sacss'mav DEMERIUM [SOTOPE EFFECTS :N THE SOLVOLYS!S 0F momma-30 , -2,2-_¢_1_2 AND 33,313 CHLOREDES Thesis for the Degree of M. S. MICHIGAN STATE UNIVERSITY UAN GEN KANG 1969 THESIS LIBRARY Michigan State University ABSTRACT SECONDARY DEUTERIUM ISOTOPE EFFECTS IN THE SOLVOLYSIS op PROPIONYL-do, -2,2-g AND -3,3,3-g3 CHLORIDES BY Uan Gen Kang The rates of solvolysis of propionyl-d -2,2-d2 0’ and -3,3,3-d chlorides were measured in 75%, 80% and 85% 3 acetone-water and different temperatures. The observed B-isotope effects are consistent with a dual mechanisn,i;g; simultaneous hydrolysis by both fimiting and nucleophilic mechanisms. For example, as the water concentration and temperature increase, the contribu- tion of limiting mechanism gradually increases to lead to greater isotOpe effects, such as: kH/kD(80%) = 0.989 t .007(-30.58°), 1.008 i .005(-10.56°); kH/kD(85%) = 0.961 t .004(-26.l7°), and kH/kD(7S%) = 1.008 t .007(-25.55°). The finding that the B-isotope effects are near one has been taken as an indication that the hydrolysis of propionyl chloride proceeds predominantly by a nucleophilic mechanism. Leffek and his co-workers (1) found that the tem- perature insensitive B-isotope effects in the hydrolysis of isopropyl esters were the result of AAH+ being zero, with Uan Gen Kang AAS* apparently controlling them. They have suggested that the observed isotope effects are due to the rotatinal bar- rier difference in the ground state between methyl- and methyl-£3. Halevi (2) has explained their results in terms of differences in the solvation of the protium compound and its deuterium analog. We find that the y-isotope effects, in contrast to the B-isotOpe effects, in the solvolysis of propionly chlor- ide are also temperature insensitive. For example, kH/kD(80%) kH/kD(85%) 0.973 i.005(-20.47°). This temperature insensitivity, how- 0.976 t .005(-25.41°), 0.976 t .010(-30.58°). 0.977 i .007(—10.57°), 0.976 t .005(-15.54°), ever, does not appear to arise from differences in the en- trOpies of activation. The AAS+ contribution to the isotope effect is zero in 80% and 85% acetone-water solutions. The temperature insensitive isotope effects appear to be solely controlled by differences in the enthalpies of activation. Thus, these results may be taken as support of the ideas of Wolfsberg and Stern (3), who have suggested that temperature independent isotOpe effects may result from compensating changes in force constants. (1)K. T. Leffek, R. E. Robertson and S. E. Sugamori, Can. J. Chem., 39, 1989 (1961). (2)E. A. Halevi, "Secondary IsotOpe Effects," Progress in Physical Organic Chemistry, Vol. 1, S. G. Cohen, A. treit- wieser, and R. W. Taft, ed., John Wiley and Sons, New York, 1963. (3)M. Wolfsberg and M. J. Stern, Pure Appl. Chem., i, 225, 325 (1964). SECONDARY DEUTERIUM ISOTOPE EFFECTS IN THE SOLVOLYSIS OF PROPIONYL-do, -3,3,3-51_3 CHLORIDES -2,2-g2 AND By Uan Gen Kang A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry 1969 c... (a #66 347120 To my wife Jung Ja ACKNOWLEDGMENTS The author wishes to express his sincere apprecia- tion to Professor Gerasimos J. Karabatsos for his guidance and encouragement throughout this research. The financial support provided by the National Science Foundation, Petroleum Research Fund and the Department of Chemistry, Michigan State University, is gratefully acknowledged. iii TABLE OF CONTENTS LIST OF TABLES . . . . . . . . . . . . . . . . . LIST OF FIGURES INTRODUCTION . . . . . . . . . . . . . . . . . . EXPERIMENTAL . . . . . . . . . . . . . . . . . . Kinetics . Preparation of Solvents . . . . . . Conductance Apparatus . . . . . . . . . . Conductance Cell . . . . . . . . . . Measurement of Time . . . . . . . . . . . Constant Temperature Bath . . . . Calibration of the Beckmann Thermometer Rate Determinations . . . . . . . Treatment of Data . . . Preparation of Propionyl Chlorides RESULTS AND DISCUSSION . . . . . . Mechanism of Acid Chloride Solvolysis . The Effect of Solvent Changes on Mechanism . The Effect of Temperature Changes on Mechanism . . . . . . . . . . . . . . . IsotOpe Effects and Mechanism . . . . . IsotOpe Effects as Criteria of Mechanism . EntrOpy of Activation and Mechanism The Origin of the Isotope Effects REFERENCES . . . . . . . . . . . . . iv Page vii 14 14 14 15 15 15 16 17 17 21 22 22 23 31 34 34 37 38 46 Table 10. 11. LIST OF TABLES Rates and isotOpe effects for l-phenylethyl chlorides corrected to 50% ethanol, 25°C Deuterium isotope effects on acidity Temperature dependence of the B-deuterium isotope effect for the solvolysis of isoprOpyl compounds in water A "temperature independent" secondary hydro- gen isotope effect Relative contribution by unimolecular and bimolecular mechanism to the rate of the benzoyl chloride hydrolysis Rates of solvolysis of prOpionyl- d0, -2 ,2- d2 and -3 ,3 3- d3 chloride in 75% acetone- water . . . . . . . . . . . . . . Rates of solvolysis of propionyl- d0, -2 ,2 <12 and -3 ,3 3- -d3 chloride in 80% acetone- water Rates of solvolysis of prOpiony1-d -2 ,2 d2 and 3, 3, 3- d3 chloride in 85% a etone- water . . . . . . . . . . . . . . . Relative contributionslnrunimolecular (k1) and by bimolecular (k ) mechanism to the rate of the benzoyl cfiloride hydrolysis Isotope effects, k H/k for the solvolysis of d- deuterated falByl. esters (RX) in water Isotope effects, kH/kD, for the solvolysis of B- -deuterated alkyl esters (RX) in water . . . . . . . . . . . Page 11 13 20 24 25 27 33 35 35 Table Page 12. Temperature and solvent dependence of the B- and y- isotope effects in the hydroly— sis of propionyl- d0, ~2J-d_2 and -3,3,Ld_3 chlorides . . . . . . . . . . . . . . . 36 13. Entropies of activation for limiting and nucleophilic solvolyses in aqueous- acetone at 50°C j. . . . . . . . . . . . . . 39 14. Transition state activation parameters for the hydrolysis of propionyl- d0’ -2, 2- .-d2 3, 3 ,3 -d3 chlorides . . . . . . . 40 15. y-isotOpe effects for the hydrolysis in water of n-prOpyl compounds . . . . . . . . 