Isotope effects in nucleophilic substitution reactions. VIII. The effect of the form of the reacting nucleophile on the transition state structure of an SN2 reaction

YAO-REN FANG AND KENNETH CHARLES WESTAWAY'

Chemistry Department, Laurentian Universi~y, Sudbury, Ont., Canada P3E 2C6

Received August 27, 1990

YAO-REN FANG and KENNETH CHARLES WESTAWAY. Can. J. Chem. 69, 1017 (1991). A spectroscopic investigation indicated that lithium thiophenoxide exists as a contact ion pair complex in dry diglyme whereas

the other alkali metal thiophenoxides exist as a solvent-separated ion pair complex in diglyme. The addition of small amounts of water converts the lithium thiophenoxide contact ion pair complex into a solvent-separated ion pair complex. A smaller secondary a-deuterium kinetic isotope effect and a larger Hammett p value are observed when the nucleophile is the contact ion pair complex in the SN2 reaction between n-butyl chloride and thiophenoxide ion in diglyme. This indicates that the transition state for the contact ion pair complex reaction is tighter with a shorter nucleophile-a-carbon bond than the transition state for the solvent-separated ion pair complex reaction. The secondary a-deuterium kinetic isotope effects for the free ion and the solvent-separated ion pair complex reactions between sodium thiophenoxide and n-butyl chloride in DMF suggest that the loosest transition state is found when the nucleophile is the free ion.

Key words: transition state, SN2, isotope, deuterium, Hammett p.

YAO-REN FANG et KENNETH CHARLES WESTAWAY. Can. J. Chem. 69, 1017 (1991). Une ttude spectroscopique indique que, dans le diglyme sec, le thiophtnolate de lithium existe sous la forme d'une paire d'ions

de contact; dans le mCme solvant, les autres thiophCnolates de mCtaux alcalins existent sous la forme d'une paire d'ions stparts par le solvant. L'addition de faibles quantitts d'eau transforme la paire d'ions de contact du thiophknolate de sodium en une paire d'ions stparts par le solvant. Pour les rtactions SN2 entre le chlorure de butyle et I'ion thiophCnolate effectuCes dans le diglyme, I'effet isotopique secondaire a du deuttrium est plus faible et la valeur p de Hammett est plus grande lorsque le nucltophile est une paire d'ions de contact. Ce resultat indique que l'ttat de transition de la rCaction impliquant la paire d'ions de contact est plus compact, avec une liaison carbone a-nucltophile plus courte, que 1'Ctat de transition de la rtaction avec la paire d'ions stparks par le solvant. Les effets isotopiques cinCtiques secondaires des deutkrium en a, observks pour les rtactions des ions libres et des paires d'ions sCparts par le solvant du thiophCnolate de sodium avec le chlorure de butyle dans le DMF suggkrent que l'ttat de transition le plus ldche est celui impliquant I'ion libre.

Mots clks : &at de transition, SN2, isotope, deuterium, p de Hamrnett.

Introduction Conductivity measurements, ultraviolet (uv) spectroscopy,

and experiments with crown ethers have shown that alkali metal thiophenoxides can exist in different forms in organic solvents (1-3). At low concentrations, alkali metal t h i ~ ~ h e n o x i d e s exist as free ions in methanol, DMF, and DMSO. At higher concen- trations, that depend on the solvent, these salts exist as solvent- separated ion pair complexes, eq. [I] .

Sodium thiophenoxide exists as a solvent-separated ion pair complex at all concentrations in the much less polar solvent, diglyme ( I).

Buncel et al. (4, 5) used a spectroscopic test to determine whether an ion pair exists in solution as a contact ion pair or as a solvent-separated ion pair. The test involves determining how changing the metal ion in an ion pair affects the absorption maximum in the uv spectrum. When the alkali metal ion is changed in a contact ion pair, the electron density on the nucleo- philic atom (the chromophore) is altered and the absorption maximum of the ion pair spectrum changes. If the ion pair is a solvent-separated ion pair, the metal ion is separated from the nucleophilic atom and changing the metal ion does not alter significantly the electron densityon the nucleophilic atom. As a result, the absorption maximum for the ion pair does not change significantly when the metal ion of the ion pair is altered.

With one exception (lithium thiophenoxide in diglyme), the absorption maximum of the uv spectrum of alkali metal thio-

'~uthor to whom correspondence may be addressed.

