SECONDARY ISOTOPE EFFECTSOF DEUTERIUM
Nov. 5 , 1963
[CONTRIBUTION FROM
THE
3497
OAK RIDGES A T I O N A L LABORATORY, O A K RIDGE,T E N N . ]
Steric Origin of Some Secondary Isotope Effects of Deuteriumla BY VERNONF. RAAEN,THEODORE K . D U N H A MDOROTHY , D. THOMPSON,'~ A N D CLAIRJ . COLLINS RECEIVED J U L Y 23, 1963 The differential method (ref. 6 ) for determinitg isotope effects has now been extended to the acid-catalyzed reactions with 2,4-dinitropheni-lhydrazine a t 0 of several other carbon-14 labeled ketones. .Ill carbonyllabeled ketones investigated exhibited isotope effects ( k * / k ) very close t o 0.95. For the reaction of acetop h e n o n e - ~ - ~ ~ e f l ~k ~ ' ~ ,1,0038 i 0.0003. By using carbon-14 as a tracer for either hydrogen or deu* l-kC = terium, the differential method was also employed for determining isotope effects due to deuterium. The results for deuterium are discussed in terms of Jencks' mechanism (ref. 10) for carbonyl reactions and are explained on steric grounds.
Shiner,* S t r e i t w i e ~ e r ,Bartell,4 ~ and Halevis have discussed possible origins of secondary isotope effects of deuterium and tritium. There appears to be general agreement',3 t h a t hyperconjugation, induction, and steric properties can contribute, although the relative importance of each does not seem to have been establ i ~ h e d . ~We , ~ now report our studies of secondary isotope effects of deuterium and also, incidentally, of carbon-14, in which we believe the hyperconjugative and inductive contributions have been minimized, thus allowing an evaluation of the magnitude of steric isotope effects caused by substitution of deuterium for hydrogen. The reactions studied were the formation, a t O o , of the 2,4-dinitrophenylhydrazones of various isotope position isomers of acetophenone, phenyl t-butyl ketone, and propiophenone. The deuteriumcontaining ketones whose isotope effects were determined with respect to the undeuterated species are shown in structures I-IV. The method used (the differential method) has been previously employed in
A = Ao ( k * l k ) ( l - f ) ( k * ' k - l ~ (1) molar radioactivity of each small sample a t fraction f of reaction A , = molar radioactivity of reactant a t f = 0 k * / k = ratio of specific rate constants for reaction of labeled and unlabeled molecules, respectively A
results are given in Table I . In order to obtain the isotope effect values ( k u ' k ~due ) only to the substituton of deuterium for hydrogen appropriate ratios from the third column of Table I were used Thus, the isotope effect in the derivatization of trideuterioacetophenone TABLE I EXPERIMENTALLY DETERMINED VALUESOF T H E ISOTOPE EFFECT I F COXVERSIoN OF KETOiSES TO THEIR 2,4-DINITROPHE%YLHYDRAZONES
Run
CH, PhCOCD3 I
PhCOC-CD3 I1
CD3
PhCOCD3CH3 111
PhCOCH2CDs
IV
the establishment of an isotope effect ( k * / k ) of 1.0085 f 0.0004 in the formation of the 2,4dinitrophenylhydrazone of a c e t ~ p h e n o n e - P - C ' ~ .In ~ determining the rate acceleration or deceleration caused b y substitution of deuterium for hydrogen, known mixtures of deuterated and undeuterated species were prepared, one of which was always labeled with carbon-14, and the rate of change of carbon-14 content as a function of fraction of reaction was determined. The method requires t h a t the isotope effects caused by the carbon-14 itself be known and these are determined in separate experiments. A11 reactants for study were purified on a preparation vapor-phase c h r ~ m a t o g r a p h . ~The carbon- 14-labeled materials were synthesized by standard methods. * The data for each run were fitted to eq. 1 by means of a nonlinear least-squares code. All experimental f I ) ( a ) T h i s p a p e r i s based upon work performed a t Oak Ridge K a t i o n a l L a b o r a t o r y , which is o p e r a t e d by Union C a r b i d e C o r p o r a t i o n f o r t h e Atomic E n e r g y C o m m i s s i o n ; ( b ) O a k Ridge I n s t i t u t e o f Nuclear S t u d i e s R e s e a r c h P a r t i c i p a n t f r o m S w e e t Briar College i n S w e e t Briar. V a . , O c t o b e r , 1900April, IYO1 ( 2 ) V J. S h i n e r , 7 e f r a h e d r o n , 5 , 213 ( l Y 5 9 ) ; V. J S h i n e r , el a i . , A n n S Y . Acad Sci., 84, 583 i1YI;O). (9) A . S t r e i t w i e s e r , J r , ibid , 84, 570 (19FO) ( 4 ) I.. S Bartell, Tetrahedron Letters. 13 ( 1 9 0 0 ) , J . A m . Chem Sac., 83, 35(i7 ( 1 9 0 1 ) . ( 5 ) E A. Halevi, e l a i . , J . C h e m . SOL, 630 (1900), 39.1, 1907, 197-1 (19.59); Telrahedron, 1, 174 (1957). (6) V . F. R a a e n , A K Tsiomis. a n d C. J . Collins, J . A m . C h e m . Soc.. 82, 5502 (19liO). (7) A Burrell K r o m o - T o g M o d e l K - 1 , fitted w i t h a 0 5-in. c o l u m n packed with Apiezon-L s u p p o r t e d on K r o m a t - F - 1 3 , w a s used. (8) See t h e E x p e r i m e n t a l section f o r details ( 9 ) We a r e i n d e b t e d t o Dr M. H . Lietzke of t h i s L a b o r a t o r y f o r w r i t i n g t h e c o d e for use with t h e I B M 7090 c o m p u t e r . E q u a t i o n 1 is t h e exponential f o r m c,f t h e e q u a t i o n derived b y A M Downes, Aurlvalran J Sci Research, S A ,
=
k*/ka
Mixture
1
PhCOCH3h
0 949 i 0 002
2
PhCOCH3"
1 0088 i
0004
3
PhCOCHz*
1 0038
+
0003
4
PhkOCDsb
0941 i
001
5
PhCOCH3/PhCOCD3
847 i
003
6
PhCOCH,/PhCOCD3 CH3
915 ==!