42 16. Temperature and solvent dependence of the y-isotOpe effect in the hydrolysis of propionyl-3,3,Ld3 chloride . . . . . . . . 44 17. Activation parameters determined from the temperature dependence of the B- and y- isotope effect of pr0pionyl- d9, -2 ,2 <12 and 3, 3 ,3 d chloride hydroly51 _3 45 vi LIST OF FIGURES Figure 1. The Hammett relations for p-substituted benzoyl chloride in 5% water and 95% (v/v) acetone . . . . . . . 2. The Hammett relations for pjsubstituted benzoyl chloride in 50% water and 50% (v/v) acetone . . . . . . . . . . . 3. Observed reaction rate constants vs. water concentration for the hyd?olysis of benzoyl chloride vii Page 29 29 32 INTRODUCTION Secondary deuterium isotope effects on the rates of reactions have been explained in terms of hyperconjugation, nonbonded interactions and inductive effects (1). In an effort to prove the importance of hypercon- jugation, which has been controversial (2), Shiner and his group have investigated several solvolytic reactions. For example, they found (3) kH/kD for the solvolysis of I to be 1.092 t .001. Since the triple bond "insulates" the non- bonded interactions between the reaction center and the site of isotOpic substitution, it is reasonable to explain the isotOpe effect in terms of hyperconjugation. CH3 CHS—(II—C _ C—R R = CH3 or CD3 c1: 1 If the demand for hyperconjugation in the transi- tion state is partly responsible for secondary isotope effects, then the B-isotope effect should decrease by re- ducing this demand. The results of Shiner and his coworkers (1a) on the solvolysis rates of a series of substituted l-phenylethyl halides confirm this prediction (Table 1). A11 a-isotope effects given in Table 1 are within 1.003 of 1 Table l.--Rates and isotope effects for l-phenylethyl chlorides corrected to 50% ethanol, 25° (la). Substituent Relative Rate kH/kD(a) kH/kD(B) p-Methoxy 11.4 - 7.6 x 105 1.157 1.113 p-Phenoxy 3.0 - 2.0 x 103 1.157 1.164 prethyl 59.0 1.157 1.200 p-Fluoro 3.0 1.152 1.211 m-Methyl 2.0 1.151 1.222 None 1.0 1.153 1.224 m-Bromo 6.6 x 10‘3 1.133 1.221 p-Nitro 2.9 x 10'5 1.098 1.151 1.154, except those of the m-bromo (kH/kD = 1.133) and p-nitro (kH/kD = 1.098) compounds. The large a-isotOpe effect (kH/kD = 1.154) is strong evidence that the mecha- nism of the reaction is limiting. The smaller a-isotope effects for the m-bromo and p-nitro compounds indicate some nucleophilic participation in the transition state. The observed B-isotope effects show that the reduction of the demand for hyperconjugation, whether due to electron- releasing para substituents (pfmethoxy and p-phenoxy), or to nucleOphilic participation in the transition state (m-bromo and p-nitro), decreases the B-isotOpe effect. Rate studies on the acetolysis of 2 (kH/kD = 1.011) by Lewis and coworkers (4) and on the solvolysis of 3 (kH/kD = 1.04) by Shiner and Verbanic (5) offer further convincing evidence for the importance of hyperconjugation. The isotOpe effect caused by deuterium substitution at such remote position is most likely due to hyperconjugation. T T R C—CH R C .l3 ”I CK CE 2 .3. R = CH3 or CD3 Nuclear quadrupole COUPIing constant studies (6), nuclear magnetic resonance chemical shift studies (7) and dipole moment studies (8) have established that deuterium is more electropositive than hydrogen. Halevi and his co- workers (9) and Streitwieser and Klein (10) have studied the effect of deuterium substitution on acid strength (Table 2) and have interpreted their results in terms of the differences in the inductive effect of deuterium and hydrogen. In all cases deuteration decreases the acid strength. On the other hand, as expected, deuteration in- creases the basicity (9b) of benzyl-a,a-d2-amine (KH/KD = 1.13). Table 2.--Deuterium isotOpe effects on acidity. AC1d KH/KD Reference DCOOH 1.035 1 .002 11 CDSCOOH 1.032 1 .002 10 (CD3)3CCOOH 1.042 1 .003 10 C6D5COOH 1.024 1 .006 10 C6H5CD2COOH 1.12 i .02 9 Lewis and his coworkers (4b) have interpreted the inverse isotope effect (kH/kD 0.988 t .005) observed in the solvolysis of 4 in terms of more effective stabiliza- tion of the transition state by the ring methyl—d3 group, as a result of its being a better electron releasing group than the methyl. H | 3 ‘f 02 5 R = CH3 or CD3 Streitwieser and Klein's (12) solvolytic studies ofpa support further the notion that deuterium is a better electron donor than hydrogen. Indeed, deuteration on the ring accelerates the reaction. However, the relative mag- nitude of acceleration per deuterium (23332 1.9%, maaa 1.5%, and 2213 1.0%) is difficult to explain. The magnitude from the mgta position relative to that from the aaaaa position is as expected, but that from the EEEE position is quite low. We might have expected a larger value from the £212 position, because of the greater positive charge at the E233 than at the maaa position. This unusual positional effect has been dichssed and working hypotheses have been given (12). Bartell (13) has explained secondary isotope ef- fects in terms of nonbonded interactions. It is intuitively very appealing to explain all secondary isotOpe effects by the following simple argument: The amplitudes of vibration of hydrogen atoms are larger than those of the deuterium atoms. Since the tetrahedral ground state is more crowded than the trigonal carbonium ion in the transition state, there is greater relief of nonbonded interactions for the hydrogen than for the deuterium compound in the activation process. The net effect is, therefore, faster reaction of the hydrogen compound. Bartell's results calculated on the basis of his model are sensitive to the assumed molecular structures. The order of magnitude, however, of the isotope effects is comparable with the experimental values (13). Mislow and coworkers (14) and Melander and Carter (15) have shown that the effective steric requirement for deuterium is less than that for hydrogen in the rate of racemization of