benzamide in 83—86# yield 24-28°, 24 hr
Cyclopropanecarboxanilide 99.4# HgSO^, CRCl, Recovered 98# of initial mass and IT-cyclopropylbenzamide consisting of initial amides Ilall^, 25°, 2.2 hr^ and a small amount of benzamide
a. The short reaction time (2.2 hr) in this experiment corresponds to the reaction time for the Schmidt reaction of cyclopropyl phenyl ketone in 99.4# sulfuric acid.
CO 85
any, reaction of the product amides with, acids to form water-soluble products which would not be isolated in the worloip. This conclusion is also consistent with the high yields (except when trichloroacetic acid was used as catalyst) of products obtained in these reactions.
It thus appears that the phenyl to cyclopropyl migration ratios reported in Table 14 are not in error due to reaction of the product amides with the catalysing acid.
Therefore, it may be concluded from Table 14 that the cyclopropyl to phenyl migration ratio in the
Sclmidt reaction of cyclopropyl phenyl ketone is 7:93
(+ 20) and is unaffected by sulfuric acid concentrations in the range 69-990, or by changing the acid from sulfuric to trichloroacetic. The cyclopropyl to phenyl migration ratio of 7:93 (+ 20) of the present work is in essential agreement with that of 5:95 previously reported by Bunco % and Cloke. The significance of the present results is that they demonstrate that this ratio is unaffected by large changes in acid concentrations.
If steric factors are responsible for the small per cent (ca. 70) cyclopropyl migration in the Schmidt reaction of cyclopropyl phenyl ketone; then it appears the steric requirements of the cyclopropyl group in this
Schmidt reaction arc similar to the steric requirements of the methyl group in the Schmidt reaction of methyl 8 6 phenyl ketone (the observed^*^ methyl to phenyl ratio is 5:95), and much less than the steric requirements of
(50) This result of Smith and Kor.ntz^^ v/as verified in the present v/ork. the isopropyl group in the Schmidt reaction of isopropyl phenyl ketone (the observed isopropyl to phenyl migration ratio is 65:35). This did not seem reasonable to Bunce and Cloke, v/ho believed the cyclopropyl group v/as migrat ing to a lesser extent than might be expected on steric grounds. These authors postulated that electronic effects might be operating to cause the cyclopropyl group to have a lov/ migration ratio in the Schmidt reaction of cyclo propyl phenyl ketone.
Bunce and Cloke hint that the same sort of electri cal effect postulated by Smith and Horv/itz^^ to explain the small cyclopropyl migration (23'p) in the Sclimidt % reaction"^ of cyclopropyl methyl ketone may be operating in the Schmidt reaction of cyclopropyl phenyl ketone.
According to Smith's hypothesis^^ the relatively electron- rich cyclopropyl group can stablize the syn-configuration
IjXIII of the ir.iinodiazoniur.-i ion, relative to that of the anti-configuration LXIV, by a kind of "chelation." Such chelation v/ould increase the population of LXIII relative to that of LXIV, and migration of the R group v/ould 87
+
0-C-R
LXIII LXIV therefore predominate.
This kind of electrical interaction postulated by Smith does not seem reasonable since (vide infra) the relative (to cyclopropyl) per cent migrations of methyl, ethyl, and isopropyl in the Schmidt reactions at 83/? sulfuric acid of the respective cyclopropyl alkyl ketones are 75/h 82,?, and 925?: the opposite result predicted by Smith’s "chelation" theory.
Postulation of any sort of electrical effect in the Sclimidf reaction of cyclopropyl phenyl ketone seems unnecessary. Ihzamination of space-filling models for iminodiazonium ions IXV and LXVI for the cases where R
R-
LXV LXVI is methyl, ethyl, isopropyl, and cyclopropyl indicates considerably more steric interference between R and the diazonium group in LXV when R is isopropyl (or even 88 ethyl) than when R is cyclopropyl. It thus appears that the cyclopropyl to phenyl migration ratio of 7:93
(+ 2^/0 in the Schmidt reaction of cyclopropyl phenyl ketone at various acid concentrations is explicable in terms of steric repulsions in the transition states leading to a non-equilibrating mixture of iminodiazonium ions LXV and LXVI (R=cyclopropyl ).
Actually, the cyclopropyl to phenyl migration ratio of 7:93 is also consistent with the idea that the iminodiazonium ions LXIII and LXIV (R=cyclopropyl) are isomerizing to one another during the reaction, so that electrical as well as steric factors determine the migration rati o. Since both these factors would seem to favor phenyl rather than cyclopropyl migration, the
7:93 cyclopropyl to phenyl migration ratio is understand able.
That the rearrangement may proceed from imino diazonium ions LXV and LXVI (R=cyclopropyl), rather than from the azidohydrinium ion, is supported by the presence in the product mixture of R-cyclopropyl-li'- phenylurea, which was isolated from the Schmidt reactions in 83-99/5 sulfuric acid and in trichloroacetic acid.
The products in the Schmidt reaction of cyclo propyl methyl ketone in the present study are (Eq 56)
N-cyclopropylacetarnide, N-rr.ethylcyclopropanecarboxamide, 89 and (in 83^ sulfuric acid present with a ten-fold molar excess of hydrogen azide) l-iriethyl-5-cyclopropyltetrazole
(LXVII) and l-cyclopropyl-S-methjlfcetrazole (LXVIIl),
. HI'Î, . . P>-CO-CII^ ■ r^îîH-CO-CH^ + p>-CO-NII-CH^
ILO V (56)
II II II II K II N--- N
LXVII LXVIII
The tetrazoles LXVII and LXVIII apparently arise from reactions of iminocarbonium ions LXIX and LXX with hydrogen azide (instead of water), followed by cycliza- tion (Eq 57).
r>-lI=C-CH^ + p>-C=N-CÏL
LXIX LXX (57)
-H -H'*'
LXVIII . LXVII
The behavior of cyclopropyl methyl ketone in its reaction with hydrogen azide using various acid catalysts presents a marked contrast to the behavior of cyclopropyl phenyl ketone in its Schmidt reaction using various acid catalysts. Table 16 shows there is a drcunatic change in the cyclopropyl to methyl migration TABLE 16 Migration Ratigs in Schmidt Reactions of Cyclopropyl Methyl Ketone at Various Acid Concentrations Number Reaction CyclopropylîMethyl Migration Ratio jo Yield^ Els: nmr 49.4^ HgSO^ 88® 4 24, 192 10 ; 90 12 ; 88
69.4/= H2^°4 95° 2 24 44 : 56 45 ; 55 83.3/ HgSO^ 90 3 24 74 ; 26 74 : 26 89.0/ HgSO.^ 85 2 24 73 : 27 -- CCl^COgH 92 3 24 27 : 73 27 : 73 COl^COgH® 90 1 192 26 : 74 --
a. See footnote a, Table 7. b. See footnote b, Table 8. c. Two different columns were used; 10* x 1/8" PPAP on Chrom W at 200° and 10' x 1/8" 205» Carbowax 20 M on Chrom W at 200 . The retention times of the amides in the product were verified by comparison with authentic samples of the amides. The glc data are considered accurate to + 2/j. d. Integrations were performed on the methyl peaks of the two amides. The methyl group of N-cyclopropylacetamide appears as a singlet at 8.05 7". The methyl group of N-methylcyclo- propanecarboxamide occurs as a doublet at 7.20 7". The nmr data are considered accurate to + 2;(. V £ ) e. The product was almost entirely unreacted ketone according to glc. o At this acid concentration some acid-catalyzed ring opening of N-cyclopropylacetamide begins to occur. g. A solution of CC1,C0_H in CHOI at 24 (± 2 ) was used. 91 ratio as a function of the acid catalyst; rcmeniher there is na change in the cyclopropyl to phenyl migration ratio as function of acid catalyst in the Schmidt reaction of cyclopropyl phenyl ketone. Also, the products are of a somewhat different type in the Schmidt reaction of cyclopropyl methyl ketone than in the Schmidt reaction of cyclopropyl phenyl ketone. In the Schmidt reaction of cyclopropyl phenyl ketone (and of the alkyl aryl ketones in general), along with isomeric amides, there is produced the urea, in both elevated sulfuric acid concentrations and in trichloroacetic acid. However, in the Schmidt reaction of cyclopropyl methyl ketone none of the corresponding urea is produced in any of the acid catalysts. Instead, the corresponding tetrazoles are produced as side products, but then only in 83m
(51) The tetrazoles were collected (as a mixture) using preparative glc, and identified by elemental analy sis, ir, nmr, and mass spectral analysis of the mixture (see Experimental). sulfuric acid in the presence of a ten-fold molar excess of hydrogen azide. No tetrazoles are formed in the
Schmidt reaction in 30^ sulfuric acid or in trichloro acetic acid, even when a ten-fold molar excess of hydrogen azide is used. (This latter fact has mechanistic impli cations which will be discussed. Vide infra. )
Beginning in 8 9 sulfuric acid, and continuing 92
through 93/’ and 99/"’ sulfuric acid, conversion of h-cyclo-
propylacetamidc produced in the reaction to acetamide
and propanal occurs (see Expérimental). Because of such
hydrolysis of one of the amides at elevated sulfuric
acid concentrations, no data are presented in Table 16
for Schmidt reactions of oyclopropyl methyl ketone above
89/^ sulfuric acid.
The problem of hydrolysis of N-cyclopropylacetamide
at elevated sulfuric acid concentrations raises the
question of the validity of the previously reported^
oyclopropyl to methyl migration ratio of 23:77. This
ratio reported by Bunce and Clolce is probably in error
since the Schmidt reaction of oyclopropyl methyl ketone was conducted in concentrated (ca. 96//) sulfuric acid
(and a chloroform solution of hydrogen aside) at 25-38°
for 12 hr. Certainly the major portion of N-cyclopro-
pylacotamide produced in the reaction will be hydrolyzed
under these conditions to propanal and acetamide,
products whose presence would have gone undetected in
the analytical procedure Bunce and Cloke used to deter mine the ratio of IT-cyclopropylacetamide to N-methyl-
cyclopropanccarboxamide.