002
7
P~I~OL-CH~~
951
001
*
*
*
*
~
CH3 CH3 8
PhCOtC-CH3* ~
CH3
9
PhCOC-CD3:PhCOC-CH1
1 0041 f 1 0020 Z k 1 002;
0007' 0009'' 000Y
1 046 f
(3015
I
*
CD3
CH3
10
PhCOCH2CH3'
0.943 =t . 002
11
PhCOCD*CH3*
0.943 i
12
PhCOCD2CH3/PhCOCH2CH3
1 U60 i .0(11
*
*
*
,
004
13 PhCOCH2CU3'/PhCOCHzCH3 0.9952 i 0006 Ratio of specific rate constants for carbon-14-labeled ( k * ) and unlabeled ( k ) species. These values are corrected for mole fraction of each species present. XI1 reactions were carried out under conditions of proved irreversibility. Only carbon-14labeled and unlabeled species present. Data of ref. 6. 'iSignificance doubtful. e The insignificant contribution of t h e terminal carbon-14 has been neglected 521 (1932). See also C J . Collins a n d M . H. I i e t z k e , J A m C'hern So' , 81, ,5379 (19.59). A l e a s t - s q u a r e s fit t o D o w n e s ' linear e q u a t i o n g a v e i d e n tical results with t h o s e r e p o r t e d i n T a b l e I T h e e r v r ( 0 ) i n k*/k w a s obtained a s u = d / z P / ( n - %)b,l Zvs = s u m of s q u a r e s of t h e residuals of fit = n u m b e r of d a t a points
n b,,
-
I , ] - e l e m e n t o f t h e matrix (X'X1-1, where X = t h e m a t r i x uf t h e partial derivatives with respect t u t h e p a r a m e t e r s
3498
V. F. RAAEN,T. K. DUNHAM, D. D. THOMPSON, AND C. J. COLLINS
Vol. h5
t * ° 0 * * 1.80
L
4.015L r
I
4.040
1.60
4.005
1.40
$ = 1.0038 i ,0003 (Run No.3 )
/ /
1.20
I
1.00
0.80
k
F
r
I
1 0.2
0
1 0.4
Fig 1 -Differential
f.
I
I
0.6
0.8
1.0
plots for runs 1, 5, 6, and 9.