compounds 9 and 1. Since the racemizations are purely conformational changes, the observed isotOpe ef- fects must be steric in origin. kD/kH = 1.13 kD/kH = 1.19 9 |\1 Brown and his coworkers (1c,16) have studied the reactions of methyl-aS-pyridines with Lewis acids and alkyl iodides. They found small or no isotope effects with the maaa and EEEE methyl-a3 substituted pyridines, but inverse isotOpe effects with the aaaaa substituted ones. The in- verse isotope effects increased as the steric requirement of the alkyl iodide and the Lewis acid became larger. For example, the isotope effects in the reaction of Z-methyl- a3-pyridine are kH/kD = 0.97 with methyl iodide, kH/kD = 0.96 with ethyl iodide, and kH/kD = 0.935 with iSOpropyl iodide. For 2,6-dimethyl-a6-pyridine a kH/kD of 0.92 was observed with boron trifluoride. On the other hand, the much smaller boron hydride (BH3) gave no isotope effect. These results are consistent with the view that the secondary deuterium isotOpe effects are caused mainly by nonbonded interactions. There seems to be little question that hypercon- jugation, inductive effects and nonbonded interactions all contribute to secondary deuterium isotope effects. In gen- eral, if in a system effective hyperconjugation is possible, it dominates over the inductive effect. For example, the solvolysis of t-butyl-a9 chloride in water gives a large normal isotope effect of 2.387, which is consistent with the predictions of nonbonded interactions and hyperconjuga- tion, but contrary to the prediction of the inductive effect. Karabatsos and his coworkers (17) has examined the question of the relative contributions of hyperconjugation and nonbonded interactions to secondary deuterium isotope effects. For the 1,8-disubstituted naphthalene system 8, in which there are strong steric interactions but no formal hyperconjugation between the site of isotopic substitution and the reaction center, the steric isotope effects calcu- lated by Bartell's method were generally higher than the experimental effects. However, where hyperconjugation is possible, E;E; acetyl chloride and a-butyl—a9 chloride, the calculated steric isotope effects were less than 10% of the experimental isotOpe effects. The authors concluded that in cases where hyperconjugation is possible the isotope effect is primarily due to hyperconjugation. R X 00 R: 8 D, CD3 CHZCK, 0002, (3020113 X l Secondary isotope effects, whether interpreted in terms of hyperconjugation, inductive effects or nonbonded interactions, arise from changes in the force constants be- tween reactants and transition states. Wolfsberg and Stern (18) have calculated isotope effects from molecular geome- tries, atomic masses, and force constants. Their results agree reasonably well with the magnitude of the experimental values. In general, lower force constants in the transition state than in the reactant cause normal isotope effects, kH/kD > 1, while higher force constants in the transition state cause inverse isotope effects, kH/kD < 1. If force constant changes determine secondary isotope effects, then the temperature dependence of these effects should depend on the differences in the correspond- ing enthalpies of activation (AAHI), not on those in the entrOpies of activation (AAS+). The relationship between the temperature dependence of isotOpe effects on the en- thalpies (AAHI) and entropies of activation (AASI) can be derived from either the Arrhenius (eq. 1) or the transition state theory (eq. 2). 1n(kH/kD) -AEa/RT +’1n AH/AD (1) - AAH+/RT + AAS+/R (2) 1n(kH/kD) Hakka and his coworkers (19) have shown that in the solvolysis of a—butyl chloride and its 99 analog the enthalpy of activation difference (AAHI) is approximately equal to that of the free energy (AAF+), with no apparent contribution from the entrOpy of activation difference (AAS+). This result supports the assumption that the force constant changes are the origin of the isotope effect. Shiner and Verbanic's results (5) on the solvolysis of pfmethyl-a3-benzhydryl chlorides (AAH+ = -318 cal/mole, AAS+ = -1.03 e.u.), Shiner's studies (20) on the solvoly- sis of 2,3-dimethyl-3-a-Z—chlorobutane (AAHI = -580 cal/mole, AASI = -l.46 e.u.) and Lewis and Coppinger's results (43) on the solvolysis of p-methyl-aS-a-phenyl chloride 10 (AAH+ = 465 cal/mole, AASI = -l.15 e.u.) show that the isotope effect depends both on AAH+ and AASI. Leffek and his co—workers (21) studied the solvoly- sis of isopropyl halides and sulfonates at a single tempera- ture. Their results could be explained by either hyper- conjugation or nonbonded interactions. But their results (22) on the temperature dependence of these isotope effects were very unusual. The AAH+ was approximately zero and the temperature independent isotope effect was due entirely to AA8+. Their results are summarized in Table 3. Three ex- planations have been given for the temperature independent isotope effect of this system. (a) Leffek and his co-workers have suggested that the observed isotOpe effect is due to the rotational bar- rier difference in the ground state between methyl and methyl-513 because of the larger steric requirement for the protium analog. In the transition state the barrier to in- ternal rotation is reduced considerably. Thus, the net effect is favorable acceleration of the protium analog. The negligible contribution to the isotope effect from AAH+ was explained by a cancellation of an effect from the rotational barrier difference and the one from the zero- point energy difference. (b) Halevi (lb) has explained the isotope effect due entirely to AAS+ by differences in the solvation of the protium compound and its deuterium analog. He assumed 11 Table 3.