Before attempting to rationalize the oyclopropyl
to methyl migration ratios observed in the Schmidt reaction
of oyclopropyl methyl ketone with various acid catalysts 95
(Table 16), the oyclopropyl to ethyl and oyclopropyl to isopropyl migration ratios for Schmidt reactions of oyclopropyl ethyl ketone and oyclopropyl isopropyl ketone using various acid catalysts will be presented. These data a.re contained in Tables 17 and 18. The oyclopropyl:
R (R = methyl, ethyl, isopropyl) migration ratios from
Tables 16, 17, and 18 are shown in Table 19 to facilitate discussion of the results of Schmidt reactions of the respective ketones using various acid catalysts.
The data in Table 19 for Schmidt reactions at
83^ sulfuric acid will be discussed first. For the
Schmidt reaction of oyclopropyl methyl ketone at 85^ sulfuric acid, the observed oyclopropyl to methyl migra tion ratio of 74:26 and the formation of tetrazoles in excess hydrogen azide (suggesting the presence of irainocarbonium ions) might seem consistent with the view (Eq 58) that the azidohydriniura ion LXXI loses water to form non-equilibrating isomeric irainodiazonium ions IXXII and LXXIl'I, the ratio of which is controlled by steric repulsions in the transition states leading to the respective iminodiazonium ions. These iminodia- zonium ions then under subsequent rearrangement to form the respective iminocarbonium ions which hydrate to form the isomeric amides, or react with hydrogen azide to form tetrazoles. TABLE 17
Migration Ratios in Schmidt Reactions of Oyclopropyl Ethyl Ketone at Various Acid Concentrations OyclopropylzEt Migration Ratio Kumhe] Reaction Yield' of Expts glc' nrp.2
52.62 HgSOa 90^ 2 168 26 74 ——— 69.42 HgSO^ 95 2 60 82 1 8 84 : 16
83.52 H2SO4 . 95 2 5, 16 82 1 8 84 : 1 8 OCl-OOgH 95 2 16, 23 26 74 29 : 71 a. See footnote a, Table 7. b. See footnote b, Table 8, c. The column used was 5' x 1/8" 15^ XE-1150 on Chrom ? at 1 7 0 ° . The glc data are considered accurate to + 1/. d. Integrations were performed on the methylene peaks of the two amides. The methy lene group of M-ethylcyclopropanecarboxamide appears as a multiplet at 6.35- 7.o o f . The methylene group of I'T-cyclopropylpropionamide appears as a quartet at 7,55-8.00 7“. The nmr data are considered accurate to + 3'/. e. The product was mostly unreacted ketone according to glc. TABLE 18
Migration Ratios in Schmidt Reactions of Oyclopropyl Isopropyl Ketone at Various Acid Concentrations Oyclopropyl : i^-Pr Migration Ratio Reaction Number d Acid Catalyst / Yield^ of Exnts Time (hr) clc® nmr
52.6/. HgSO. 87® 2 120, 192 82 : 18 69.4/ HgSO^ 95 2 15, 46 96 : 4 90 : 10
83.3/ HgSO^ 97 3 15 92 : 8 92 : 8
CCl^COgH 88 2 24 48 : 52 49 : 51 a. See footnote a, Table 7. b. See footnote b, Table 8. c. The column used was 5’ x 1/8" 15^ XF-1150 on Ghron P at 170 . Retention times of the amide products were verified by comparison with retention times of authentic samples of the amides. The glc data are considered accurate to + Ija. d. Integrations were performed on the isopropyl carhinyl proton (5.60-6.22 7" )of N-isopropylcyclopropanecarboxamide and on the isopropyl carhinyl proton (7.3- 7.0 and oyclopropyl carhinyl proton (7.1-7.3 fy of IT-cyclopropylisohutyramide, The nmr data thus obtained are probably accurate to only + 4/L e. The product was mostly unreacted ketone according to glc. VO VJ1 96
TABLE 19
Oyclopropyl:R Migration Ratios in Schnidt Reactions of Cyclopropyl-R Ketones at Various Acid Concentrations
Oyclopropyl:R Migration Ratio Acid Catalyst R = Me R = Et R = i-Pr
500 HgSO^ 10 90 26 74 82 : 18
69.40 H2S04 44 56 82 18 96 : 4
83.30 HgSO^ 74 26 82 18 92 : 8
CClgCOgH 27 73 26 74 48 : 52
But this view that steric repulsions in the transition states leading to the iminodiazonium ions
LXXII and IXXIII actually controls the oyclopropyl to methyl migration ratio in the Schmidt reaction of cyclo- propyl methyl ketone at 83^ sulfuric acid is not consis tent with the migration ratios observed when methyl is replaced by ethyl or isopropyl. Table 19 shows the oyclopropyl to ethyl migration ratio at 830 sulfuric acid is 82:18 and the oyclopropyl to isopropyl migration ratio at 830 sulfuric acid is 92:8.. Thus, the per cent of oyclopropyl migration increases as the steric bulk of the group opposite it in the ketone increases, a result clearly contrary to that predicted by the view that steric repulsions in the transition states leading from the azidohydriniurn ion LXXI to the isomeric imino diazonium ions LXXII and LXXIII are responsible for the 97
,n : ïï -Ng + HgO |^K=C-CH, j^NHCOCII 3 -H' LXXII
-H+ V
tetrazoles (58)
IXXI
-BLO HNr
-ïï. -1- H^O [)>_C-CH |^C=N-CE P>COIÎIICH^ 3 5 LXXIII cyclopropyl to methyl migration ratio of 74:26.
Furthermore, if the iminodiazonium ions LXXII and
IXXIII exist largely in what presumably— due to conjuga tion between the sigma bond of the cyclopropane ring and' the pi bond of the carbon-nitrogen double bond— are their most stable conformations, LXXIV and LXXV, then molecular models of LXXIV and LXXV show there is no discernable difference between the steric requirements of methyl and cyclopropyl in LXXIV and LX]{V, 9 8
Il II
LXXIV IXXV
An explanation of the cyclopropyl to alkyl migration ratios reported in Table 19 for Schmidt reactions at S3p sulfuric acid— also consistent with the formation of tetrazoles in excess hydrogen azide— might be that the ratios result predominantly from electrical rather than steric effects. It is conceivable that the iminodiazonium ions IXiCVI and LXXVII formed in these systems might isomerize to one another since the double-bond character of the carbon-nitrogen double bond may be diminished in LXXVI and LXXVII due to a rather large contribution from resonance from LXXVIII
(Eq 59), which is stabilized by cyclopropyl carbinyl
P>-C-R -•---► [)>-C-R -I ► P>-C-R (59)
LXXVI LXXVIII LXXVII resonance. Isomerization of iminodiazonium ions LXXVI and LXXVII would allow electrical effects to in some measure determine the cyclopropyl to alley 1 migration 99
ratios, and cyclopropyl might (for electrical reasons) migrate hotter than the alley! groups.
Considering only the hybridization of the bonding
orbitals of the migrating carbon, one would expect that the cyclopropyl group would not migrate better than an alley! group to a partially positive nitrogen.
This is so because the migrating carbon in an alley! % group uses an sp-^ hybridized orbital, whereas the migrating carbon in the case of cyclopropyl uses an 2 2 orbital which is ca. sp * hybridized, of higher s character than the alley! carbon orbital, making the electron more tightly bound and less able to stabilize the partially positive nitrogen to which it is becoming bonded in the migration step. Indeed, such an effect as this may be responsible for the migration ratios 52 observed in the Baeyer-Villiger oxidation of cyclopropyl
(52) R. R. Sauers and R. 17. Ubersax, J. Org. Ohem., 30, 5959 (1965). ketones, where both ethyl and isopropyl migrate much better to a partially positive oxygen than does cyclo propyl.
Clearly there must be some effect in the Schmidt reaction of the cyclopropyl alkyl ketones of the present study which is overcoming this unfavorable hybridization of the cyclopropyl group and allowing cyclopropyl to 100
migrate to a greater extent than alkyl groups to a
partially positive nitrogen. It is conceivable that
the cyclopropyl group in iminodiazonium ion LXXVI can
stabilize the transition state leading to cyclopropyl
rearrangement by delocalization of the sigma bonds of
the ring which are high in p character. Such stabiliza
tion might come about in either of two ways.
One way in which cyclopropyl migration from
LXXVI might be assisted is illustrated in L’q 60. In
R
LXXX LXXVI LXXIX (60)
-, -f [ >
LXXIX, where the cyclopropane ring is in the plane of the paper and not in conjugation with the iinine group, as the nitrogen begins to leave there is participation by one edge of the cyclopropyl group with the partially
formed vacant orbital on the imine nitrogen. In LXXX this participation is more advanced. In LXiSXI the migration of the cyclopropyl group is more complete and 101 the process makes use of the migrating hond and both edges of the oyclopropyl group. Such cyclopropyl ring- edge participation has been postulated by Rhodes and 55 Takino to explain the cyclopropyl to methyl migration
(53) Y. 3. Rhodes and T. Takino, J, Arn. Chen. See., 92, 5270 (1970). ratio of 56:1 observed in the acetolysis of 2-cyclopropyl-
2-methylpropyl brosylate.
An alternative means by which cyclopropyl migration from LXjCVI might be assisted is shov/n in Sq 61. In
II C - f { (61) + LXXVI LXXXII
C-R c-A
LXXXIV IXXXIII
LXXXII, where the cyclopropane ring is directed into the paper and is in conjugation with the maino group, as the nitrogen begins to leave there is participation 102 by the back lobe of the orbital of the cyclopropane ring.
In LX^CCIII this participation is more advanced, and the cyclopropyl group is well on its way to migrating from carbon to nitrogen. This type of cyclopropyl partici- pation has been suggested previously.
Thus, regardless of the details, cyclopropyl participation nay stabilize the transition state leading from the iminodiazonium ion LXXVI to the iminocarbonium ion LXXXIV, resulting in greater migration of the cyclo propyl group than of the aUq^i group.
