contemporary hiftory
Columbia LEONARD edited University FINE by: New York, NY 10027
ERIC S. PROSKAUER
Frank C. Whitmore and Steric Hindrance A Duo of Centennials Harry S. Masher Stanford University, Stanford, CA 94305 Thomas T. Tidwell University of Toronto. Scarborough Campus, Scarborough. ON, Canada M1C 1A4 The origin of the theory of steric effects can be traced to the report 100 years ago by Friedrich Kehrmann, then a 24year-old assistant a t the University of Freihurg in Germany, that o-substituted quinones are less reactive than the unsubstituted derivatives (eq 1) (1)
p%pFv NOH
(1)
0 NOH NOH Kehrmann extended his work to other systems (2a), but despite his defense of his priority for discovery of this effect (26, c), the credit is often given to Victor Meyer, who first ~ublishedin 1894 his work on the effect of steric effects in esterifiration, without acknowledgement of Kehrmann's contributions (3). Rudolf Wersrheider in Vienna also vublished in 1895 his studies of iteric effects in esterificaiion, with due mention to Kehrmann's work, and is credited with first using the expression steric hindrance (4). As with any major scientific discovery there were important antecedents to Kehrmann's insights, and the ohsewation of Hofmann in 1872 (5) that tertiary aryl amines are resistant to alkylation is prominent among these. However, i t was the studies of Kehrmann, Meyer, and Wegscheider that alerted the chemical community to the importance of this effect. The concept of steric hindrance rapidly found wide acceptance, and a review in 1928 (6) discussed how this factor influenced the esterification of carboxvlic acids and hvdrolvsis of acid derivatives, substitution on aromatic suh&rat& additions to aldehydes and ketones, and aromatic rearrangements. However, while many of these early workers had a general idea that crowding could affect chemical properties, only rudimentary understanding of the relevant reaction mechanisms was available a t the time, so that the specific role of steric hindrance was often not correctly appreciated. There was a missed opportunity in the early part of the. Presented at the Frank C. Whltmore Centennial Symposium at the 194th National American Chemical Society Meeting. New Orleans, August 30-September 4.1987.
century for the application of the theory of steric hindrance to the understanding of the triphenylmethyl radical, discovered by Moses Gomberg a t the University of Michigan in 1900 (7). Gomherg showed that the radical was in equilihrium with a dimeric structure, but after intense discussion in the literature the head-to-head hexaphenylethane structure 1was accepted for the dimer, and it was only in 1969 that it was demonstrated that the unsymmetrical structure 2 for the dimer in equilibrium with triphenylmethyl is correct (eq 2) (7b) Ph&_
_
,Ph
The symmetrical structure 1is extremely crowded with a very weak central C-C bond. This point was considered by Gilbert Newton Lewis in 1916 (8),and he concluded that the mass of the groups increasinp the centrifunal force a t the central bondaas;esponsible jbr the instahiky of heraarylethanes (8).Today it is reropnized that it is the nonbonded repulsion between the qoups that causes the lability of highly substituted ethanes. I t was appreciated by James Bryant Conant a t Harvard that bulky alkyl groups would also contribute to the instability of ethanes, and during the 1920's he showed that the facility of dissociation of 1,2dialkyltetraarylethanes was enhanced in the order t-Bu > iPr > E t > Me (eq 3) (9). Recently it has been shown (9d) that, for R = t-Bu, the dimeric material in this equilibrium has the unsymmetrical structure analogous to 2.
Proper appreciation of the steric crowding present in hexaphenylethane could have caused more serious consideration of the merits of the unsymmetrical dimeric structure and led t o its acceptance many years earlier. Conant alsosought to prepare hexa-tert-butylethane (9a), with a clear interest in the possible dissociation of this compound into radicals, but the project foundered in the first step when the reaction of tert-butylmagnesium chloride with di-tert-hutyl ketone gave none of the addition product, but only reduction (eq 4) (9a) Volume 67 Number 1 January 1990
9
Addition of carbocations to alkenes, the reverse of the cleavage in eq 5, is a reaction of great significance to petroleum refining, as i t permits the conversion of isobutene to isooctane for use in gasoline. The immediate relevance of the carbonium ion theory of rearrangements to industrial practice was well recognized by Whitmore, and the theory was frequently presented to industrial audiences (13, 14). With the addition of the bydride transfer step from isobutene introduced by Bartlett and Schmerling (15), the theory of Whitmore explained the conversion of isobutene to isooctane (eq 6).
Figure 1. Frank C. Whitmore.