--Temperature dependence of the B-deuterium isotope effect for the solvolysis of isopropyl compounds in water (22). ISOprOpyl Isopropyl Isopropyl Methanesulfonate Toluenesulfonate Bromide Temp. kH/kD Temp. kH/kD Temp. kH/kD 30.001 1.547 30.017 1.545 69.994 1.324 25.000 1.551 30.001 1.548 69.993 1.317 20.002 1.551 25.005 1.539 65.002 1.322 12.514 1.547 24.999 1.542 60.000 1.318 12.501 1.540 20.005 1.543 59.933 1.315 5.000 1.555 15.003 1.545 55.005 1.313 10.003 1.537 40.005 1.312 6.008 1.542 40.005 1.317 Compound (AAHI cal/mole) (AASI e.u.) Isopropyl Methanesulfonate 7 i 28 -0.84 i 0.1 ISOprOpyl p-toluenesulfonate -21 1 14 -0.93 i 0.05 -35 i 15 -0.65 i 0.05 Isopropyl bromide 12 that charge dispersal is more effective in the deuterated compound, thus reducing the degree of solvation of the deuterio compound with respect to that of the protio com- pound. The more effective solvation of the protio compound reduces its AH+ with respect to that of the deuterio analog. But in this water solvolysis system, this solvation energy gain for the protio compound is counterbalanced by the energy loss in breaking the hydrogen bonds among the water molecules. Thus, the net effect is the entropy gain due to the breaking of the quasi-crystalline water structure. (c) Wolfsberg and Stern (18) have interpreted the temperature independent isotope effect by using force con- stant changes. They showed that it is possible to obtain large temperature independent isotope effects, if some force constants which give rise to small frequencies increase in the transition state, while others that give rise to large frequencies, such as stretching frequencies, decrease. The results of a model calculation are shown in Table 4. Whatever the real answer may be, it is clear that in order to define better the origin of secondary isotOpe effects, we need more experimental data, especially on the temperature and solvent dependence of these effects. The work described in this thesis deals with this problem in the solvolysis of propionyl chloride. 13 Table 4.--"Temperature independent" secondary hydrogen isotope effect. (CD3)2CHX ——————> [(CD3)2CD-----X]+a T(°K) kH/kD 100 1.4678 250 1.4088 280 1.4110 300 1.4130 320 1.4151 340 1.4170 360 1.4188 380 1.4200 3The following force constant changes were assumed: O fCH°1n CH3, 4.8 ——> 3.5 m1111dyne/A; f orsion’ 0.15 ——> 1.0 md-A and fHCC in CH3, 0.68 ——> 1.0 md- . One HCCC torsion coordinate was employed per methyl group. EXPERIMENTAL Kinetics Preparation of Solvents Conductivity Water.--Conductivity water was pre- pared by passing distilled water through a column filled with alternate layers of "Baker Analyzed" reagent Dowex léX8 anion exchange resin and "Baker Analyzed" reagent Dowex 50 W-X8 (cation exchange resin). The Dowex 1-X8 was cxnnverted to the hydroxide form by treating it with con- centrated potasium hydroxide solution and then washing it with.distilled water. The conductivity water prepared in 6 mho/cm. this way had a specific conductance of about 2 x 10' It was regularly checked by measuring the conductance be- fore preparation for mixed solvents. Conductivity Acetone.--The Conant-Kirner method (23) Was used to prepare conductivity acetone. Acetone (Fisher certified A-18), 1.52, was refluxed with 80 g. of potassium ~Permanganate and five pellets of potassium hydroxide for three hours. It was distilled as described by Papaioannou (17b). The acetone obtained in this way had a specific 8 Conductance less than 1 x 10' mho/cm. l4 15 Mixed Solvents.--Mixtures of acetone and water were prepared by weighing the water and acetone to the nearest 0.5g. with a Torbal balance as described by Evans (24). Conductance Apparatus The conductance was measured by means of a Wayne- Kerr Conductance bridge (model B 221, Wayne-Kerr Co. Ltd.) equipped with a Wayne-Kerr Autobalance Adaptor (model AA 221). Conductance Cell For the kinetic studies of the hydrolysis of the acid chlorides two cells were used; one of them was made of a 250 m1 Erlenmeyer flask and the other of a 500 m1 Erlenmeyer flask. The rest of the cell was the same as described by Papaioannou (17b). With the 250 ml cell one drop of acid chloride was used, whereas with the 500 ml cell two dr0ps of acid chloride were used. The obtained rate constants were essentially the same from both of them. The cells were stored with used reaction solvent at least 3 hr. before use to avoid adsorption of ions during a kine- .tic run. They were rinsed five times with conductance water and twice with conductance acetone before use. Measurement of Time A precision Scientific electronic digital timer (no. 69237, Precision Scientific Co.) accurate to 1/100th 16 of a minute was used. Constant Temperature Bath The bath used is described by Papaioannou (17b). A Beckman Differential Thermometer (Arthur H. Thomas Co.) was used to monitor the bath temperature. The bath was covered all around with Styroform so as to be insulated from room temperature changes. After immersing the cell, the inside of the bath was insulated from the outside with a Styroform cover fitting the cell very well. The tempera- ture control with this bath was better than 0.003° over a temperature range from -30° to -10°. The bath was equipped with a submersible magnetic stirrer (model 700, Henry Troemner, Inc.). Calibration of the Beckmann Thermometer The Beckmann differential thermometer was cali- brated by means of a platinum resistance thermometer (no.' 8163, Leads Northrup Co.) as described by Evans (24), and by means of a quartz thermometer (2801 A, Hewlett-Packard). The temperature sensing part of the quartz ther- ~mometer was cycled between temperature bath and water near room temperature until the ice-point reading became con- stant. Ten readings were taken from the quartz thermometer in °C 1a. the Beckmann Thermometer. The average of readings from the quartz thermometer was corrected against the 17 provided chart at each temperature and for the deviation from the ice point. The corrected temperature was equated with the average of the Beckmann differential thermometer readings, so that the Beckmann readings could be converted directly to centigrade. Rate Determination After the conductance cell was filled with solvent, about 