The relative migration order ne (26^)> Et (18^^> i-Pr (8‘/o) observed in Schmidt reactions of cyclopropyl alley 1 ketones at 85^ sulfuric acid, is consistent with the view (for which there is experimental^^ and theore tical^^ evidence) that alkyl groups are expected to favor
(54) S. Flisar, J. Renard, and D. 2. Simon, J. Am. Chem. Soc., 92, 6955 (1971).
(55) S. Flisar, J. Am. Chem. Soc., 94, 1068 (1972), a positive site in the order ile> Et > i-Pr, i._e., in the so-called "hyperconjugative order.” This could account for the relative migration of the allcyl groups, regardless of whether cyclopropyl migration is occurring by the pathway shov/n in Eq 60 or that shown in Eq 61.
In iminodiazonium ion LXXVII (Eq 62) the alkyl 103
b -%^ p>-C=ÎT-R (62) LXXYII
R = Ile, Et, _i-Pr group is migrating to a partially positive nitrogen; and it is conceivable that the relative migration order sc might he lie > Et> ^-?r, since the amount of negative charge on the migrating carbon is also in the order
Me > Et> _I-Pr. Such a "hyperconjugative order" has been observed in the formation of sv/ittefionic carbocations 54- from the decomposition of primary ozonides, in some c-z eg solvolyses, * in the reaction of diasomethane with ketones, and in migrations to carbonic centers. In the pinacol rearrangement, however, the order t-3u » so Et> lie is observed, ^ rather than the "hyperconjugative order."
(56) D, J. Cram and J. P. Knight, J. Am. Ohem. Soc., 74, 5839 (1952).
(57) II, 0. House, E. J. Grubbs, and W. F. Gannon, J, Am. Chem. Soc., 82, 4099 (i960).
(58) A. R. Kraska, Ph. P. Pissertation, The Ohio State University, Columbus, Ohio, 1971.
(59) R. li. Stiles and R. P. Mayer, J. Am. Chem. Soc., 81, 1497 (1959). 104
If cyclopropyl Migration occurs by the pathway shown in Eq 61, then an alternative explanation of the relative migration order of the allcyl groups in Schmidt reactions of cyclopropyl alkyl ketones in 830 sulfuric acid suggests itself. Referring to Eq 63, it is clear
y R=He, Et, i-Pr ^ LXXVI “ LXXVII that (for steric reasons) there will be less of the anti-cyclonronyl iminodiazonium ion L1ÎXVI than of the syn-cyclonropyl iminodiazonium ion LXXVII when R is
^-Pr than when R is I-Ie or Et. However, it might be that cyclopropyl migration is more facile when R is i-Pr than when it is lie or Et, because the cyclopropyl group in DCXVI is more firmly held in position for cyclopropyl participation when R is i-Pr than when R is Et or He,
V/hen R is i-Pr (and to a lesser extent. Et), the more stable conformation of the anti-cyclopropyl iminodiazonium ion appears from molecular models to be
LXXVI (in which the cyclopropane ring is directed into the paper), rather than LX^rvi’ (in which the cyclopropane ring is in the plane of the paper), for in LXXVI’ there is some steric interference between the cyclopropane 105
1 ^ 4
LXXVI LXXVI' ring carbons and the R group. If this is so, then v/hen R is i-Pr the cyclopropane ring is more firmly held in the conformation shov/n in LXXVI— from which cyclopropyl migration can readily occur via the pathway shov/n in Eq 61— than when R is me or Et. In this case, then, the relative migration order, Lîe > Et > i-Pr, for the allq^’-l groups in the Schmidt reaction of cyclo propyl allcyl ketones in 83n sulfuric acid is due to steric acceleration of cyclopropyl migration by the bulkier allcyl groups (i-Pr and St).
It is significant that the order lie > Et > i-Pr is not the relative order of allcyl migration in Schnidt reactions of allcyl phenyl Icetones^^ and dialkyl ketones°^‘
(60) Reference 19 and the present work (vide supra).
(61) This work; vide surra.
Por allcyl phenyl ketones, the migration order (relative to phenyl) is i-Pr(65/'j)> Et(15m) > me(5/j). Por the diallcyl ketones the migration order (relative to methyl) is 106
j^-Pr(80>0 Bt(66^), Such migration orders are explicable
if the isomeric iminodiazonium ions produced in Sclunidt reactions of alkyl phenyl ketones and diallcyl ketones do not isomerize to one another during the reaction, for then steric rather than electrical effects determine the migration order of the alkyl groups.
The results of Schmidt reactions of the cyclo propyl allcyl ketones in 50/; sulfuric acid (see Table 19) will now be discussed. Table 19 shows that in decreasing the sulfuric acid concentration from 85m to 50^ the methyl migration (relative to cyclopropyl) increases from 26^ to 90/j. Thus, in the Schmidt reaction of cyclo propyl methyl ketone in 50?; sulfuric acid methyl migrates much better than cyclopropyl, whereas in 83/'; sulfuric acid cyclopropyl migrates considerably better than methyl.
This certainly suggests a mechanistic change as a result of changing the sulfuric acid concentration from 83?; to
50?;. Furthermore, that no tetrazoles were formed in the
Schmidt reaction of cyclopropyl methyl ketone in 50?; sulfuric acid in the presence of a ten-fold excess (with respect to ketone) hydrogen azide is permissive but not conclusive evidence for the absence of any iminocarbonium ions. These considerations suggest the rearrangement mechanism shovm in Eq 64.
The azidohydriniurn ion 1X}[XV undergoes direct rearrangement to the protonated isomeric anidcs, rather 107
np alkyl cyclopropyl Migration i migration i R., - N H C - < 1 ^ ------r>-C-H ► IN-ITEC-PD -1- - Î Î 2 Jx - 1 ^ 2 H %2
i m v (64)
R = Me, Et, i.-?r than dehydrating to isomeric iminodiazonium ions which subsequently rearrange to iminocarbonium ions, which hydrate to give the isomeric amides. Such a mech anism is consistent with the absence of any evidence for iminocarbonium ions and with the expectation that dehydration of the azidohydriniurn ion IZXXV should be less likely in the poorer (relative to 83m sulfuric acid) dehydrating medium of 5Op sulfuric acid.
The mechanism of Eq 64 can account for the cyclopropyl to methyl migration ratio of 10:90 if it is assumed that the transition state for methyl migration is stabilized by cyclopropyl carbinyl resonance, so that methyl rather than cyclopropyl migration will occur predominantly.^^
(62) The cyclopropyl to methyl migration ratio of 10:90 observed in the Schmidt reaction of cyclopropyl methyl ketone at 50'p sulfuric acid concentration is similar to the cyclopropyl to n-butyl migration ratio of 4:96 reported (G. H. Potter, Ph. D. Thesis, Rensselaer Polytechnic Institute, 1953) in the acid- 108
catalysed rearrangement of n-butyldicyclopropyl- carbinyl aside; another case where cyclopropyl carbinyl resonance in the transition state was postulated in order to account for the low cyclopropyl to alkyl migration ratio.
That the transition state for methyl migration might be stabilized by cyclopropyl carbinyl resonance seems reasonable. The conformation of the azidohydrinium ion which presumably maximises stabilization due to cyclopropyl carbinyl resonance is shown in LXXXYI.
IXXXTI IXXXVII LXXXVIII
In this conformation, as R migrates the cyclopropyl group is in a conformation which allows maximum overlap between its carbon-carbon bonds (high in p character) and the vacant orbital left at the migration origin; such overlap presumably stabilizes the transition state for methyl migration. However, a space-filling model of
LXXXVI shows that as the number of atoms in the six position increases there is steric interference in this conformation (see IXXXVII), forcing the cyclopropyl group to assume a position (see KtXXVIIl) which decreases 109
the possibility of cyclopropyl carhinyl resonance.
Such steric inhibition of cyclopropyl carbinyl ^ *7 resonance may explain the observed (Table 19) decrease
(63) For other examples see; J. Berson, D, bege, G. M. Clarke and R. G. Ber-pr.an, J. An, Chen. Soc., 90, 3240 (i960); II. C. Brovm and J. D. Cleveland,"IT. An. Chen, Soc., 88, 2031 (1966).
in allcyl migration in the Schmidt reactions of cyclopropyl allcyl ketones in 30/^ sulfuric acid as R is changed from methyl to ethyl to isopropyl. If so, the results for the Sclrnidt reaction of cyclopropyl isopropyl ketone in
30^ sulfuric acid (the cyclopropyl to isopropyl migration ratio is 81:19) imply that when cyclopropyl carbinyl resonance is sterically inhibited the isopropyl group
stabilizes an incipient carbonium ion better than the
cyclopropyl group.
If in the Schmidt reaction of cyclopropyl methyl
ketone at 30/' sulfuric acid the predominant pathway of
the reaction involves stabilization of an incipient
carbonium ion by cyclopropyl carbinyl resonance, whereas
in the Schmidt reaction of cyclopropyl isopropyl ketone
at 305' sulfuric acid the predominant pathv/ay of the
reaction involves stabilization of an incipient carbonium
ioii by an isopropyl group, then one would expect (since
a cyclopropyl group stabilizes an incipient carbonium
ion much better than an isopropyl group^^) that the rate 110 of the Schmidt reaction of cyclopropyl methyl ketone
(64) H. 0, 3rov.m and J. D. Cleveland, J. Am. Chem. Soc., 88, 2051 (1966). at 50'/j sn.lfuric world be significantly greater than the rate of cyclopropyl isopropyl ketone at 50/Ô sulfuric acid. The relative rates at 50^ sulfuric acid as deter mined from competition experiments are:
0 0 0 . [>C-Giy > [>0-Zt > p>-C-i-Pr
25 6.4 1.0
Por Sclmiidt reactions of cyclopropyl allcyl ketones in molten trichororacetic acid (Table 19, vide sunra), the similarities (with the exception of cyclo propyl isopropyl ketone) of the cyclopropyl : alkyl migration ratios to those observed when the reaction is carried out in 50); sulfuric acid suggests the sane mechanism (Eq 64) is operating in molten trichloroacetic acid as in 50;' sulfuric acid. However, the nearly 1:1 migration ratio of cyclopropyl to isopropyl in the
Schmidt reaction of cyclopropyl isopropyl ketone in trichloroacetic acid is anomolous.