(CH&CM&I
+ t-Bu&=O
-
t-Bu2CHOH+ CH2=C(CHa)2 695%
(4)
This report appeared in 1929 (9a) and no douht attracted the eye of Frank Whitmore, who that year assumed the position of Dean of the School of Chemistry and Physics at Pennsylvania State College. Whitmore was horn in 1887, just before the appearance of Kehrmann's paper, and his remarkable career has been summarized in an article by Martin D. Saltzman (10). l h e high point of Whitmore's career was a famous article in 19:32 "The Common Hasis of lntramolecular Hearranaements" (Il), a theoretical paper that both popularized the carbocation with its open sextet of eledrons and also used this species to explain the paths of many diverse rearrangements. Crowded and strained compounds were of pivotal importance in the development of this theoretical analysis. as these substrates both facilitated the generation of carhocations and increased their propensity for rearrangement and fragmentation. The unified interpretation of these phenomena by the electronic theory of organic chemistry was the critical part of Whitmore's landmark paper. Imnortant evidence for the theory was the acid dehvdration df di-tert-butylcarbinol, prepaked by reduction di:tertbutvl ketone. This reaction gave a 7'?-yield of trimethylethylene at 180 "C and was interpreted as involving formation of the cation 3, which was "doubly a positive neopentyl system" that reacted further by methyl migration to the cation 4, which reversibly lost a proton to give nonenes or cleaved to give trimethylethylene (eq 5) (12a). 10
Journal of Chemical Education
Whitmore's industrial affinities are pointed up by the pilot-plant scale of many of the procedures followed in his work. Thus oxidations of 200-mol batches of alkene utilizing 36 kg of sodium chromate are reported, and highly sophisticated distillation apparatus was used for the purification of - the products (16). The favored mode of building up the branched organic structures involved the formation of ketones by the reactions of carboxylic acid derivatives with Grignard reagents and the further reaction of the ketones with Grignard reagents to give tertiary alcohols. The failure of the more crowded systems to undergo addition reactions led to detailed study by Whitmore of the enolization and reduction processes (cf. eq 4). Whitmore's ideas also accommodate the carhonium ion rearrangements of camphene hydrochloride studied by Meerwein (eq 7) (17). Steric effects are clearly important in these strained and crowded substrates, and the interrelation of steric and electronic influences on the reactivity of these molecules led to a long and bitter controversy.
The growth in interest in steric hindrance as indicated by the listings in the Chemical Abstracts Decennial Indexes under this topic up to 1946, and for 1956 under the new heading "Steric Effects" are shown below. A period of accelerating activity in this field coincides with Whitmore's puhlication of 1932, and was no douht stimulated by the activities of Whitmore, Ingold, Brown, Bartlett, Newman, and others after that date.
CA Index
Steric hindrance citations
1907-1916 1917-1926 1927-1936 1937-1946 1947-1956
20 29 66 135 742 (sleric effects)
Whitmore's publication in 1932 coupled with the development of the theory of nucleophilic substitution processes by the Hughes and Ingold school in England led to great interest in solvolytic reactions. In 1939 Bartlett and Knox published their studies of the solvolvsis of the bridgehead chloride 5, which wasvastly less reactive than the acyclic model 6 (orenared .. . from a carbinol reported by Whitmore) (18). This study showed ~ n e ~ u i v o c a l l ~unimolecular the nature of solvolvsisoftertiorychlorides,andthe preference for coplanarity bf the intermidiate carbonium ion. The greater reactivity of the crowded chloride 6 relative to tert-butyl chloride was noted but the connection of this effect with the crowded structure was not commented on.
In a contemporary study of crowded organic molecules in the 1930's Louis P. Hammett at Columbia carried out cryoscopic measurements of the formation of long-lived acylium ions from the reaction of crowded aryl carboxylic acids in concentrated sulfuric acids (19). The longevity of these species was attributed to the diminution in steric interactions between the acyl group and the ortho substituent on conversion of the protonated acid to the acylium ion (eq 8).