can be caiculated by two completely separate and independent methods, the results being identical within f 2 X the estimated error
(iz), :i::
=
=
1 1 1 9 f 0005 (from runs 1 and 5,
0.990
t Fig 2 -Differential
plots for runs 3 and 13
ments demonstrated t h a t acetophenone forms its 2,4dinitrophenylhydrazone about 207, more rapidly = 1 104 5 0 002 (from runs 2 and 6' than m-nitroacetophenone, and a t about one-half to oneTable I ) third the rate a t which p-methoxyacetophenone undergoes reaction. Secondly, i t was also demonstrated t h a t The deuterium isotope effects ( k o /kH) calculated from acetophenone reacts approximately two times faster Table I are listed in Table 11. The data for runs 1, than propiophenone and about forty times faster than 5 , A, and 9 are plotted in Fig. 1, and the data for runs 3 phenyl t-butyl ketone. I t thus seems an inescapable and 13 are given in Fig. 2. These plots are typical and conclusion t h a t steric factors are more important during demonstrate the value of the differential method. these reactions than electron-donating or electronFigure 2 illustrates that even the very small isotope withdrawing substituent effects. Thirdly, substitution effects reported in Table I are meaningful. of deuterium for hydrogen is said to favor inductive TABLE I1 electron release2 and to hinder hyperconjugative electron release.*s3 Since both I and I1 react faster SUMMARY OF h j k ISOTOPE ~ EFFECTS I N THE CONVERSION OF KETONES1-11. TO THEIR ~ , ~ - D I S I T R O P H E N Y L H Y D R A Z O Nthan E S their undeuterated partners, and since hydrogen hyperconjugation should be unimportant during the Reference run No Compound kD/kH (Table I ) reaction of 11, i t appears t h a t hydrogen hyperconjugation cannot be involved during reaction of I , provided 1 PhCOCD;, ( I ) 1.119 f 0 005 1 and 5 we assume t h a t the same factor is responsible, in both 2 PhCOCDi(1) 1 . 1 0 4 f 002 2 and 6 compounds, for the acceleration of rate. Finally, i t is CH, difficult to reconcile the result for compound IV with 3 PhCOC-CDa (11) 1.046 f ,0015 9 the other data of Table I1 on the basis of hyperconjugative or inductive effects. It is, of course, possible CD:, t h a t severe structural changes can alter the mechanism 4 PhCOCD2CH3(111) 1 . 1 2 4 f ,005 10, 11, and 12 by changing the rate-determining step, and this point 5 PhCOCHzCDa (IV) 0.9952 f .0006 1.7 needs further investigation. I t has not yet been Given in Chart I is a scheme outlining some reactions established also, whether there must be just one underwhich are probable during formation of the 2,4-dilying cause for the isotope effects reported in runs 1-4 nitrophenylhydrazone of acetophenone. l o I n addition of Table 11. to these reactions, base attack on the free ketone and If we assume, however, t h a t the isotope effects given the repression of base concentration b y hydrogen ion in Table I1 have a common cause, and further that there must also be considered.1° From our data it is not is no change in mechanism with the structural changes possible to state with certainty which of these reactions in the reactants, then all of the results of Table I 1 can is rate-determining under the conditions employed. be accommodated if the rate-determining step in these The following facts, however, allow some empirical reactions is the attack by base on the conjugate acid conclusions to be drawn. First, competitive experiof the ketone (step 2 , Chart I ) . The increased rate owing to deuterium substitution (compounds I , I I (101 W P J e n c k s , el ai , J A m Chcm. Sor , 8 1 , 475 (19.59). 82, 1773, 1778 I!lliO) and 111) is then explained as a result of decreased steric -
5
*
"085 0 915 f 0 Ooo4 002
Table I )
SECONDARY ISOTOPE EFFECTSOF DEUTERIUM
Nov. 5 , 1963 CHARTI Ph
I @C-OH I CD,
RNHNHz
W
0
Ph 0 1 RNHNH2C-OH I CD3
&
0
Ph I @ RNHNHC-OHz I CD3
Ph RNHN=C'
'CD,
crowding in the transition state for step 2 . T h e lack of rate acceleration exhibited by w-trideuteriopropiophenone (IV) could be a conformational effect, since there is no possible conformation which can be assumed by I1 in which a methyl group does not interfere with the entering group, whereas compound IV can assume two conformations which interfere no more than acetophenone itself. We are unable to explain a t this time the two, small, secondary isotope effects of carbon-14 (runs 2 and 3, Table I). One further point is worthy of mention. A common procedure in determining isotope effects by the method of competing reactions involves the accumulation of the first 3 to 6% of reaction product, followed by a comparison of the isotopic content of the accumulated product with t h a t of initial reactant." We have noticed during several experiments t h a t the first few per cent of reaction product often exhibit quite anomalous isotopic contents when compared with isotopic contents of small aliquots removed a t intervals during the entire course of the reaction. One typical example is given in Fig. 3. These data indicate the possibility of serious error in the evaluation and interpretation of isotope effects which have been determined solely on the basis of the isotopic content of the initial fraction of reaction product. These errors are often quite duplicable even with reactants which have been prepared and purified separately,12 and can be misleading not only with respect to the magnitude but also can indicate an incorrect direction of the isotope effect. Experimental Materials.-Ketones I and I11 were prepared through the base-catalyzed exchange between the parent ketones and DeO. Ketone I1 (also labeled with carbon-14) was prepared from hexadeuterioacetone through reaction with methyl-C14-magnesium iodide t o hexade~terio-tert-butyl-(methyl-C~~) alcohol, which was converted t o the chloride. The lert-butyl chloride was diluted (11 : 1 ) with unlabeled tert-butyl chloride, and thence converted to the Grignard reagent whose reaction with benzo(11) See. f o r example, C. G Swain a n d E R T h o r n t o n , J . Org. C h e w . . 26, 4808 (1961). (12) Prof. J. F. E a s t h a m of t h e University of Tennessee i n f o r m s us t h a t h e h a s observed t h e same phenomenon d u r i n g t h e application of t h e differential m e t h o d t o a n evaluation of t h e Sa2/Sas isotope e f f e c t in t h e reaction of ~;ulfur-35-labeled thiophenoxide ion with 2,4-dinitrochlorobenzenet o yield phenyl dinitrophenyl t h i o e t h e r .
3459