In conclusion, there appear to be tv;o mechanisms operating in the Schmidt reaction of cyclopropyl allcyl ketones, and in each electrical factors operate to a Ill
significant extent to determine the migration ratios
observed. One mechanism operates at elevated sulfuric
acid concentrations and is characterized by rearrangement
of partially-equilibrated isomeric irninodiazoniiua ions which allows electrical effects (namely, neighboring-
group participation by the cyclopropyl group) to operate
and influence migration ratios. The other mechanism
operates at low sulfuric acid concentrations and in molten trichloroacetic acid and is characterized by rearrangement of azidohydriniurn ion directly to products; allowing cyclopropyl carbinyl resonance to determine the product ratio, except where there is steric inhibition
of such resonance.
If indeed these two mechanisms of rearrangement occur, the implication is that neighboring-group participation by the cyclopropyl group occurs in iminodiazonium ion LXXYI (Sq 60,61)— which presumably/ is produced in 83m sulfuric acid— but not in azidohy drinium ion JjUXY (Eq 64), the species supposedly under going rearrangement in 50^ sulfuric acid.
On the one hand, there may be steric factors in
iminodiazonium ion LXXVI, but not in azidohydriniuii ion liXIXY, which facilitate neighboring-group participation by the cyclopropyl group. If the mechanism for cyclo propyl participation is that shovm in Eq 60, it is 112
difficult to see v/hat these steric factors are; for it
seems that the kind of cyclopropyl participation shown
in 2q 60 for irninodiazoniura ion LXXYI could occur equally well in the azidohydriniui.i ion LXXXV, if only steric
factors are considered. If, however, the mechanism of neighboring-group participation by cyclopropyl is that
shovm in 2q 61, then cyclopropyl participation (and migration) would be much less liltely in azidohydrinium
ion LXXXY than in iminodiazonium ion LXXYI (2% 61); for the cyclopropyl group is not firmly fixed in the position for cyclopropyl participation in LXXXY as it is in LXXVI.
On the other hand, there may be electrical factors in iminodiazonium ion LXXYI, but not in azidohydriniurn ion LXCCY, which facilitate cyclopropyl participation and migration. For example, the nitrogen to which migra tion occurs in iminodiazonium ion LXXYI is probably more electron demanding than the nitrogen to which migration
occurs in azidohydrinium ion L]iXXY, since the hybridiza- 2 tion of the nitrogen in niXYI is ca. sp v/hereas the % hybridization of the nitrogen in iXXXY is ca. sp . Such hybridization differences night create more of a demand for electron donation from the cyclopropyl group in
LXXYI than in LXXrV, so that cyclopropyl neighboring- group participation and migration occurs in L]ŒYI but not in LXXXY. EXPERIMENTAL
General Procedures and Techniques
Melting Points. Melting points were determined on a
Thomas Hoover Capillary Melting Point Apparatus and are uncorrected.
Boiling Points. Boiling points were obtained as the compounds distilled at atmospheric pressure unless other wise noted. Thermometer corrections were not made.
Elemental Analyses. Elemental analyses were performed by Chemalytics, Inc., Tempe, Arizona and by Micro-
Analysis Inc., Wilmington, Delaware.
Infrared Spectra. Infrared spectra were determined on a Perkin Elmer Infracord. The spectra of solid compounds were obtained using potassium chloride wafers, and the spectra of liquid compounds were obtained from neat liquid films on sodium chloride plates.
Nuclear Magnetic Resonance Spectra. Nuclear magnetic resonance spectra were determined on a Varian A-60
Analytical NTIR Spectrophotometer using deuteriochloroforra as solvent and tetramethylsilane as internal standard.
113 114
Gas-Llguicl Chromatography. Gas-liquid chromatography was a major source for obtaining analytical data on the ratio of amides in the Schmidt reaction of ketones. The analyses were carried out on an Aerograph Hy-Pi, Model
600-D gas chromatograph using a hydrogen-flame ionization detector and connected to a 1 millivolt Honeywell recorder,
Nitrogen was used as the carrier gas.
Quantitative measurements were made by comparing the relative peak areas of the isomeric amides. Relative peak areas were obtained using the method of multiplying the peak height times the width at half-height or triangu- lation. It was assunied (and verified for some pairs of isomers) that the isomeric amides had equal response on the flame ionization detector. There is substantial evidence^^ that such an assumption is valid.
(65) Relative areas are proportional to percentage composition. E. M. Fredericks and F, R. Brooks, Anal. Chem., 28, 297 (1956).
(66) \'I. A, Dietz, J. Gas Chromatog., _5, 68 (1967).
Preparative Gas-Liouid Chromatography. Preparative gas-liquid chromatography was sometimes employed in the separation and identification of Schmidt reaction products.
The products were collected in small traps prepared from test tubes fitted with a vented septum and a suitable inlet made of glass tubing. The traps were cooled with 115
Dry Ice-isopropanol or ice water, depending on the volatility of the compound being trapped. Depending upon the efficiency of the column used, sample sizes varying from 50 to 150 microliters were used.
Preparation of Acid Catalysts. The sulfuric acid solu tions were prepared from Baker reagent grade concentrated sulfuric acid. The more dilute acids were prepared by adding a measured amount of concentrated sulfuric acid to a weight of water sufficient to give the approximate
50^, 69/^, 83/>, 89#, and 94# by weight solutions desired.
By adding 30# sulfur trioxide in sulfuric acid to con centrated sulfuric acid in the ratio of 1:4 by volume, a solution approaching 99# by v/eight sulfuric acid was produced. To determine the true concentrations, a measured volume of each acid was diluted in water and titrated with standardized sodium hydroxide solution.
The weight percentages of sulfuric acid were calculated using the relationship:
# wt = molarity x molecular weiaht lo X specific gravity' of solution
The percentages by weight of sulfuric acid as determined by this method were: 49.4#, 52.6#, 69.4#, 83.3#, 89.0#,
93.7# and 99.4#.
Conditions for Effecting Schmidt Reactions
Apparatus. A 100 ml, 3-neck flask was equipped with a 116 magnetic stirrer, a thermometer and a vial for adding sodium azide. One neck of the flask was connected to an inverted water-filled graduated cylinder which measured semi-quantitativoly the progress of the reaction by the volume of nitrogen evolved.
To help prevent significant temperature variation, especially during addition of sodium azide, the reaction mixture was rapidly stirred while immersed in a water bath at room temperature (22-24°). When trichloroacetic acid was the catalyst, the temperature was maintained at approximately 63° by use of a constant temperature oil bath. The temperature range for an individual
Schmidt reaction was no more than 4 degrees.
Proportion of Reagents to Ketone. Sodium azide was added in approximately 10^ molar excess with respect to ketone. Analytical grade chloroform and sulfuric acid were added in constant quantity of 50 ml and 10 ml respectively (large excess). V/hen trichloroacetic acid was used as catalyst, 30 g of the acid was added to the ketone; under these conditions no chloroform or sulfuric acid was used.
Order of Addition of Reagents. In all experiments, when chloroform was employed, it was added to the ketone, and the mixture stirred to effect complete solution. The acid was added with rapid stirring, keeping the temperature 117 rise to a minimum. Sodium aside was then added to the mixture in small quantities over a period of 15-30 minutes,
Method of Isolation of Products. The reaction mixture, after nitrogen evolution had ceased, was poured into
150 ml of cold water. The reaction flask was thoroughly rinsed with water and chloroform, and the washings com bined with the aqueous mixture, which was then extracted with chloroform. With the higher molecular weight amides extraction with three 100 ml portions of chloroform gave nearly quantitative product recoveries, hut with lower molecular weight amides extraction with six to nine 100 ml portions of chloroform was necessary to obtain adequate product recoveries. The chloroform extracts were combined, filtered through a cone of anhydrous sod: urn sulfate, and the solvent removed on a flask evaporator.
Product Identification and jlnalysis
Product Identification. Most amides from Schmidt reactions were identified by comparing the gas-liquid chromatography retention times and nuclear magnetic resonance spectrum of the product mixture with those of authentic samples of the individual amides. In cases where authentic samples of the amides were not readily 118 obtained, the individual amides were isolated by preparative gas-liquid chromatography of the product mixture. The amides were then identified by nmr, ir, and mass spectral analyses,
For the Schmidt reaction of isopropyl phenyl ketone and cyclopropyl phenyl ketone, column chromato graphy of the product mixture resulted in the isolation of the individual amides, which were identified by comparison (ir and mixture melting point) with authentic samples of the amides.
Most often the ureas or tetrazoles produced as minor side-products in Schmidt reactions were not isolated, but their presence was inferred from thin-layer chromatography and mass spectral analyses of the product mixtures. However some of the ureas and tetrazoles were isolated and characterized, as indicated below, li-Isonronyl-IM-Phenylurea. A 0,80 g sample of the reaction product from the Sclinidt reaction of isopropyl phenyl ketone in molten trichloroacetic acid was chromatographed on silica gel using benzene-ethyl acetate
(9:1) as elutant. One of the last materials eluted from the column was 0,077 g of iT-isopropyl-N'-phenylurea, mp 155.5-156,5°; ir, 5500 (urea K-Ii) and 1640 cmT^ (C=0); nmr, 2,80r(m, 5, aromatic hydrogens), 6,07 T(rn, 1,
-CH(CH^)2 ), 8,92 f'(d, 6, -CH(CH^)g); mass spectrum, 178 119
(parent peak). Aral, Calcd for 0, 67.59;
H, 7.92; K, 15.71. Found: C, 67,42; H, 7.83; N, 15.26.
H-Cyclopropyl-II'-Phenylurea. A 0.88 g sample of the reaction mixture from the Schmidt reaction of cyclopropyl phenyl ketone in 99/^ sulfuric acid was chromatographed on silica gel using benzene-ethyl acetate (9:1) as elutant.
