April 5, 1960
COMMUNICATIONS TO THE EDITOR
The absorbance of the final solution was read immediately a t the 335 mp maximum. Since the optical density a t 335 mp decreased more rapidly with this system, fast work and careful timing and extrapolation to zero or mixing time were
1829
important. The titration curve was plotted as before. These data are presented in Table 111. HUNTSVILLE, ALA.
COMMUNICA.TIONS T O T H E E D I T O R BRIDGED POLYCYCLIC COMPOUNDS. XII. A made by the addition of hydrogen bromide to MECHANISM FOR THE HUNSDIECKER REACTION'~2 Aldrin (VI). Ib and I I b were shown to be epi-
Sir:
meric by dehydrobromination with alkali to VI. Ib and I I b were isolated from the reaction of Ia and IIa with bromine in carbon tetrachloride. The bromides were inert toward the reaction conditions and isolation procedures, and the acids related to Ia and Ib could be recovered unisomerized from their silver salts. The acids, IC (m.p. 221-222') and IIc (m.p. c1 216-217') were prepared by the reaction of ~ x oand - ~endo-bicyclo [2.2.1]-5-heptene-2-carboxylic , acid,6respectively, with hexachlorocyclopentadiene. x IIa, X = COzAg The acids gave the acid chlorides, Id (m.p. 100.5Ia, X = C02Ag b, X = Br b , X = Br 101.5') and I I d (m.p. 111.5-113'), which in turn C, X = COzH C, X = COzH were treated with sodium peroxide to form I11 d, X = COCl d, X = COCl (m.p. cu. 111') dec.) and IV (m.p. ca. 133O, dec.). of the acyl peroxides I11 and IV in bromotrichloro- All of the compounds gave satisfactory elemental methane was all exo (Ib). If the latter reaction analyses. Each peroxide decomposed largely into ester and only the exo bromide Ib in refluxing bromotrichloromethane. The alcohol and acid portions of each ester had the configuration of the starting acid. Infrared and isotope-dilution analyses showed that the bromide from either peroxide contained very little, if any, IIb. The Hunsdiecker reactions of Ia and IIa in the dark in refluxing carbon tetrachloride gave broh h mides whose compositions as measured by infrared and isotope-dilution techniques were Ib, 69 2% and IIb, 31 rt 2%. The configuration of the initial silver salt did not affect the bromide composition, nor did addition of benzoyl peroxide or sym1' VI trinitrobenzene. The large amount of endo bromide reflects the stereochemistry of the reaction of the (IIb) is striking. free radical V with bromine donors, some mechaThe insensitivity of the composition of the nism other than the reaction of V with bromine or bromide mixture to the configuration of the initial acyl hypobromite must be involved in the Huns- acid is inconsistent with any stereospecific inversion diecker reaction of Ia and IIa; a free radical is, or cyclic process, while the formation of substantial however, generally accepted as the intermediate in amounts of endo bromide is inconsistent with a this reaction.3 free-radical-chain process in which the radical V I b (m.p. 178.5-1792") and I I b (m.p. 109.5- reacts with a bromine donor.6 The data are 110.5') result from the reaction of hexachlorocyclo- consistent with the concept of geminate recombinapentadiene with the mixture obtained by the tion of an alkyl radical and a bromine atom, formed Diels-Alder reaction of vinyl bromide and cyclo- by decomposition of the intermediate acyl hypo~ e n t a d i e n e . ~The ex0 bromide I b also can be ( 5 ) K. Alder, G. Stein, M. Liebmann and E. Rolland, A n n . , 614,
The Hunsdiecker reaction of bromine with the silver salts Ia and IIa gave a mixture of Ib and IIb, although the bromide formed by decomposition
*
(1) Previous paper in series: S. B. Soloway and S. J. Cristol, J . Org. Chem., accepted for publication. (2) The authors are indebted to the Shell Development Company for
partial support of this research. (3) For pertinent references see: C. V. Wilson in R. Adams, "Organic Reactions," Vol. IX, John Wiley and Sons,Inc., N. Y., 1957,Chapter 5 ; R.G.Johnson and R. K. Ingham, Chem. Reus., 66,219(1956). (4) J. D. Roberts, E. R. Trumbull, W. Bennett and R . Armstrong, THISJOURNAL, l a , 3116 (1950).
197 (1934). ( 6 ) A referee has suggested that the stereochemistry of the model reaction of V with bromotrichloromethane may not be comparable t o t h a t of V with the smaller molecule bromine or with the acyl hypohalite. The conclusion that no chain reaction process is involved is based upon the assumption that these are comparable and that c x o attack on such radicals'is general. (7) S. J. Cristol and R. P. Arganbright, THISJOURNAL, 1 9 , 6039 (1957).
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COMMUNICATIONS TO THE EDITOR
bromiteS within a solvent cage. As this involves the reaction of two high-energy species in close proximity and with presumably a low activation energy, the relative lack of selectivity between endo and exo attack in the Hunsdiecker reaction, compared to the usual tendency for ex0 attack on such ring systems, is understandable.8 While the evidence in this system appears consistent only with the radical geminate recombination mechanism, we are continuing our investigation of the Hunsdiecker reaction to determine whether other mechanisms are available to i t in other systems or under other experimental conditions.