200 ml for the small cell and about 400 ml for the large, it was immersed into the temperature bath and al- lowed to completely equilibrate for about one hour. The solvent conductance, which was generally less than 0.1 x 10'6 mho, was recorded. One or two drops of acid chloride were added, depending on whether the small or the large cell was used. At the same time, the timer was started and the solution was stirred at least for one minute. The ini- tial reading was taken when the capacitance had become fairly constant. Conductance readings, two per minute, were taken over the first three half-lives. The infinite value was obtained after 13 half-lives and exactly at the same time for all deuterated and undeuterated compounds. Treatment of Data The first order rate constants were determined by a least squares solution of the integrated first order rate expression. l8 ln(Cw - Ct) = -kt + 1n C00 COD = conductance at infinite time Ct = conductance at time t. Conductance was taken as directly proportional to ‘the concentration of hydrochloric acid formed. However, silight temperature independent deviations were observed in aJJl solvents. Since we are mainly interested in the rela- txive rate constants between deuterated and undeuterated acixi chlorides measured under the same conditions, the ob- .serwred slight deviations would not lead to appreciable error. A rate constant obtained from a typical kinetic run.:is shown in Table 5. The reported average rates are the Inean of at least three independent runs, which were al- terruited usually in the order a0, a2 and as. The uncertainty inditzated is the standard error 0. , _ 2 1/2 ° = “(Xi ‘ *9/11] 1 xi = observed rate R. = mean. 1 Rate ratios, kH/kD, are the ratios of the corres- ponding means. The uncertainty indicated is the standard e . . . rIWDIT obta1ned from the folloW1ng relation: 19 Table 5.--Run number 228, propionyl chloride, 75% acetone/ water, 253°K. Conductance at infinity = 6.56800- 004. Time Conductance Calculated k R 3.02 .79800—004 4.72148-003 -4.12048-003 3.55 .18800-004 4.72901-003 -3.24000-003 4.03 .49800-004 4.74289-003 -3.21792-004 4.56 .78800-004 4.74330-003 -2.52899-004 5.07 .03200-004 4.75082-003 2.00555-003 5.55 .22800-004 4.74988-003 1.88390-003 6.02 .39800-004 4.75464-003 3.76262-003 6.54 .55800-004 4.75135-003 2.79622-003 7.04 .69200-004 4.75087-003 2.80900-003 7.55 .81000-004 4.74934-003 2.31842-003 8.04 .90800-004 4.74688-003 1.28176-003 8.55 .99600-004 4.74268-003 -7.90676-004 9.06 .07200-004 4.73797-003 -3.40089-003 9.55 .13600-004 4.73397-003 -4.73076-003 Rate Constant = 4.74422-003 Std. Dev. of k1: 6.08859—006 20 2 1/2 0' D . (1H kH/kD EH The average rate constants at the different tempera- tures were used to determine the thermodynamic activation parameters AS+ and AHI from the following equation: logc‘E/T) = 7%}?- (l/T) + z—éngfi + 108(k/h) where k is the average rate constant, T is the absolute temperature, R is the gas constant, k is Boltzmann's con- stant and h is Plank's constant. Two computer programs were used to calculate the activation parameters; one by an iterative least square method (Acteng Program), in which the deviations from the "best" line were weighed, and the other by a single least squares solution (Active Program) of log(E/T) 1a. 1/T. The isotope effects (kH/kD) obtained at different temperatures were used to calculate the dif- ference in enthalpy (AAHI) and entropy (AASI) of activation from the following equation and by a single least squares solution of 1n kH/kD 1a. 1/T by the Program Hand: _ AAH+ AASI ”(kn/kn) " "ar— * ‘9'“ All manual calculations were performed on a Wang calculator (Model 320 K). 21 Preparation of Propionyl Chlorides All propionyl chlorides were prepared by the method of Brown (25). To a round-bottomed flask equipped with a vigeaux fractionating column and standard distillation head was added 5 g. of prOpionic acid and 40 g. of benzoyl chloride. The reaction mixture was heated very rapidly so that the propionyl chloride could be distilled as soon as possible into a receiver which was cooled with a dry ice- acetone mixture. The acid chloride boiled somewhat low due to dissolved hydrochloric acid. The distillate was re- fluxed for 30 minutes to degas the hydrochloric acid. The distillation was repeated twice. Overall yield was about 70%. The purity of the propionyl chloride was checked by comparison of its infrared spectrum with that appearing in the Sadtler Index (26) and by nmr. Nmr was used to de- tect the presence of benzoyl chloride and the extent of the deuteration. Both deuterated compounds were nmr pure. The extent of deuteration of the -3,3,3-a chloride was 3 assumed to be the same as that of its precursor propionic- 3,3,3-_d_3 acid (98%). The propionyl chlorides were stored in glass vials with polyethylene st0ppers which were sealed with "parafilm" plastic. They were kept inside a desiccator. RESULTS AND DISCUSSION Mechanism of Acid Chloride Solvolysis Acid chlorides may react with nucleophiles either by a limiting (Snl), or/and by a nuchleophilic mechanism, depending on the reaction conditions. The nucleophilic. mehcanism may be either an SnZ or an addition-elimination (AE) mechanism. The AE mechanism is favored over the Sn2, because it can explain the observed carbonyl oxygen exchange with the oxygen of the solvent water in the hydrolysis reaction (27). In highly polar solvents and high temperatures the limiting mechanism, eq. 3, tends to predominate. O R.D.S. + fast /0 IL _ / On the other hand, in non-polar solvents and low tempera- tures,the nuchleophilic mechanism, eq. 4, tends to predominate. o (INI || R.D.S. H 0 R—C—C£< 2 > R—C—CZ fa5t> R—CBr>H>CH3<10-3sec-1 ‘IE><10-35ec-1 'kH/k ATSEP° 222 d0 4.690 4.706 1.016 -20.55 225 dO 4.683 228 do 4.744 223 d2 4.647 4.655 1.019 1.011 1.005 -20.55 226 d2 4.619 229 d2 4.698 224 d3 4.892 -4.916 1.017 0.957 t.005 -20.55 227 d3 4.898 230 E3 4.957 206 d0 2.683 2.646 1.012 —25.55 210 d0 2.681 215 ‘dO 2.612 217 d0 2.607 219 d0 2.672 220 dO 2.648 221 do 2.616 207 d2 2.613 2.626 1.015 1.008 i.007 -25.55 211 d2 2.687 213 d2 2.628 216 d2 2.590 218 d2 2.610 208 d3 2.755 2.758 1.004 0.960 t.005 “35353 212 d3 2.767 214 as 2.752 189 d0 1.415 1.404 1.005 -30.58 191 d0 1.394 194 do 1.404. 