One of the last materials eluted from the column was
0.080 g of IT-cyclopropyl-K’-phenylurea, mp 164.5-165.5°; ir, 3500 (urea h-H) and 1635 cm"^ (C=0); nmr, 2.70 T
(m, 5, aromatic hydrogens), 7.45 T(m, 1, D K ^ ) , 9.55 T
(m, 4, cyclopropyl hydrogens); mass spectrum, 176 (parent peak). Anal. Calcd for ^8.16; K, 6.86;
N, 15.89. Found: C, 68.18; H, 6.87; K, 15.94.
K-Bthyl-H*-para Bromonhenylurea. A 0.70 g sample of the reaction mixture from the Schmidt reaction of ethyl para-bromophenyl ketone was chromatographed on silica gel using benzene-ethyl acetate (9:1) as elutant, giving as one of the eluted materials 0.07 g of N-ethyl-N'-para- bromophenylurea, rap 211.7-212.7°; ir, 5500 (urea N-H) and
1635 cm”^ (0=0); nmr, 2.52 T'(m, 4, aromatic H), 6.82 T
(m, 2, -CHgCH^), 8.88 r(t, 5, -CHgCH^); mass spectrum,
242 and 244 (parent peaks of equal intensity). l-I-Icthyl-5-CyclopropyItetrazole and l-Cyclopropyl-5-
Kethyltetrazole. The reaction mixture from the reaction of methyl cyclopropyl ketone in 83^ sulfuric acid and 120 a ten-fold excess of sodium aside was subjected to preparative gas-liquid chromatography using a column of
6 ’ X 20fo SE-30 on Chrom W at 175°. The tetrazoles, which constituted ca, 40^ (by nmr) of the mixture, were not separated by this column but were collected as a mixture; ir, 1525 and 1550 cm“^ (h=lJ and C=U); nmr,
5.85 ir(8, /N-CHL), 6.42r(m,[>(^ ), 7.551" (s, ^C-CH=),
8.70 7" (m, cyclopropyl hydrogens), mass spectrum, 124
(parent peak), 95, 82, 68, 67, 43, 41, corresponding to the fragmentation pattern observed^^ in the mass spectra of other tetrazoles. Anal. Calcd for C^HgN^; 0, 48,37;
(67) D, M, Porkey and \'J. R, Carpenter, Org. Mass, Spectroa., 2, 433 (1969).
H, 6.49; N, 45.13. Found; C, 48.16; H, 6.26; II, 45.09.
Integration of the methyl peaks (5.85 Tand 7.35
T ) appearing in the nmr established the ratio of 1-methyl-
5 cyclopropyltetrazole to l-cyclopropyl-5-methyltetrazole as 16:84.
Product Analysis. The two major sources for obtaining the ratio of amides produced in the Schmidt reaction of ketones were gas-liquid chromatography and nuclear mag netic resonance spectroscopy. The different columns and conditions employed in the gas-liquid chromatographic . 121 analyses and the different nnr absorptions used in the nuclear magnetic resonance integrations are described in the various Tables in the Results and Discussion section of this thesis.
Sources of Ketones
Purchased. The following ketones were purchased and used as supplied by Aldrich: cyclopropyl phenyl ketone, isopropyl phenyl ketone, ethyl phenyl ketone, ethyl para-anisyl ketone, methyl cyclopropyl ketone, and methyl ethyl ketone. Ethyl para-bromophenyl ketone, ethyl meta-tolyl ketone, and ethyl para-tolyl ketone were pur chased and used as supplied by K and K Laboratories,
Inc. Methyl isopropyl ketone and methyl neopentyl ketone were purchased and used as supplied by Chemical Samples
Company. In addition, ethyl meta-nitrophenyl ketone was purchased from K and K laboratories. Inc., but was found to contain about 707^ meta-nitrobenzoic acid in addition to the desired ketone. The meta-nitrobenzoic acid was extracted from the mixture with aqueous sodium hydroxide to yield (upon recrystallization from isopropanol) ethyl meta-nitrophenyl ketone as a light yellow solid, mp
98-99°; lit^G mp 98°.
(68) T. D. Barry, Chem Ber., 6, 1007 (1873) 122
The remainder of the ketones employed in this study were synthesized as indicated below.
Isoprooyl para-Tolyl Ketone. Aluminum trichloride
(31 g, 0.23 mole) was suspended in toluene (300 ml) in a 1 liter three-necked, round-bottomed flask fitted with a motor-driven stirrer, dropping funnel, thermometer, and hydrogen chloride trap, and isobutyryl chloride
(25 g, 0.23 mole) was added at such a rate as to maintain the temperature at 25-30°. The mixture then stood for
0,5 hr before it was poured into 300 ml of water. The toluene layer was separated, and the aqueous layer extracted with ether. The ethereal extract was combined with the toluene layer, dried (Drierite), concentrated under reduced pressure, and fractionally distilled under reduced pressure to give isopropyl nara-tolyl ketone
(27 g; 73#), bp 99-101° (5 mm); lit^^ bp 235-236°.
(69) A. Claus, J. Prakt. Chem., 4^, 474 (1892).
Isoprooyl nara-Anisyl Ketone. To a mixture of anisole
(36 g, 0.30 mole) and dry aluminum chloride (52 g, 0.40 mole) in carbon disulfide (300 ml) was added with stir ring isobutyryl chloride (33 g, 0.30 mole) at such a rate as to maintain the temperature at 24-25°. The mixture was allowed to stir for 10 rain before hydrolyzing 123 with cold, dilute sulfuric acid and extracting with
ether. The ethereal extracts were drisd (sodium sulfate), concentrated under reduced pressure, and fractionally distilled under reduced pressure to give isopropyl para-anisyl ketone, (47.5 g; 805^) bp 125-129° (5 mrn); lit?0 bp 148° (13 mm).
(t o ) a . Sosa, Ann. Chim., 14, 5 (1940). lleopentyl Phenyl Ketone. To an ice-cooled suspension of aluminum trichloride (26.6 g, 0.20 mole) in benzene
(100 ml) was added a solution of tert-butylacetyl chlor ide (20.2 g, 0.15 mole) in benzene (50 ml) at such a rate as to maintain the temperature at 8-12°. After the addition was complete the mixture was allowed to stand overnight at room temperature. The mixture was then poured into acidified water (200 ml), the benzene layer was separated, and the aqueous layer extracted with ether. The organic layers were combined, dried (sodium sulfate), concentrated under reduced pressure, and fractionally distilled under reduced pressure to give neopentyl phenyl ketone (18.3 g; 70^), bp 61-65° (0.8 mm); n^^ 1.4997; lit^^ bp 115.2-116.2° (10 mm),
1.5056. 124
(71) B. Berliner and P, Berliner, J, Am. Chem, See., 72, 222 (1950).
Ethyl Cyclonro'pyl Ketone. A solution of ethylnagnesium bromide was prepared from magnesium (11.1 g, 0.45 mole),
ethyl bromide (49 g, 0.45 mole), and anhydrous ether
(50 ml). To the solution of Grignard reagent, cooled by
an ice bath, a solution of cyclopropyl cyanide (20.1 g,
0,30 mole) in anhydrous ether (50 ml) was added slowly with stirring. After addition, the mixture was refluxed for 0,5 hr. To the cooled mixture was then added ice water (50 ml), followed by dilute sulfuric acid (50 ml).
The other layer was separated and the aqueous layer was
extracted with ether. The etheral extracts were combined, washed with 5^ sodium bicarbonate solution (50 ml), washed with water (50 ml), dried (sodium sulfate), and concentrated on a steam bath to give a bronze-colored liquid (17 g), which the ir showed had an 0-H absorption
in addition to the carbonyl absorption. Gas-liquid
chromatography of the material showed a minor peak
(ca, 5^), presumably due to ethyl cyclopropyl carbinol.
The crude liquid was fractionally distilled at reduced pressure to give ethyl cyclopropyl ketone (9.3 g; 325b), bp 46-47° (30 mm); n^^ 1.4267; lit^^ bp 131.8 (769 mm), n^^ 1.4298. 125
(72) P. Bruylants, Bull, soc, chim. Beiges, 519 (1925)
Iso-prouyl Cyclouropyl Ketone. A solution of isopropyl magnesium bromide was prepared from isopropyl bromide
(64 g, 0.52 mole), magnesium (13.1 g (0.54 mole) and anhydrous ether (250 ml). To the solution of Grignard reagent was slowly added cyclopropyl cyanide (33.6 g,
0.50 mole) in anhydrous ether (50 ml), and the mixture was refluzced for 46 hr, at which time an aliquot of the reaction mixture was taken and shown by ir to consist largely of ketone with some cyclopropyl cyanide still present. To the reaction mixture was added, with cooling and stirring, water (100 ml) followed by dilute sulfuric acid (100 ml). The organic layer was separated from the aqueous layer, which was then extracted with ether. The ethereal extracts were combined, concentrated on a steam bath, and refluxed for 12 hr with 30^ potassium hydroxide solution to remove unreacted cyclopropyl cyanide. The aqueous layer was extracted with ether and the etheral extracts were combined, washed with water (50 ml), dried
(magnesium sulfate), concentrated on a steam bath, and distilled at atmospheric pressure on a short-path column to give isopropyl cyclopropyl ketone (24 g; 42^), bp
140-143° (750 mm); n^^ 1.4255; lit?^ bp 141.0-141.4°
(761 mm), n^° 1.4298. 126
Preparation of Amides
H-Isoproryll)enzamide. Benzoyl chloride (6 ml, 50 mmole) was added slowly to isopropylamine (5 ml, 55 mmole) in 20/% aqueous sodium hydroxide (30 ml). The
solid material which formed was filtered and dried on a
porous plate. Two recrystallizations from cyclohexane-
petroleum ether (60-110°) yielded B-isopropylbenzaraide
(4.0 g; 70^) as white needles, mp 102.0-102.4°; lit^^ mp 105-104°.
(73) H. I-T, Ki8smarm and J, Williams, J. Am. Chem. Soc., 72, 5525 (1950).