Similarly esters of trimethylbenzoic acid are hydrolyzed by dissolving them in concentrated sulfurir acid, forming the acylium ion, and then diluting with water (20). The preparation by Whitmore of aliphatic carboxylic achivhlv ramified strurtures from oxidations of com. ids . -.with - ~ - -~~ - m~~ plex hydrocarbons (16) was instrumental in the demonstration of the quantitative dependence of acid strength on steric crowding. This work was taken up hy M. S. Newman a t the Ohio State University (21). ~e&& developed wide interests in steric effects, including the ionization constants of crowded aliphatic acids, and promulgated the "rule of six" and "six number" for estimating the degree of steric crowding. This rule is .'In reactions involvinx addition to an unsaturated function, the greater the number of atoms in the six position the greater will be the steric effect" (21a. . . hJ. . ---- -A significant paper (21c) reporting measurements of acid dissociation constants of aliohatic acids bv Hammond and Hogie acknowledges that most of the compounds studied were suonlied bv Newman and came from the collection of whitmore. In an interview with the author Newman related that the
origin of his interest in steric effects was the carcinogenic effects of crowded alkyl groups in polycyclic aromatic bydrocarbons, an area he has pursued for 50 years. Perhaps the most lasting of his contributions will he the influential text on steric effects he edited in 1956 (22). Another major development in the 1920's and 1930's that had imuortant imolications for the later evolution of suantitative iheories of steric effects were the preparation df optically active biphenyls (7) by G. H. Christie and J. Kenner in England (23a) and the later extensive study of these compounds by Roger Adams (236). These compounds have restricted rotation about the bond connecting the two aryl rings due to steric interference of the R groups in the planar transition state and thus give an effective guide to the steric bulk of the substituents. These barriers were calculated by Wsstheimer (24), in the first use of the now widespread method of molecular mechanics.
Fuson and co-workers found that aldehydes and ketones substituted with bulky aryl groups could exist as stable enols, as in the example shown (25). Mes
r\ Mes 2,4,6-trimethylphenyl woH =
CH3
Mes
Whitmore's syntheses of crowded alcohols utilized organomagnesium reagents. but organolithium compounds were never popular in his lahoratory. However in 1911 a team of well-known Harvard chemists consisting of P. D. Hartlett, C. G. Swain, and R. R.Woodward reported that the reaction of terl-butyl chloride and lithium in ether gave tert-butyllithium, identified by carbonation with rarbon dioxide to give trimethylacetic acid @6). The evolution of an unidentified gas that was absorbed in concentrated sulfuric arid during the reartion was also reported, and reaction of the terfhutyllithium with hexamethylacetone was reported to give di-tert-hutylcarhinol, isobutylene, and a supposed bimolecular reduction product of hexamethylacetone (eqs 9,lO).
A
~
~~~
~
In experiments carried out a t the same time Gilman and co-workers (27) found that tert-butyllithium cleaved ether a t room temperature, that is, under the conditions of its oreoaration bv Bartlett. Swain, and Woodward, but that it could be prepared in petroleum ether at room temperature in 504O~vield.althoughthe reaction wassometimeserratic and failed-in one out of five experiments. I t was predicted "that additional experiments in various laboratories will remove the particular difficulties" in this preparation, but 20 years later one of the present authors still experienced failure in this preparation. Fortunately, since the early 1960's tert-butyllithium in hydrocarbon solvents has been commercially available, thus saving a great deal of effort in research laboratories.
. .
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11
In 1946 the French workers Vavon and Colin (28) also reported the preparation of tert-butyllithium (called "pseudobutyl") in petroleum ether and reported its reaction with diisopropyl ketone t o give the tert-butyldiisopropylcarbinol (eq l l ) , while Young and Roberts reported a similar preparation of sec-butyl-diisopropylcarbinolin 1944 (29).
Addition with allylic rearrangement; (4) Reduction; (5)Enolization: ( 6 ) Condensation: and (7) Coordination comolex formation hithout further reaction: His illustrations of'(2)(4) are shown in eqs 18-20, respectively.
In response to the publication of Young and Roberts there appeared in 1945 a report by Bartlett and Schneider (30) of the preparation of tri-tert-butylcarbinol by the reaction of sodium with tert-hutyl chloride and hexamethylacetone in ether (ea 12). Later i t was shown that tri-tert-butylcarbinol could helnore easily prepared from henamethylacetone and tert-hutyllithium in ether at -70 OC or in hydrocarbon solvents (31).
The cleavage of diethyl ether by organolithiums was found to involve ethylene formation, and in the presence of terthutyllithium this reacted with eventual formation of tertbutyl neohexyl ketone (eqs 13-15) (31~). t-BuLi + (C,H&O
-
t-BuH
+ LiOEt + C H H H ,
(13)
Later the supposed reductive dimerization product from he~ameth~lacetnne and sodium was shown also to contain an ethylene moiety derived from diethyl ether (eq 16) (32).