[Traduit par la rkdaction]

TABLE 1. The absorption maxima for the lithium, sodium and cesium thiophenoxide ion pair complexes in DMSO, DMF, CH30H, and

diglyme at 20°C

Amax (nm)

Salt DMSO DMF CH30H Diglyme

phenoxide ion pair complexes in methanol, in DMF, in DMSO, and in diglyme does not change significantly, Table 1, when the alkali metal ion is altered ( I ) . Thus, the spectroscopic technique used by Buncel et al. to identify the structure of ion pairs indicates that all of the ion pair complexes, except for the lithium thiophenoxide in diglyme, are solvent separated (1-3). The large change that is found in the absorption maximum when lithium is substituted for sodium in the alkali metal thiophenox- ide ion pair complex in diglyme indicates that the form of the lithium thiophenoxide ion pair complex is different from that of the other alkali metal ion pair complexes and suggests that the lithium thiophenoxide exists as a contact ion pair complex in diglyme.

We are unable to explain why the absorption maximum for the contact ion pair complex is greater than that found for the solvent-separated ion pair complex. It is worth noting, however, that the change observed in the absorption maximum when the solvent-separated ion pair complex is converted into the contact

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1018 CAN. I . CHEM.

ion pair complex (A,,, increases from 304 nm to 325 nm) is in the same direction as the change found when the free ion is converted into the solvent-separated ion pair complex, i.e., A,,, increases from 235 nm for the free ion to 267 nm for the solvent-separated ion pair complex in methanol and from ap- proximately 280 nm for the free ion to 305 nm and 308 nm for the solvent-separated ion pair complex in DMSO and DMF, respectively (1). Thus, the absorption maximum always moves to longer wavelengths as the interaction with the cation in- creases.

Secondary a-deuterium kinetic isotope effects and Hammett p values have been measured for the solvent-separated (sodium and potassium) and the contact (lithium) ion pair complex reac- tions to determine how the form of the reacting nucleophile affects the transition state structure of the SN2 reaction between n-butyl chloride and thiophenoxide ion in diglyme, eq. [2].

Results and discussion The secondary a-deuterium kinetic isotope effects found for

the SN2 reactions (2, 6) between n-butyl chloride and the sol- vent-separated (sodium thiophenoxide) ion pair complex and the contact (lithium thiophenoxide) ion pair complex are shown in Table 2. The secondary a-deuterium kinetic isotope effect of 1.07 found for the contact (lithium thiophenoxide) ion pair complex reaction in diglyme at 20°C is significantly lower than that found when the nucleophilic reagent is the solvent- separated (sodium thiophenoxide) ion pair complex (kH/kD = 1.14). Thus, it appears that the form of the reacting nucleophile has a marked effect on the magnitude of the secondary a - deuterium kinetic isotope effect and transition state structure.

Small amounts of a more solvating solvent, water, were added to the dry diglyme used in the lithium thiophenoxide contact ion pair complex experiments in an effort to convert the contact ion pair complex into the solvent-separated ion pair complex and confirm that the different secondary a-deuterium kinetic isotope effect was, indeed, due to a change in the form of the reacting nucleophile. The results in Table 3, and Fig. 1, show that this is possible. When small amounts of water are added to the dry diglyme, the secondary a-deuterium kinetic isotope effect initially remains constant. However, when the amount of water is increased from 2.0 to 3.0%, the isotope effect jumps from 1.07 to 1.12. Increasing the amount of water to 4.0% leads to a further increase in the isotope effect, i.e., to 1.13, a secondary a-deuterium kinetic isotope effect that is within experimental error of the isotope effect found when the solvent-separated sodium thiophenoxide ion pair complex is the reactant, Table 2. Increasing the amount of water in the solvent still further, i.e., to 7.5%, does not alter the secondary a - deuterium kinetic isotope effect of the lithium thiophenoxide reaction.

The ability to change the secondary a-deuterium kinetic iso- tope effect for the lithium thiophenoxide contact ion pair com- plex reaction from 1.07 to 1.14, the isotope effect for the reaction of the solvent-separated (sodium thiophenoxide) ion

TABLE 2. The secondary a-deuterium kinetic isotope effects for the SN2 reactions between n-butyl chloride and the solvent-separated and con- tact ion pair complexes of alkali metal thiophenoxides in diglyme

at 20°C

Salt/ kH x lo3 kD x lo3 solvent (L m01-' S-I) (L m0l-I s-'1 (kH/kD)a

Contact ion pair complex

Li+ -SC6H5/ 2.607 k 0.05" 2.436 * 0.042" 1.070 k 0.028~ dry diglyme

Solvent-separated ion pair complex

Na+ -SC6H5/ 5.627 k 0.087 4.927 & 0.031 1.142 k 0.019 dry diglyme Li+ -SC6H5 1.184 k 0.002 1.046 & 0.002 1.131 2 0.002 4% aqueous diglyme K+ -SC6H5 12.75 ? 0.007 11.30 k 0.002 1.128 ? 0.007 0.5% acqueous diglyme

"Standard deviation from at least three kinetic runs. q h e error is 1/kD[(AkH)' + (kH/kD)' X (Ak,)']'/' where AkH and Ak, are

the standard deviations for the rate constants for the undeuterated and deuterated substrates, respectively (1).