190 d2 1.414 1.422 1.004 0.988 1.004 -30.58 192 d2 1.429 196 d2 1.422 193 d3 1.502 1.495 1.004 0.939 1.004 -30.58 >195 d3 1.486 197 d3 1.505 198 d 1.490 25 Table 7.--Rates of solvolysis of propionyl -d , -2,2-d2 and -3,3,3-d3 chlorides in 80% acetgne-wateF. fig? IsotOpe k><.10-35ec”1 'EXIO-Ssec'1 kH/kD ngp. 152 dO 6.433 6.4361:.021 -10.56 153 d0 6.544 154 do 6.385 155 d0 6.414 164 d0 6.611 166 dO 6.162 168 dO 6.452 170 d0 6.365 173 do 6.473 174 d0 6.451 175 d0 6.437 177 d0 6.501 157 d2 6.275 6.381:1.022 l.088:t.005 -10.56 167 dz 6.412 169 d2 6.439 171 d2 6.413 172 d2 6 366 176 d2 6.384 113 d0 3.906 3.908:t.023 -15.54 116 d0 3.976 119 d0 3.818 121 do 3.934 123 dO 3.906 112 d2 3.856 3.904:1.016 1.001:1.007 -15.54 115 d2 3.927 118 d2 3.888 120 d2 3 900 120 d2 3.883 122 d2 3.978 111 d3 3.966 3.981 1.007 0.982:1.006 -15.54 114 d3 3.996 117 d3 3.983 102 d0 2.251 2.241:1.004 ~20.47 105 dO 2.237 108 d0 2.245 101 d2 2.217 2.239:1.012 l.001:1.007 -20.47 104 d2 2.240 106 d2 2.276 110 d2 2.223 100 d3 2.322 2.318:t.009 0.967 t.021 -20.47 103 d3 2.321 109 d 2.341 26 Table 7 (Continued) fig? IsotOpe k><10-3sec.1 EXIO'Ssec 1 kH/kD ngp. 41 d0 1.265 1.2483t.003 -25.41 42 d0 1.242 43 d0 1.261 47 d0 1.245 52 do 1.228 55 do 1.245 59 d0 1.249 62 d0 1.242 65 d0 1.257 68 do 1.244 44 d2 1.278 1.2625t.003 0.988it.010 -25.41 46 d2 1.261 50 d2 1.267 54 d2 1.254 58 d2 1.263 61 dz 1.254 64 d2 1.270 66 d2 1.253 48 (13 1.285 1.2782t.005 0.9762t.005 -25.41 49 d3 1.288 51 d3 1.276 53 d3 1.245 57 d3 1.280 60 d3 1.298 63 d3 1.281 65 d3 1.273 179 do 0.6681 0.6782t.004 -30.58 182 do 0.6687 184 do 0.6885 186 do 0.6912 188 do 0.6771 204 do 0.6727 180 d2 0.6823 0.685:t.003 0.989:t.007 -30.58 181 d2 0.6760 183 d2 0.6960 .185 d2 0.6858 187 d2 0.6950 202 9.2 0.6769 201 d3 0.6880 0-694zt.006 0.9761:.010 -30.58 203 d3 0.6850 205 d 0.7096 27 Table 8.--Rates of solvolysis of propionyl -g , -2,2-<_1_2 and -3,3,3-£1_3 chloride in 85% acetoRe-water. fig? Isotope kXIO-Ssec- EXIO'ssec 1 kH/kD T§$p° 138 d0 3.140 3.163i .006 -10.57 141 30 3.160 144 30 3.178 147 30 3.163 162 go 3.175 137 d2 3.254 3.2112t.012 0.985: .004 -10.57 140 32 3.200 143 32 3.126 146 32 3.175 156 32 3.218 158 32 3.245 159 32 3.257 160 32 3.204 161 32 3.225 163 E2 3.208 136 (13 3.321 3.237 .023 0.977 t.007 -10.57 139 as 3.213 142 33 3.165 145 33 3.249 148 ES 3.235 126 dO 1.924 1.927 .004 -15.54 128 30 1.935 130 30 1.913 132 ED 1.937 125 (12 1.942 1.971 .010 0.978 t.005 -15.54 127 32 1.972 129 32 1.999 131 §2 1.972 124 d3 1.969 1.975 .010 0.976 t.005 -15.54 '133 33 1.973 134 33 1.967 135 E3 1 993 89 d0 1.098 1.115 .005 -20.47 92 30 1.118 95 HO 1.120 98 H 1.124 Table 8 (Continued) 28 fig? IsotOpe kXIO-35ec Tc‘.><10"3$ec-1 kH/kD TSEP‘ 88 d2 1.053 1.120zt.020 0.9952t0.18 -20.47 91 32 1.140 94 32 1.141 97 g2 1.149 87 (13 1.134 1.146 t.003 0.9731t.005 -20.47 90 33 1.142 93 is 1.150 96 (13 1.155 99 {13 1.148 76 (10 0.5841 0.581 i .017 ’26-]? 79 30 0.5827 82 30 0.5818 86 go 0.5751 75 d2 0.6021 0.604 1.003 0.961 t.004 -26.17 78 32 0.6011 81 32 0.5997 84 32 0.6091 85 :12 0.6103 74 d3 0.5982 0.595 Ii.0.3 0.976It.039 -26.17 77 33 0.5914 80 33 0.5868 83 6 0.6050 29 Figure l.--The Hammett relations for .8 -substituted benzoyl chloridesin 5% water and 9 % (v/v) acetone.(29) 1.5 1.0 0.5 0 n I 1 I EJR—q£1 l l 1 -0.4 ' 0 7 ‘024' 0.8 Figure 2.-—The Hammett relations for R-substituted benzoyl chloridesin 50% water and 50% (v/V) acetone.(29) 30 amounts of o-nitroaniline, Gold and his co-workers (30) have shown that benzoyl chloride reacts by a nuchleOphilic mechanism in 80% acetone—20% water (w/w). However, it does react about 50% by a limiting mechanism in 50% acetone-50% water (w/w) solution. Bender and Chen (31) have studied the hydrolysis of p-substituted 2,6-dimethy1benzoy1 chlorides in 99% ace- tonitrile—1% water solvents. The neutral and acid-catalyzed hydrolyses of these compounds proceed by a limiting mecha- nism, as supported by a common ion effect, salt effect, the large negative Hammett p value correlated with 0+, and by no carbonyl oxygen exchange. In 95% dioxane-S% water sol- vent, which has a lower dielectric constant, Bunton and his co-workers (27) have found that the carbonyl oxygen of the mesitoyl chloride does exchange with water. This indicates that this sterically hindered acid chloride hydrolizes, at least partially, by an AB nucleOphilic mechanism. The tetrahedral intermediate was even more clearly demonstrated in the alkaline solvolysis of mesitoyl chloride (21). For example, in the presence of catalytic amounts of hydroxide ion, the order of the relative rate of p-substituted com- , pounds is the reverse of that of the acid or neutral hydroly- sis. It is now accelerated by electron-withdrawing groups and retarded by electron-donating groups. The Hammett cor- relation has a p = 1.2 (31). 31 The Effect of Temperature Change on MeChanism Kelly and Watson (32) have studied the hydrolysis of benzoyl chloride at high water concentrations in acetone- water solution at various temperatures. Their results, along with those of other investigators, are shown in Figure 3. The results shown in Figure 3 are consistent with a dual mechanism. In low water concentrations, benzoyl chloride hydrolizes by a nucleophilic mechanism. As the ionizing power of the solvent increases, the mechanism shifts from a nucleOphilic to a limiting, as shown by the changes in the $10pe of the curves in Figure 3. At 0° and 10 mole/liter [H20] the mechanism has partly changed from nucleophilic to limiting. By using the dual-mechanism the authors have derived eq. 5. k = (0.00920T - 1.14) obs. k2[HZO] 8 + k1[H20] (5) The calculated rate constant kobs. agrees within 110% with all the observed experimental data that have been included here. The calculated relative contributions by k1 (uni- molecular) and k2 (bimolecular) to the hydrolysis rate at various temperatures are shown in Table 9. kOBS/[HZO] 32 5 10 20 H20 (moles/liter) $0 100 Kelly and Watson Archer and Hudson Gold Oliver and Berger Hudson and Wardill Figure 3.