The connection of radical stability with steric bulk was apparent to Conant in the 1920's (9) and was explicitly pointed out by Bartlett and Schneider in 1945 (30), who drew attention to the obvious interest in the preparation of tri-tert-butyl radical, as the dimeric hexa-tert-butylethane would be prohibitively strained. This prediction was confirmed when the radical was eventually prepared by Ingold and co-workers, as the molecule showed no tendency for dimerization (eq 17) (33).
Whitmore's work on steric hindrance prior to World War I1 included extensive experimental examination of the effects of crowding on Grignard reactions. One of the graduate students involved in this project was R. S. George, and an experimental paper based on his work was published in 1942. At the American Chemical Society Meeting in Atlantic City in September 1941,Whitmore presented a paper coauthored by George entitled "The Common Basis of the Reaction of Grignard Reagents with Carbouyl Compounds". This title echoed the epochal 1932 paper, "The Common Basis of Intramolecular Rearrangements", and the content of this talk is known because the color slides prepared for the talk survive and also because a manuscript for publication with the same title was prepared soon afterward (35). Whitmore's talk and manuscript considered seven processes, namely (1) 13-Addition; (2) 1,CAddition; (3) 1,212
Journal of Chemical Education
This discussion emphasized the crucial role of the mutual interaction of atoms a t the 1,6-positions, as shown in eqs 1820, and the role of the cyclic complex in product formation (35). The slides for the lecture were photographs of a set of unique early molecular models made in the Penn State workshops especially for this purpose, and an example clearly illustrating the six-membered transition state of eq 19 is shown in Figure 2. Whitmore's lecture was widely quoted in the literature, but even though the written manuscript was essentially complete, it was not submitted for publication during Whitmore's lifetime. One reason was surely the pressure of war work. Another may well be that Whitmore was troubled by the need to acknowledge properly the many previous glimpses of the importance of six-membered cyclic transition states in the literature and his inability to find time to distribute the credit properly. When Whitmore died soon after the war, the same manuscript was submitted by George to Journal of the American Chemical Society, but it was rejected on the basis that it contained no experimental work (35b). However, his ideas on the topic had become widely known, and were generally accepted by 1950. The importance of such electrocyclic transition states has been shown to be even more general, and they occupy a central place in the current theory of organic chemistry. Late in his career Whitmore became involved in organosilicon chemistry (36), and this work was carried on for many years by his student Leo Sommer, first at Penn State and then a t the University of California, Davis. Organosilicon chemistry has grown phenomenally, and much of this ad-
steric hindrance had fallen into "disrepute" as a result of its indiscriminate use by early organic theorists. Ten years later hereviewed the topic (40a) and citedfroma textbook of 1941 that "Steric hindrance . . . has become the last refuge of the puzzled organic chemist." Brown's view that steric effects were in "disrepute" in 1946 is rather overdrawn in view of the many developments in this area since Whitmore's 1932 paper cited above. However, there was a contemporary view from Great Britain emphasizing electronic effects and stating regarding ortho substituent effects that "these observations cannot be interpreted on the basis of a purely geometrical steric hindrance as envisaged by Victor Meyer" (39). Other reviews by Hughes and Ingold also emphasized electronic factors in the S Nreactions ~ and deemphasized steric acceleration (40c, d), and Brown's lively arguments with the English school of physical organic chemistry typified the combative nature of his a n ~ r o a c hto chemistrv. Sinre Whitmore's death quantitative methods have heen thrdominant a o ~ r o a c htothestudvofstericeffects.and this trend is of increasing importance today. In the 1950's a t Penn State R. W. Taft develo~eda correlation of steric and polar effectson aliphatic reactivity, and his work owed rnurh to Whirmore's ~repararianof crowded aliphatic arids that revealed large influences of steric effects (41). Other major advances in the calculation of steric factors extended the work done hy Westheimer and Ingold in the 1940's, and include studies of the dissociation of the carboncarbon bond by Riichardt and Beckhaus (42) and detailed calculations of transition state strains (43), particularly using the methods of molecular mechanics (44). Reviews of recent developments have appeared (4547). ~
~~
~
.~.