Isohutyranilids. Isobutyric anhydride (8 ml, 50 mmole) was added slowly to a stirred mixture of aniline (2 ml,
26 mmole) in 20^ aqueous sodium hydroxide (50 ml). The filtered solid material was recrystallized twice from petroleum ether (60-110°) to give isobutyranilide (4.0 g;
95/%) as white needles, mp 105.1-105.5°; lit^^ rap 106-107°.
(74) H, Staudinger and E. Hauser, Ilelv. Chim, Acta,, . 4, 895 (1921).
H-Isopronyl-nara-Toluamide. para-Toluyl chloride (8 g,
50 mmole) v/as added slowly to a stirred mixture of isopropylamine (5 ml, 35 mmole) in 20^ aquious sodium 127 hydroxide solution (50 ml). The white solid which formed was recrystallized from ethanol-water to give N-isopropyl- para-toluamide (5.5 g; 85/0 as white needles, mp 155.2-
153.5°; ir, 5500 (amide IT-H) and 1625 cm“^ (0=0); nmr,
2.50 T(q, 4, J=36 Hz, aromatic hydrogens), 5.70r(m, 1,
J=7 Hz, -CH(CH^)2 ), 7.65 r(s, 5, par a-01^); 8.77
(d, 6, J=7 Hz, - 011(01:^)2 ).
H (para-Tolyl)-Isobutyramide. Isobutyric anhydride (8 ml,
50 mmole) was added slowly to a stirred mixture of para-toluidine (2.5 g, 25 mmole) and 20/' aqueous sodium hydroxide solution (50 ml). The white solid which formed was recovered by filtration and recrystallized from ethanol-water to give H (para-tolyl)-isobutyramide (5.3 g;
82^).as white platelets, mp 107.4-108,1°; lit^^ rap 109°.
(75) 0, A. Bishoff, Ann, Ohem,, 27^, 173 (1894).
N (para-Anisyl)-l8obutyramide. To para-anisidine (6,15 g,
50 mmole) in chloroform (25 ml) and 10;S aqueous sodium hydroxide (40 ml) was slowly added with stirring iso butyryl chloride (7.0 g, 70 mmole). The liquid phases were separated, and the chloroform layer was dried and the solvent removed under reduced pressure to give a gray solid, which was recrystallized from benzene-petroleum ether (60-110°) to give K (para-anisyl )-isobutyramide 128
(7.4 g; 79/») as white needles, mp 107-108°; lit^^ mp
108-110°.
(76) J. 0. Cannon and G. L. V/ehster, J, Am. Pharm. Assoc., 42, 740 (1955).
P-Is0nr0nyl-nara-A.nisamide. To a stirred mixture of isopropylamine (3 ml, 35 mmole) and 20?^ aqueous sodium hydroxide (30 ml) was slowly added nara-anisoyl chloride
(9 g, 50 mmole). Recrystallization of the white preci pitate from ethanol-water yielded N-isopropyl-nara- anisaraide (5.5 g; 82^) as white needles, mp 115-117.5°.
N (para-Bromonhenyl)-?ro'plonamide. To a stirred mixture of para-bromoaniline (1.7 g, 10 mmole) 20^ aqueous sodium hydroxide (30 ml) was slowly added propionyl chloride
(1.2 g, 13 mmole). The white precipitate was recrystal lized from ethanol-water to give N (para-bromophenyl )- propionanide (2.6 g; 72/») as white crystals, mp 146.3-
146.7°; lit?? mp 149°.
(77) P. D. Chattaway, J. Chem. Soc., 81, 817 (1902).
IT-Phenylpronionamide. To a stirred mixture of aniline
(1.0 g, 11 mmole) in 20^ aqueous sodium hydroxide (30 ml) was slowly added propionyl chloride (1.3 g, 14 mmole).
The white precipitate was recrystallized from ethanol- 129 water to give W-phenylpropionainide (l.O g; 66^o) as white crystals, mp 105.6-106.3°; lit^^ mp 104-104.5°.
(78) H. \'I, Underwood, Jr. and J. 0. Gale, J, Am. Ohem, Soc., 56, 2117 (1934).
K-CycloprooylbenzajTiide. Benzoyl chloride (12 ml, 0,10 mole) was slowly added to cyclopropyl amine (2.5 ml, 0.035 mole) in 20^ aqueous sodium, hydroxide (30 ml). The solid material was recrystallized twice from ethanol to give
ïï-cyclopropylhenzamide (4.0 g; 71/') as white platelets, mp 97-98°; lit?^ mp 98.5°
(79) U. Kishner, Chem. Zentralh., 76, 1704 (1905).
Oyclonronanecarhoxanilide. Cyclopropanecarboxylic acid chloride (3.6 ml, 40 mmole) was slowly added to a stirred mixture of aniline (1.9 ml, 25 mmole) in 20^ aqueous sodium hydroxide (30 ml). The solid precipitate was recrystallized twice from methanol-water to give cyclo- propanecarboxanilide (4.0 g; 70/') as white platelets, rap 110.6-111.4°; lit^° mp 111-112°. .
(80) L. I. Smith and S. UcKenzie, Jr., J. Org. Chem., 15, 74 (1950).
II-Phenyl-tert-Butylacetamidc. To a stirred mixture of 150 aniline (4.6 g, 50 nniole) and 20^ aqueous sodium hydroxide
(30 ml) vas added tert-hutylacgtyl chloride (10.0 g, 75 mmole), The solid precipitate was collected and recry stallized from benzene-petroleum ether (60-110°) to give il-phenyP.-t ert-butylac et amide (4.5 g; 47fO as white cry stals, mp 130.0-130.8°; lit^^ mp 125-126°. iT-ïï e on ent y lb en z ami d e. A sample of the amide was collected by preparative gas-liquid chromatography (9' x a ” 5/^ Fi’AP on Chrom 17 at 225°) and the white solid was found to have a mp of 110-111°; lit^l mp 112-113°.
(81) IT. J, Leonard and E, V/. ITenmiensen, J. Am.. Chem. Soc., 71, 2808 (1949).
IT-Methylcyclonropanecarboxamide. To a stirred solution of 40^ aqueous methylamine (20 g, 250 mmole) at -73° was slowly added cyclopropanecarboxylic acid chloride (9.0 g,
86 mmole). The mixture was stirred for 0.5 hr before extracting with chloroform. Removal of solvent under reduced pressure yielded a crude white solid (9.0 g) which was sublimed to yield IT-methylcyclopropanecarboxamide
(7.0 g; 82#) as a white solid, mp 60.0-60.6°; lit^^ rap
55-57°.
(82) J. P. Hopkins, R. P. Neighbors, and 1. V. Phillips, J. Agr. Pood Chem., 501 (1967). 151
I'J-Cycl Q-pro -pyl acotamidG, To cyclopropyl amine (12.5 g,
0,22 mole) in chloroform (200 ml) and 207'^ aqueous
sodium hydroxide (125 ml) at 0° v/as slowly added with
stirring acetyl chloride (23,5 g, 0.30 mole). The
mixture stirred for 0.5 hr, after which the chloroform
layer was drawn off and the aqueous layer extracted with
chloroform. The chloroform layers were combined, dried
(sodiura sulfate), and the solvent removed under reduced
pressure to give a crude white solid (19.7 g) which was
recrystallized from acetone at -78° to yield h-cyclo-
propylacetamide (17.0 g; 787^) as a white solid, mp
51-52°; llt^S mp 44-48°.
(83) 1, A, Paquette, J. R. lialpass, and 0. R. Rrow, J, Am. Chem. Soc., 92, 1980 (1970).
R-Ethylcyclopronanecarboxamide. To a stirred mixture of
ethylamine (1.35 g, 30 mmole), chloroform (25 ml), and 107^
aqueous sodium hydroxide (25 ml) was slowly added
cyclopropanecarboxylic acid chloride (3,1 g, 30 mmole).
The aqueous layer was extracted with chloroform, and the
chloroform layers were combined, dried (sodium sulfate),
and the solvent removed under reduced pressure. The crude white solid was recrystallized from petroleum ether (60-
110°) at -78° to give H-ethylcyclopropanecarboxamide
(2,7 g; 8070 as a white solid, mp 59.0-60.0°; ir, 3300 132
(amide N-H) and 1625 cm”^ (0=0); nmr, 6.72 T(m, 2,
-CHg-OH^), 8.48r(m, 1, ÜX^), 8.8$ T(t, 3, -OHgC^),
9.15 7"(m, 4, cyclopropyl hydrogens).
H-Cyclonronylnroniona-mide. To a stirred mixture of
cyclopropylomine (1.7 g, 30 mmole), chloroform (25 ml),
and 10^ aqueous sodium hydroxide (25 ml) was slowly added propionyl chloride (3.7 g 40 mmole). The aqueous layer was extracted with chloroform, and the chloroform extracts were combined, dried (sodium sulfate), and the solvent removed under reduced pressure. The crude solid was recrystallized from petroleum ether (60-110°) at -78° to give K-cyclopropylpropionamide (2.4 g; 10'^) as a white solid, rap 42.5=43.5°; ir, 3300 (amide N-H) and 1625 cni”^
(0=0); nmr, 7.28 T(m, 1, (X^), 7.77 r(q, 2, J=7 Hz,
-CHgOH^), 8.85 r(t, 3, J=7 Hz, -CHgOH^), 9.35 r(ra, 4, cyclopropyl hydrogens).
N-Cyclonronylisobutyraraide. To a stirred mixture of
cyclopropylaraine (1.14 g, 20 raraole), chloroform (25 ml), and 10^ aqueous sodium hydroxide (25 ml) was slowly added isobutyryl chloride (3.2 g, 30 raraole). The mixture was stirred for 0.2 hr and let stand overnight before extrac tion with chloroform. The wliite solid isolated from the chloroform extracts was recrystallized from petroleum ether
(60-110°) to give N-cyclopropylisobutyramide (2.24 g; 88;=) as white crystals, rap 91.6-92.0°; ir, 3300 (amide N-H) 135 and 164-0 cra~^ (0=0); nrar, 7.25 r(m, I, ^ ^ ) , 7.60?" (ra, 1, -CHCCHj)^), 8.88 r(d, 6, -GlKC^)^), 9.40 T
(m, 4, cyclopropyl hydrogens).