--Observed reaction rate constants 13. water concentration for the hydrolysis of benzoyl chloride. 33 Table 9.-—Relative contributionsInrunimolecular (k%) and by bimolecular (k ) mechanism to the rate 0 de hydrolysis. benzoyl chlori the Temp. 0°C k2 10 k1 x 1016 o 1.81 6.90 15 5.32 38.9 25 10.3 112 35 19.0 300 45 33.4 880 55 56.6 2100 34 IsotOpe Effects and Mechanism Isotope Effects as Criteria of Mechanism Llewellyn and his co-workers (34) investigated the secondary hydrogen isotope effects of a series of alkyl esters in water. Some of their data are summarized in Tables 10 and 11. Shiner and his co-workers (1a) have suggested that, in general, the a— and B-secondary isotOpe effects are near one, or inverse, for nucleophilic reactions and much larger for limiting reactions. Thus, secondary isotope effects may be used as criteria for deciding the mechanism of a reaction. The observed B—isotOpe effects near one indicate that the hydrolysis of propionyl chloride proceeds pre- dominantly by a nucleophilic mechanism. They are consistent with the dual mechanism. For example, as the water concen- tration and temperature increase, the contribution of the limiting mechanism gradually increases to lead to greater isotOpe effects (Table 12). The results are also consistent with the unified mechanism suggested by Evans (24). /, R-C/O + H O R = CH CH \.CI 2 3 2 - OH2 l 6+OH2 "7 OH @ 8+1 .5' I R—C = 0<— R—C = 0 <—> R—C—O _ R—C-OH I G) I l I 02 _8-02 cz _ c1: (A) (B) 35 Table lO.--Isotope effects, kH/k , for the solvolysis of a-deuterated alkyl esgers (RX) in water. Leaving Group Methyl-d3 Ethyl-d2 ISOpropyl-d1 Tosylate 0.96 1.038 1.134 Methanesulfonate 0.96 1.037 1.143 Iodide 0.87 0.968 1.050 Bromide 0.90 0.983 1.069 Chloride 0.92 Reference 34(a) 34(b) 34(b) Table 11.--Isot0pe effects, kH/kD, for the solvblysis of B-deuterated alkyl esters (RX) in water. fir Leaving Group Ethyl-d3 IsoprOpyl-d6 .t-Butyl-dg Tosylate 1.018 1.551 Methanesulfonate 1.028 1.545 ‘ Iodide 1.033 1.313 Bromide 1.031 1.336 Chloride 2.530 Reference 21 21 19 36 Table 12.—-Temperature and solvent dependence of the B- and y-isotope effects in the hydrolysis of propionyl-d0, 2,2-d_2 and -3,3,3—d3 chlorides. (% Aciiixg7fiater) Temp' 0C kHz/sz kH3/kD3 85 -26.17 0.961 i .004 0.976 i .039 -20.47 0.995 i .018 0.973 i .005 -15.54 0.978 i .005 0.976 t .005 -10.57 0.985 1 .004 0.977 i .007 80 -30.58 0.989 i .007 0.976 i .010 -25.41 0.998 i .010 0.976 t .005 -20.47 1.001 i .007 0.967 t .021 -15.54 1.001 t .007 0.982 t .006 -10.56 1.008 t .005 75 -30.58 0.988 t .004 0.939 t .004 -25.55 1.008 t .007 0.960 1 .005 -20.55 1.011 t .005 0.957 t .005 37 As the ionizing power of the solvent and the temperature increase, the transition state shifts toward (A), i191 one where the carbon-chlorine bond has been extensively broken (more limiting like). It should be emphasized that the above argument will be invalid in special cases. For example, Shiner and Humphrey (35) have shown that the iso- tOpe effect for the solvolysis of compound 92, where effec- tive hyperconjugation is possible, is 1.14. Such an isotOpe effect is consistent with the expected limiting mechanism of the reaction. On the other hand, the kH/kD for compound gg,where the bridgehead C—H (or C—D) bond is in the nodal plane of the carbonium ion, is 0.986. EntrOpy of Activation and Mechanism Long and co-workers (36a) and Schaleger and Long (36b) have suggested that the entrOpy of activation might serve as a convenient criterion of mechanism. Since in a nucleOphilic hydrolysis a water molecule participates in 38 the bond formation with loss of its translational and rota- tional freedom, they predicted that reactions proceeding by nucleophilic mechanisms will have lower entropies of acti- vation relative to those of reactions proceeding by limiting mechanisms. Experimental results summarized in Table 13 are con- sistent with their prediction. The entropies of activation for the hydrolysis of the pr0piony1 chloride (Table 14) are consistent with a dual mechanism for this reaction. As the water content increases, the entropies of activation become less negative, an indication that the contribution of the limiting mechanism is increasing. The Origin of the Isotope Effects As pointed out in the introduction, isotope effects have been assumed to arise from changes in force constants. These changes have been attributed to hyperconjugation, nonbonded interactions and inductive effects. The present results may be interpreted in terms of either hyperconjuga- tion or nonbonded interactions. Hyperconjugation.--On the basis of infrared studies, Katon and Feairheller (38) have assigned two stable con- formations, 10a and 10b, for priopionyl chloride in the ground state. Stiefvater and Wilson have proved that propionyl fluoride exists in two analogous stable conformations, the 39 Table 13.-~Entropies of activation for limiting and nucleo- philic solvolyses in aqueous-acetone at 50°C (37). Substrate Solvent (%Acetone-Water) AS¥7(e.u.) (a) Limitinngechanism - t-BuCK 70 -10.89 80 -12.41 t-BuBr 70 -10.20 80 -11.23 MeOC6H4CH2C£ 70 -11.99 80 -14.21 MeOC6H4CHZOTs 85 -10.29 PhZCHCZ 70 -10.26 80 -12.96 N02C6H4CHPhC£ 70 - 9.96 NOZC6H4CHPhBr 70 - 8.38 NOZC6H4CHPhOTs 85 - 8.12 (b) Nucleophilic Mechanism PhCH2C£ 70 -23.96 PhCHZBr 70 -23.75 PhCHZOTs 85 -19.62 PhCHZOTs 70 -16.64 40 Table 14.