~~~
Figure 2. Original slide of molecular models showing the six-membered cyclic bansition state for the addition of formaldehydeto benrylmagnesium chloride (see eq 19, text). The magnesium is the largest atom in the center and is coordinated to one ether mlecule. The models were constructed at Penn State, and color slides of them were used to illustrateWhitmore's lectureat the 1941 ACS meeting in Atlantic City.
vancement can be traced to Whitmore. Some spectacular examples of crowded organosilicon compounds have been reported, for example, 8 and 9, by Hideki Sakurai, in Japan (37). t-BuMe2Si \ /SiMe2-t-Bu
/"=%SiMe3
(Me3Si)zC=C(SiMe3)2
MeSi
8
9
In 1946 H. C. Brown published an important paper in the history of steric effects entitled "A New Steric Effect in Organic Chemistry" (38a). This paper summarized work recently published from Brown's laboratory at Wayne University on steric effects on the stabilities of addition compounds of amines and trialkylborans. Brown argued for the existence of two types of strain: "F-strain", or the interactions between bulky groups on the two halves of a molecular complex, and "B-strain", or back strain, which is the increase in strain in one fragment associated with a change in geometry from trigonal-planar to tetrahedral (eq 21). R,&~R,
R,B
+ NR,
(21)
These effects were extended to include other phenomena, including Whitmore's theory of molecular rearrangement in neo~entvlalrohol: the fncilitv of this process was ascrihed to carbon (eq 22). the^-stiain a t the
~~
Conclusion Thus the 1888 discovery of steric hindrance by Kehrmann was followed nearly a half-century later by Whitmore's paper in 1932 that used studies of the reactivities of crowded organic compounds to develop a general theory of molecular rearrangement and to establish the role of carhocations as both viable and important reaction intermediates. Even though Whitmore's later theoretical analysis of Grignard reactions with the strong dependence of the reaction course on steric effects was never published, his ideas were widely known and are incorporated in the currently accepted theory of organic chemistry. Today the importance of steric effects is seen to be pervasive in chemistry, and the elucidation of the precise structure of reaction transition states is one of the major goals of current research. The greatest achievementsusing the theory of stericstrain are yet to come and will feature the quantitative application of the theories of steric effects, aided by rapid computer calculation of molecular and transition state structures and their modem graphical representation. Literature Clted I. Kohrmann,F.Chem.Rar.1888.21.331&3321. 2. lalKahrmann,F.Chrm.Ber1890.23.131-136. (hl Kehrmann.F.Chem.Ber. 1908.41. 4357-4368. lc1 Obituary: Goldstoin, H. H d u . Chim. Aclo 1932.15, :315-349.
Similarly unpublished results on the ionization of crowded tertiary chlorides were noted (38a) in which fast rates of ionization were noted and assigned to a reduction in B-strain on reaction. These studies were published a few years later (386). R,CCl
-
R,C+
+ C1-
Brown began his report of 1946 (38a) by arguing that electronic factors were overemphasized in theoretical discussions of organic chemistry (39) and that the concept of
3. is1 Mover. V. Chem Bpi. 1894.27.510-612. lbl M P Y F ~V.; , Sudborough. .I. J. Chem. ~~~.1894,27,1~80-1592. 4. (a) W ~ ~ c h e i d oR. r , Monol. Chem. 1895. 16. 75-152. (b) Wegocheidor, R. Monat. (cl Wegrcheider, R. C h o n Ber. 1895.28,146&1471. Chsm. 1897,I8.629-657. 5. Hofmsnn,A. W . Chem. Rer. 1872.5.704-719. 6. Anschutz. L. Angew. Chem. 1928,41,691-696. 7. (a) Gumberg.M. J A m ChsmSor. 1900.22.757-771.(hl For aroviewreeMcBride.J. M. Tetrahadion 1974,30,2009-2022. 8. Lewis. G. N.Proc.Nat. Arod. Sci. USA 1916,2,686592. Cham. Abslr. 1917,11,587. 9. (a)Conant,J.B.;Blatt,A.H. J.Am.Chem.Soc. 1929.61.1227-1236,ih1Cnnant.J.B.; Bigelnw.N.M.J.Am.Chem.Soc.1928.50.204L-2049. (e)Conant,J.B.;Smsll.L.F.; S1uan.A. W. J.Am. Chrm. Soe. 1926.48.1743-1767. (dlZarkadis, A. K.; Neumann. W. P.;Marx,R.:Uzick, W. Chrm. RIP. 1985,l18,45C-466. 10. Saltzman, M.D. C H E M T E C H 1985484-489. 11. Whitmore. F. C. J . A m Chem.Soe. 1932.54.3274-3263. 12. la1 Whimore. F. C.; Stahly. E. E. J . Am. Chem. Soc. 1933, 55,41534157. Ibl Whitmore,F.C.:Fleming, G. H. J. Am. Chrm.Soe. 1933,5.5,4161-4162. 13. Whitmore.F. C. Ind.Eng. Chem. 193628.94-95. 14. Whitmore.F. C.Chem. Enz.Neua 1948.26.66Rb74.
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