K-Isopro-Dylcyclo'oro'Danecarboxamide. To a stirred mixture
of isopropylamine (1.8 g, 30 mmole), chloroform (25. ml), and 10^ aqueous sodium hydroxide (25 ml) was slowly added cyclopropanecarboxylic acid chloride (2.1 g, 20 mmole).
The mixture stood overnight before extraction with chloro form, The chloroform extracts yielded a crude v;hite. solid
(2,4 g) which was recrystallized from petroleum ether
(60-110° ) to give IT-isopropylcyclopropanecarboxamide
(2,1 g; 83p) as white crystals, mp 90.0-90.5°; ir, 3300
(amide IT-H) and 1640 cm~^ (0=0); nrar, 5.90 7'(m, 1,
-cgcn^)^), 8.58r(m, 1, (X^), 8.84T(d, 6, -OlKCH^)^),
9.21 f(m, 4, cyclopropyl hydrogens).
IT-l-Iethylisobutyramide. To a stirred solution of 40^ aqueous methyl amine (2.4 g, 30 mmole) and 105^ aqueous sodium hydroxide (25 ml) was added isobutyric anhydride
(6.4 g, 40 mmole). The aqueous phase was extracted with chloroform, and the chloroform extracts were combined, dried
(sodium sulfate), and the solvent removed under reduced pressure to give IT-methylisobutyrarnide (2.7 g; 9050 as a clear liquid which was not purified further; ir, 3300
(amide K-H) and 1640 cmT^ (0=0); nmr, 7.20?'(d, 3, -OH^),
7 .50/-(m, 1, -011(011^)2 ), 8.85r(d, 6, -011(0^ ) 2 ). The 134 literature^^ gives; mp 20°, bp 110° (17 mm).
(84) A. P. N. Franchimont, Chem. Zen.tralb., II. 1960 (1913).
M-Isopropylacetamido. To a stirred mixture of isopropyl amine (1.2 g, 20 nmole) and lOy: aqueous sodium hydroxide
(30 ml) was added slowly acetyl chloride (2.3 g, 30 mmole).
The aqueous layer was extracted with chloroform, and the chloroform layers were combined, dried (sodium sulfate), and the solvent removed under reduced pressure to give
N-isopropylacetamide (1.8 g; 90^) as a clear liquid which was not further purified; ir, 3300 (amide N-H) and 1640 cm"^ (0=0); nmr, 5.92 r(m, 1, -Cn(CH^)j), 8.05 r(s, 3,
C^-CO-), 8.86 r(d, 6, -CH(CH^)2 ). The literature^^ gives a bp of 89-90° (9 mm) for N-isopropylacetamide,
(85) K. G. iVyness, J. Ohem. Soc., 2934 (195B).
N-Iiethylpropionarnide. To a stirred mixture of 40/j aqueous methylamine (2.4 g, 30 mmole) and 10^ aqueous sodium hydroxide (30 ml) was added slowly propionyl chloride (3.7 g, 40 mmole). The aqueous layer was extracted with chloroform, and the chloroform extracts were combined, dried (sodium sulfate), and the solvent removed under reduced pressure to give N-rnothylpropionamide 135
(1.5 g; 505^) as a clear liquid which was not purified further; ir, 3300 (amide N-II) and 1640 (0=0); nrar
7.20r(d, 3, -OH?), 7.70 r(q, 2, J=7 Hz, -GILCH^), 8.83r
(t, 3, J=7 Hz, -CHgCH^). The literature gives: rap
-43°, bp 146° (90 rara).
(86) G. F, D ’Alelio and E. K. Reid, J. Ara, Chera, Soc., 109 (1957).
Preparation of Acid Chlorides
Those acid chlorides which could not be readily purchased were synthesized frora the appropriate carbox- 87 ylic acid using the procedure of Cason.
(87) J. Cason, Org. Syn., Coll. Vol. 2» 169 (1955). para-Aniso7,l Chloride. In a hood, thionyl chloride (22 ral,
0.30 mole) was added to anisic acid (31.5 g, 0.21 raole) in a three-necked, round-bottomed flask fitted with an addition funnel, reflux condenser, drying tube, and a device for the entrainment of the gases (sulfur dioxide and hydrogen chloride). The mixture was refluxed for 2 hr at which time the condenser was replaced by a modified
Claisen still head and the excess thionyl chloride, fol lowed by the uara-anisoyl chloride, was distilled off at 136 reduced pressure. The yield of -oara-anisoyl chloride was 23.5 g (64^0, bp 143-146° (18 mia); lit^® bp 145°
(14 mm).
(88) A. Schoonjans, Chem. Zentralb., 2, 616 (1897). para-Toluyl Chloride. This acid chloride was prepared using the same procedure as was used for para-anisoyl chloride. The yield of para-toluyl chloride was 71^, bp 123-125° (33 mm); lit^S bp 125° (36 mm).
(89) G. T. Morgan and E. A. Goulson, J. Chem. Soc., 19.29 . 2208.
Product Recovery Studies
Product recovery studies were often run on either a mixture of authentic amides of a Schmidt reaction or
on the individual amides in order to determine whether
selective destruction (either by sulfonation of hydroly
sis) of one of the isomeric amides was occurring after its
formation in the Schmidt reaction.
In general, it was found that the amides produced
in the Schmidt reaction of alkyl aryl ketones did not react with the reaction medium when 50-93/^ sulfuric acid
or molten trichloroacetic acid was employed as the acid 137
catalyst. However, when 990 sulfuric acid was employed
as a catalyst, H-aryl amides were selectively destroyed
(presumable by sulfonation), except in those cases where
electron-withdrawing substituents (e.g., para-bromo and
meta-nitro ) were present on the phenyl ring. V/hen
electron-donating substituents (e.g., oara-methyl, meta-
methyl, para-methoxyl ) were present on the phenyl ring
the N-aryl amide was selectively destroyed, not only in
990 sulfuric acid, but also in 930 sulfuric acid.
For Schmidt reactions of cyclopropyl ketones it was found that the I'T-cyclopropyl amides underwent
selective hydrolytic ring-opening when the sulfuric acid
concentration was greater than 850, but were stable
in molten trichloroacetic acid (except for H-cyclo-
propylbenzamide ).
The amides from the Schmidt reaction of dialkyl
ketones are stable in 50-990 sulfuric acid and in
trichloroacetic acid.
Some examples of the product recovery studies
follow.
H-Isonropylbenzamide and Isobutyranilide. A 2.00 to 1,00
synthetic mixture of N-isopropylbenzamide to isobutyrani
lide was stirred at 25-26° for 18 hr in chloroform (50 ml), 930 sulfuric acid (10 ml), and sodium aside (0.2 g).
V/orlcup yielded 950 of the initial mass, which was shov/n 138 by colimn chromatography to consist of N-isopropyl- benzamide and isobutyranilide in a ratio of 1.96 to 1.00,
A similar result was obtained using 99^ sulfuric acid.
Thus, the ratios of isomeric amides reported for the
Schmidt reaction of isopropyl phenyl ketone are not a result of selective destruction of one of the isomeric amides during the course of the reaction.
N (meta-Tolyl )-Propionomide and îT-Ethyl-meta-Toluamide.
I'l (meta-tolyl)-propionamide (0.20 g) was stirred at
23-25° for 5.2 hr in chloroform (50 ml), sodium azide
(O.l g) and 99^ sulfuric acid (10 ml). Workup yielded a yellow solid (O.Olg; 20^^). Treatment of the amide under the same conditions except using 93^ sulfuric acid for 4 hr gave 0.14 g (70fO of a white solid. Sulfonation of the amide probably occurred in these systems.
By contrast, when IT-ethyl-meta-toluamide (0.20 g) was subjected to Schmidt reaction conditions in 99^ sulfuric acid for 5.2 hr, workup yielded 100# of the original amide.
K-Cyclonropylbenzamide and Oyclourouanecarboxanilido.
ÎJ-cyclopropylbenzamide (0.16 g) was stirred in a mixture of chloroform (50 ml), 93^ sulfuric acid (10 ml), and sodium azide (0.06 g) for 24 hr at 24-28°. Workup yielded a white solid (O.IO g; 83^) which was identical
(ir and mixture melting point) to an authentic sample of 159 bcnzamide. Treatment of another sample of ri-cyclo-
propylhenzarnide with molten trichloroacetic acid for 20 hr resulted in recovery of a white solid (90^) shown by
ir and tic to consist of the initial amide and benzamide.
Cyclopropanecarboxanilide, however, was recovered unchanged in 100/' yield when similarly treated with 93^
sulfuric acid and molten trichloroacetic acid,
N-Oyclonronylacetamide and iT-Kethylcyclonropanecarboxamide.
In the Schmidt reaction of methyl cyclopropyl ketone using 89-SS/j sulfuric acid as catalyst some acetamide is produced from the ring-opening hydrolysis of îT-cyclo- propylacetamide. This fact was established by isolating acetamide (using preparative gas-liquid chromatography) from both the Schmidt reaction mixtures and from the mixture produced when U-cyclopropylacetamide was subjected to the Schmidt reaction conditions in 89-99# sulfuric acid. However, the I'l-cyclopropylacetaraide was stable to
50-83# sulfuric acid and molten trichloroacetic acid.
The H-methyl cyclopropane carboxamide is stable in 50-96# sulfuric acid and molten trichloroacetic acid.
Preparation and Beckmann Rearrangement of Ketoximes
The methods used for the preparation and
Beclcmann rearrangement of the ketoximes are described 140 for Isopropyl phenyl ketoximes and were the same for all the ketoximes.