Vol. 82 CsHaCOCl
m.p. 313-316' (dec.), ~~-N-benzoyl-3carboxy- 1,2,3,4-tetrahydroisoquinoline(I I), m .I). K hlnO I 170-172", neut. equiv., 2 5 0 KzC03 -7 DL-a-benzaniitlo&(o-carboxypheny1)-propionic acid (111), m.p. 210€I CI 211 ", neut. equiv., 138 ----e~r,-l-keto-3-carboxyHzO 1,2,3,4-tetrahydroisoquinoline(IV), r11.p. 234-235 CHsOH (dec.), neut. eqttiv., 191 ---+ ~~-1-ket0-3-carbosociz methoxy- 1,2,3,4-tetrahydroisoquinoline(I') , m .p. 114-115", gave an acid (IV) and methyl ester (V) that were identical with those obtained by the first method of synthesis. With D- and L-phenylalanine the above sequence of reactions gave D-I,m.p. 280' (b, G. S. Hammond, THISJOURNAL, 77, 334 (1955). DEPARTMENT OF CHEMISTRY STANLEY J . CRISTOL (dec.); L-I,m.p. 274" (dec.); D-11, m.p. 156-158", l!NIVERSITY O F COLOR.4DO J O H N R. DOUGLASS [aI2'D 34"; L-11, m.p. 164", [ff]"D -34"; D-111, BOULDER,COLORADO WILLIAMC. FIRTH,JR. m.p. ca. 181-184.5", [ a 3 z 5 119"; ~ L-111, m.p. 180ROBERT E. KRALL 182", [a]2 0 -105'; ~ D-IV, m.p. 234-236.5", [a] RECEIVED JAXUARY 18, 1960 -44'; L-IV, m.p. 236-238", [ a ]2 5 41 ~ O ; D-V, n1.p. 87-89', [ a ] 2 5 -79" ~ and L-v,m.p. 58-90', [ a ] " D 76". All rotations were determined in methanol AN INVERSION OF THE USUAL ANTIPODAL with a solute concentration of ca. 2%. SPECIFICITY OBSERVED IN or-CHYMOTRYPSIN When the D- and ~~-1-keto-3-carbomethoxyCATALYZED REACTIONS' 1,2,3,4-tetrahydroisoquinolineswere allowed to Sir: It is known that the antipodal specificity en- react with a-chymotrypsin, in aqueous solutions a t countered in a-chymotrypsin catalyzed reactions is 25" and pH 7.9 and a t substrate concentrations of relative rather than absolute.2,3 However, when- approximately 10-3Af and an enzyme concentration ever antipodal specificity has been evident it has of approximately 10-6M, it was observed that been only the L-enantiomorph that has been ob- whereas the DL-mixture was hydrolyzed rapidly served to react a t the more rapid rate. Thus, it is to the corresponding acid and methanol only to an generally believed that a-chymotrypsin exhibits a extent of 50% the D-enantiomorph was hydrolyzed predominant antipodal specificity for substrates completely and a t a more rapid rate. A prelimipossessing the L-configuration although it is recog- nary analysis of the kinetics of hydrolysis of the nized that such antipodal specificity may be lost DL-mixture indicated that under the above condieither wholly or in part with certain types of sub- tions the L-enantiomorph present in the Dr,-mixture participated in the reaction primarily as a conipetistrates. In 1957 i t was suggested4 that one of the enantio- tive inhibitor rather than as a substrate. morphs of l-keto-3-carbomethoxy-1,2,3,4-tetra- When i t is appreciated that D-1-keto-3-carbois hydrohydroisoquinoline might be found to be a substrate methoxy-l,2,3,4-tetrahpdroisoquinoline of a-chymotrypsin. The DL-ester was first syn- lyzed in the presence of a-chymotrypsin a t a rate thesized by condensation of o-cyanobenzyl bromide comparable in magnitude to the rates of hydrolysis with diethyl acetamidomalonate to give ethyl DL-a- of several acylated-L-phenylalaninemethyl esters carbethoxy - a - acetamido - P - (0 - cyanophenyl)- under similar experimental conditions and that propionate, m.p. 104-105 ", which was saponified, L - 1 -keto - 3 - carbomethoxy - 1,2,3,3- tetrahydrodecarboxylated and cyclized to ~~-1-ket0-3-car-isoquinoline, in common with a number of acylatedboxy-1,2,3,4-tetrahydroisoquinoline, m.p. 235-237" D-phenylalanine methyl esters, is hydrolyzed a t a (dec.), and the DL-acid esterified to give the desired far slower rate and can function as a competitive DL-methyl ester, m.p. 114-115". When this DL- inhibitor in the above reaction it becomes evident ester was allowed to react with a-chymotrypsin, that a-chymotrypsin and not a hitherto undisin aqueous solutions at 25" and p H 7.0 to 8.0, a closed enzyme, present as an impurity in the arapid hydrolysis was observed until approximately chymotrypsin preparation, is responsible for the 50% of the DL-ester had reacted. With this demon- observed preferential hydrolysis of the above Dstration of not only substrate activity, but also of enantiomorph. In our observation of an inversion rather than of a n marked antipodal specificity, a stereospecific synabolition of the traditional antipodal specificity of thesis of n- and ~-l-keto-3-carbomethoxy-l,2,3,4tetrahydroisoquinoline, from D- and L-phenylala- systems involving a-chymotrypsin we have demonnine, was undertaken after it had been determined strated that the predominant antipodal spec$city of CHzO such systems can be determined by the structure of the that the reaction sequence DL-phenylalanine substrate and that it i s not an invariant property of DL-3-carboxy-1,2,3,4-tetrahydroisoquinoline (I), the enzyme. The significance of this conclusion with respect to the mechanism of enzyme action (1) Supported in part by a grant from the National Institutes of is obvious. For one, i t suggests that if the conHealth, Public Health Service. (2) H. l'eurnth : m l G W,Schwert, C h r m . Revs., 46, 69 (1950). formation of the active site of the enzyme is essen( 3 ) R. XI r i w k . unpii' lished experiments cimdiicted in these laboratially invariant then combination of the substrate tories. with the active site must involve interactions (4) 12. L. Bixler, Ph.I). Thesis, Calif. Inst. Tech., Pasadena, lB.57.