--Transition state activation parameters8 for the hydrolysis of prOpionyl-do, -2,2-d2 and -3,3,3-d3 chlorides. Solvent Isoto 6 181(6) AH+(b) 151(6) AH1(c) (% A/W) p (e.u.) (cal/mole) (e.u.) (cal/mole) 75 d0 -12.7:t.7 14,193 1171 -12.7:t.5 14,169 :122 d2 -l3.9:t.7 13,904 1172 -13.9:t.2 13,881: 55 d3 -13.5:t.7 13,95921172 -13.6:t.1 l3,935:t'29 80 d0 -15.7:t.3 13,822:t 80 -lS.7:t.4 13,7982: 91 d2 -16.2:t.3 13,6932: 80 -l6.2:t.4 13,670:t 91 d3 -15.0:t.4 13,984 :111 -15.0:t.3 13,962:t 84 85 d0 -18.2:t.4 13,536 1111 —18.2:t.4 13,515:1102 9.2 -18.7: .4 13,380_+.111 -18.7.t .6 13,3641150 d3 -18.2:t.4 13,525:tlll ~18.2:t.4 l3,499:th9 (é)Calculated from the data in Tables 6 through 8. (b)Ca1culated from Acteng. (C)Ca1culated from Active. 41 cis one being favored over the gauche by 1290 i 50 cal/mole (39). In the ground state, therefore, effective hypercon- jugation involving the a-hydrogens is possible. CH3\_/O H\/—/ H’Z \ x CH3 if \( ——— X = CK or F .199 According to the unified or dual mechanism proposed for the hydrolysis of the propionyl chloride the demand for hyperconjugation is reduced in the transition state of the nucleophilic mechanism due to a decrease in the partial positive charge on the carbonyl carbon. Consequently, the difference in the zero point energy (AZPE) increases in the transition state. The observed isotope effect should thus be inverse (kH/kD < 1). On the contrary, in the limiting mechanism the hyperconjugative demand increases in the transition state. Accordingly, the difference in zero point energy in the transition state decreases and should lead to a normal isotope effect (kH/kD > 1). Nonbonded Interactions.--The results may also be rationalized in terms of nonbonded interactions. When the transition state is more crowded than the ground state, the force constant associated with the isotopic bond increases. Consequently, the difference in the zero point energy be- comes larger in the transition state than in the ground state and leads to an inverse isotope effect. The nucleOphilic 42 mechanism of the hydrolysis of propionyl chloride falls in this category. The limiting mechanism on the other hand would fit the case where the transition state is less crowded than the ground state. y-Isotope Effects in the Solvolysis of Propionyl Chloride.--Leffek and his co-workers (40) observed inverse isotOpe effects in the hydrolysis of various d-propyl esters in water (Table 15). They interpreted the observed 5-8% inverse y-isotope effects in terms of increased nonbonded interactions in the transition state. Halevi (1b) gave an alternate explanation in terms of inductive effects. A much smaller effect (kH/kD = 0.990 t 0.006) was obtained by Leffek (41) in the hydrolysis of d-propy1-3,3,3-d3 bromide in 50% (v/v) ethanol-water solvent mixture. Table lS.--y-isot0pe effects for the hydrolysis in water of d-propyl compounds. Compound T°C kH/kDCi.006) Benzenesulfonate 54.183 0.947 Methanesulfonate 60.004 0.943 Bromide 80.009 0.921 Iodide 90.003 0.924 43 Jewett and Dunlap (42) have interpreted the inverse isotope effect (kH/kD = 0.983) in the aqueous alcoholysis of £1 and the normal isotope effect (kH/kD = 1.132) in the solvolysis of la in terms of inductive and hyperconjugative effects, respectively. RSCCH2C(CH3)ZC£ 11 R = CH or CD 3 3 trans RCH = CHCHC£CH3 12 The observed 2-4% inverse y-isotope effects in the solvolysis of propionyl chloride and its deuterated analog (Table 16) can be explained in terms of both inductive and nonbonded interactions. They are consistent with a dual mechanism, provided the contribution of the nucleophilic path is greater than that of the limiting path. Temperature Insensitivity of the y-Isotope Effects.-- As pointed out, Leffek and his co-workers (22) found that the temperature insensitive B-isotope effects in the hydroly- sis of isopropyl esters were the result of AAH+ being zero, with AA81 apparently controlling them. We find (Table 16) that the y-isotope effects, in contrast to the B—isotOpe effects, in the solvolysis of propionyl chloride are also temperature insensitive. This temperature insensivity, however, does not appear to arise from differences in the entrOpies of activation. 44 Table l6.--Temperature and solvent dependence on the y-isotope effect in the hydrolysis of propionyl -3,3,3-d_3 chloride. Solvent (%A/W) Temp. °C kHs/kD3 85 -26.17 0.976 t .039 -20.47 0.973 t .005 -15.54 0.976 t .005 -10.57 0.977 f .007 80 -30.58 0.976 t .010 -25.41 0.976 t .005 -20.47 0.967 i .021 -15.54 0.982 t .006 75 -30.58 0.939 i .004 -25.55 0.960 t .005 -20.55 0.957 1 .005 45 In Table 17 are summarized the differences in the entrOpies of activation (AAS+) and the enthalpies of acti- vation (AAH+) which were calculated by using eq. 7. 1n kH/kD = -AAH+/RT + AA8+/R (7) The results show that the AAs+ contribution to the isotOpe effect is zero in 80% and 85% acetone-water solutions. The temperature insensitive isotope effects appear to be solely controlled by differences in the enthalpies of acti- vation. Thus, these results may be taken as support of the ideas of Wolfsberg and Stern (18), who have suggested that temperature independent isotOpe effects may result from compensating changes in force constants. Table 17.--Activation parameteréidetermined from the tempera- ture dependence of the B- and y-isotope effect of pr0piony1-d0, -2,2-d2 and 3,3,3-d3 chloride hydrolysis. Solvent Isoto e AAH:F AAS+ (% Acetone/Water) p (cal/mole) (e.u.) 75 d2 281 i 67 1.1 i .3 93 232 1 92 0.8 1 .4 80 d2 132 i 20 0.5 i 0 d3 21 i 60 0.0 i .2 85 d2 152 i 119 0.6 i 5 d3 138 i 157 0.0 i .0 (a)Calculated from Hands. 10. (a) (b) (C) (a) (b) REFERENCES V. J. Shiner, Jr., W. E. Buddenbaum, B. C. Murr and G. Lamaty, J. Am. Chem. Soc., 22, 418 (1968). E. A. Halevi, "Secondary IsotOpe Effects," Pro- gress in Phys. Org. Chem., Vol. 1, S. G. Cohen, . Streitwieser, and R. W. Taft, ed., John Wiley and Sons, New York, 1963. H. C. Brown, M. E. Azzaro, J. G. Kaelling and G. J. McDonald, J. Am. Chem. Soc., 88, 2514 (1966). M. J. S. Dewar, Hyperconjugation, Ronald Press Co., New York, 1962. Tetrahedron,é, 105-274 (1959). V. J. Shiner, Jr., J. Am. Chem. Soc., $3, 2643 (1964). (a) (b) V. V. . W. Simmons and J. H. Goldstein, J. 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