Isonronyl Phenyl Ketoximes. To hydroxylamine hydro chloride (3.0 g, 44 mmole) dissolved in water (20 ral) was added 10/6 aqueous sodiura hydroxide (15 ml) and iso propyl phenyl ketone (3.0 g, 20 raraole). Just sufficient ethanol was added to dissolve the ketone and give a homo geneous solution. The mixture was refluxed on a steam hath for 4 hr, after which most of the ethanol was re moved under reduced pressure. The aqueous solution was extracted with chloroform, and the chloroform extracts were combined, dried (sodium sulfate), and the solvent removed under reduced pressure to give a mixture of isopropyl phenyl ketoximes (3.3 g; 100^) as a white solid; ir, 3200 (broad, 0-H) and 1630 cm*"^ (sharp, 0=H).
The nmr integrations of the signals at 6,38 ?"
(m, carbinyl proton syn to oxime OH) and 7.17 ?'(m, carbinyl proton anti to oxime OH) established that the ratio of syn- i s o propyl phenyl ket oxime to an t i- i s opr opyl phenyl ketoxime^^ is 46:54, in accordance with the obser- 01 vation-" that the oxime oxygen induces a paramagnetic
(90) The syn and anti designations are with respect to the alley 1 group.
(91) W. D. Phillips, Ann. New York Acad. Sci., 70, 817 (1958). 141 dovmfield nuclear magnetic resonance shift for the proton syn to the oxirae oxygen.
To the oxime mixture (2.0 g, 12 mmole) in dry ether (25 ml) at 0° v/as added phosphorous pentachloride
(5,1 g, 15 mmole) portionv/ise over a period of 0.3 hr v/ith stirring, after which the mixture was allov/ed to warm to room temperature and stand for 2 hr. The mixture v/as then poured on to ice, the ether evaporated in a current of air, and the mixture extracted with chloroform. The chloroform extracts v/ere then combined, dried (sodium sulfate), and the solvent removed under reduced pressure to give a white solid (1.8 g; 907') consisting of a mix ture of îî-isopropylhenzamide to N-phenylisobutyramide in the ratio of 48:52, as shov/n by nmr integrations of the signals at 5.70T (carbinyl proton of Il-isopropylbenzamide) and 7.42 T(carbinyl proton of K-phenylisobutyramide).
Cyclonronyl Phenyl Ketoximes, The mixture of ketoximes was analyzed by nmr, and the ratio of s^-cyclopropyl phenyl ketoxime to anti-cyclopronyl phenyl ketoxime was found to be 71:29 by integrating the signals at 7.67r(m, carbinyl proton syn to the oxime OH) and 8,17 7"(m, carbinyl proton anti to the oxime OH),
The Beclonann rearrangement of the mixture of cyclo propyl phenyl ketoximes produced a mixture of IT-phenyl- cyclopropanecarboxamide to K-cyclopropylbenzamide in the 142
ratio 79:21 as shov/n by integration. of the nmr signals at
7,12 f (m, oarbinyl proton of N-oyclopropylbcnzaniide ) and
8.30 T (m, oarbinyl proton on N-phenylcyclopropanecarbox-
araide ).
Methyl Cyclonronyl Ketoxir.^es. The mixture of ketoximes
consisted of syn-methyl cyclopropyl ketoxime and anti-
q p methyl cyclopropyl ketoxime in a ratio of 65:35, as
shown by integration of the nmr. signals at 8,32 7"
(s, methyl hydrogens syn to the oxime OH) and 8,50 7^
(s, methyl hydrogens anti to the oxime OH).
McLaren and Schachat^ have carried out the
(92) The syn and anti designations are with respect to the methyl group.
(93) A. D. McLaren and R. E. Schachat, J. Org. Chern,, 14, 254 (1949).
Beckmann rearrangement (using phosphorous pentachloride in ether) on the mixture of methyl cyclopropyl ketoximes and determined the ratio of the isomeric amides thereby produced by hydrolyzing the amide mixture and analyzing for the amines produced. Using this technique McLaren and Schachat reported that the ratio of N-cyclopropyl- acetamide to U-methyl cyclopropane carboxamide produced in the Becla.iann rearrangement of the ketoxime mixture was 88:12, 143
Determination of the Relative Rates of Reaction of Ketones in the Schmidt Reaction
I'or a number of pairs of ketones the relative rates of ScMidt reactions were determined by competition experiments in which the ketones (present in a large excess vfith respect to hydrogen aside) were allowed to compete for a limited amount of hydrogen aside. Gas-liquid chromato graphy of the reaction mixture allowed quantitization of each of the isomeric amides present, which (after correc tion for the relative initial amount of each starting ketone and the relative glc response for each amide) per mitted the relative rates of reaction to be calculated. An example will illustrate the procedure.
To methyl cyclopropyl ketone (1.68 g, 20 mmole) and isopropyl cyclopropyl ketone (1.12 g, 10 mmole) in 85/^ sulfuric acid (10 ml) and chloroform (50 ml) was added all at once sodium azide (0.15 g, 2 mmole). After 0.3 hr, while the reaction was still incomplete, the reaction mixture was worked up. Gas-liquid chromatography (10 ' x
1/8" 20/3 Garbo wax 20 M on Chrom \J at 175°) of the reaction mixture— after correction for the difference in initial amount of starting ketones and the relative glc response of each amide— established that the relative rate of the
Schmidt reaction in 85^ sulfuric acid of methyl cyclopropyl ketone to isopropyl cyclopropyl ketone was 4:1. APPENDIX A
Product Recovery Studios in 99/' Sulfuric Acid of Sose Amides of Brackenridge's Work
T h e product recovery data shown in Table 20 for 2 some of the product amides of Brackenridge's study indicate that a significant amount of the isomeric amide with the more electron-rich aryl group attached to the amide nitrogen may have been lost (via sulfonation) during the reaction, resulting in the reporting of spurious amide ratios for Schmidt reactions.
144 145
TABLE 20"
Product Recovery Data in 99/^ Sulfuric Acid for Some Amides of Brackenridge's Study
^ Recovery ^ Recovery Amide After 3-4 hr After 24
N(raeta.-nitronhenyl)-benzamide 100 100
N-phenyl-m e t a-ni t rob enz amide 94 27
K(meta-chlorophenyl)-benzamide 100
E-phenyl-m e t a- chi or ob en z ami de 90
N(rneta-tolyl )-benzamide 0 —~
N-phenyl-meta-toluamide 70
N-phenylcyclohexanecarboxam.ide 76 12
T h e amides were stirred at room temperature in a mixture of 10 ml 99/: sulfuric acid, 50 ml chloroform, and a small amount of sodium azide for the indicated period of time before worlcun. APiEKDIX B
Preliminary Studies Employing Sulfur Dioxide As the Solvent in the Schmidt Reaction
Some preliminary studies were done to see whether the use of the very polar liquid sulfur dioxide (bp -10°) as a solvent in Schmidt reactions might significantly alter the ratio of amides observed, from that observed when chloroform was used as solvent.
Schmidt Reaction of Acetophenone in Sulfur Dioxide.
To acetophenone (1.2 g, 10 mmole) at -78° in a 125 ml three-necked, round-bottomed flask fitted with a gas inlet tube, a gas outlet tube, and an addition funnel for solids, was added sulfur dioxide (10 ml, 22 mmole), followed by 89# sulfuric acid (l ml, 16 mmole) and sodium azide (0.71 g, 11 mmole). The reaction was allowed to proceed with stirring by a magnetic stirrer for 4.5 hr, during which time the temperature of the reaction vessel was allowed to rise to -15°. The usual worlcup of the reaction mixture gave a mixture of unreacted ketone and isomeric amides, which was washed with petroleum ether to remove unreacted ketone and give
146 147 a white solid (0.16 12^o), which the nrar showed con sisted of H-phenylac et amide and li-iriethylbenzaiaide in the ratio 96:4. This ratio is essentially the same as that observed (95:5) when chloroform is used as solvent, so for acetophenone use of sulfur dioxide instead of chloroform as solvent does not change the ratio of isomeric aiaides produced in the Schmidt reaction.
Schmidt Reaction of Methyl Ethyl Ketone in Sulfur
Dioxide. The Schmidt reaction in sulfur dioxide using
89^ sulfuric acid was effected in the same way as above except the temperature was maintained at -60 to -78° for the duration of the reaction (2,5 hr). Gas-liquid chromatography of the material showed it to consist of unreacted ketone (ca. 90;0 and IT-ethylacetaraide and
I'T-raethylpropionamide in the ratio of 80:20, This ratio is somewhat different from that observed (66:34) when the reaction is carried out in 89!)^ sulfuric acid at room temperature using chloroform as the solvent.
Furthermore, this observed difference is not entirely a temperature effect, for carrying out the Sclmidt reaction in;89/^ sulfuric acid and chloroform at -78° resulted in a ratio of K-ethylac et amide to Il-raethylpropionamide of 70:30. 140
Schmidt Réaction of Kethyl Cyclonropyl Ketone in Sulfur
Dioxide. VDien the reaction v/as effected in 85/-> sulfuric acid for 3 hr at -75° to -78°, there v/as no detectable reaction. But maintaining the reaction temperature at -12° to -20° for 2,5 hr resulted in a minor amount of reaction.
The reaction mixture resulting from workup v/as shov/n by glc to consist of unreacted ketone (ca. 90/^)and
N-methylcyclopropanecarboxaraide; no N-cyclopropylacetamide v/as observed in the glc.
This latter result is quite different from the result observed when the Schmidt reaction of methyl cyclopropyl ketone is carried out in 83^ sulfuric acid at room temper ature using chloroform as solvent— v/here the ratio of
IJ-cyclopropylaoetamido to k-methylcyclopropanecarboxamide is 74:26— and indicates a spectacular change in the amide ratio resulting from changing the solvent from chloroform to sulfur dioxide.
This nearly complete reversal in amide ratios is not the result of different reaction temperatures, for effecting the Schmidt reaction of methyl cyclopropyl ketone in 83/^ sulfuric acid and chloroform at -14°to -18° results in a ratio of N-cyclopropylacetamide to N-rnethyl- cyclopropanccarboxamide of 66:34; nearly the same ratio as observed (74:26) when the reaction was carried out at room temperature in 83^ sulfuric acid and chloroform.