TABLE 3. The secondary a-deuterium kinetic isotope effects for the SN2 reaction between n-butyl chloride and lithium thiophenoxide in various

mixtures of aqueous diglyme at 20°C

Percent kH X lo3 kD x lo3 water L mol- ' s- ' L mol-I s-I

None 2.607 k 0.050" 2.436 * 0.042" 0.5 2.029 + 0.016 1.880 k 0.013 1.0 1.670 k 0.0059 1.544 * 0.007 2.0 1.338 ? 0.01 1 1.247 k 0.009 3.0 1.215 & 0.007 1.0835 + 0.0018 4.0 1.1836 k 0.0016 1.0464 k 0.0017 7.5 0.91503 ? 0.00017 0.80946 k 0.0004

'Standard deviation from at least three kinetic runs. ?he error is 1/kD[(AkH)' + (kH/kD)' x (AkD)2]1/' where AkH and Ak, are

the standard deviations for the rate constants for the undeuterated and deuterated substrates, respectively ( 1).

pair complex, by adding water is strong evidence that the change in secondary a-deuterium kinetic isotope effect is due to a change in the form of the reacting nucleophile rather than to a change in the cation. The contact ion pair complex is presum- ably converted into the solvent-separated ion pair complex be- cause water is a more ionizing solvent than diglyme and solvates the ions in the ion pair complex more strongly.

The secondary a-deuterium kinetic isotope effect for the reaction of a different solvent-separated ion pair complex, potassium thiophenoxide, was measured in an effort to confirm that the change in the isotope effect was due to a change in the form of the reacting nucleophile and not to a change from the lithium to the sodium cation. The secondary a-deuterium ki- netic isotope effect for the reaction with the solvent-separated potassium thiophenoxide ion pair complex is 1.13, Table 2. In fact, the isotope effects for all the reactions of the solvent- separated ion pair complexes are identical within experimental error. Thus, the different (smaller) secondary a-deuterium ki- netic isotope effect is only found when lithium thiophenoxide is used in dry or almost dry diglyme and the uv spectrum indicates

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FANG AND WESTAWAY 1019

% H20 ADDED

FIG. 1. 'The secondary a-deuterium kinetic isotope effect versus the percent water added to dry diglyme in the SN2 reaction between n-butyl chloride and the lithium thiophenoxide ion pair complexes.

that the form of the reacting nucleophile is different, i.e., the contact ion pair complex.

Form of reacting nucleophile and transition state structure Once it had been established that different secondary a -

deuterium kinetic isotope effects were found for the contact ion pair complex and the solvent-separated ion pair complex reac- tions, it was interesting to determine how the form of the reacting nucleophile affected the structure of the SN2 transition state.

Secondary a-deuterium kinetic isotope effects and Hammett p values can be used to elucidate the structure of the transition states in the SN2 reactions (7, 8). The initial state for the secondary a-deuterium kinetic isotope effect in both the contact ion pair complex and the solvent-separated ion pair complex reactions is the same, i.e., n-butyl chloride. Thus, the very different secondary a-deuterium kinetic isotope effects observed for the solvent-separated and contact ion pair complex reactions in diglyme require that the transition states for these two SN2 reactions be significantly different. One might worry that changing the solvent from 1% aqueous diglyme to 4% aqueous diglyme would affect the magnitude of the secondary a-deuterium kinetic isotope effect because the partially formed chloride ion in the transition state could be more strongly sol- vated by hydrogen bonding to the extra H20 molecules present when the reaction was done in 4% aqueous diglyme. This change in solvent would not affect the magnitude of the secon- dary a-deuterium kinetic isotope effect significantly, however. Theoretical calculations of the secondary a-deuterium kinetic isotope effect in the SN2 reaction between benzyl chloride and an alkoxide ion (9) indicate that solvating the developing chlor- ide ion with three hydrogen bonds to H20 only changes the isotope effect by 0.0002. Since adding three hydrogen bonds (altering the reduced mass of the developing chloride ion) has a negligible effect on the secondary a-deuterium kinetic isotope effect, the different isotope effects observed in 1% and 4% aqueous diglyme must be due to a change in transition state structure. The magnitude of the secondary a-deuterium kinetic isotope effect is primarily dependant on the C,-H(D) out-of- plane bending vibrations and, therefore, on the steric crowding around the C,H(D) bonds in the SN2 transition state (7, 8, 10). In fact, the C,-H(D) out-of-plane bending vibrations will be of higher energy (the secondary a-deuterium kinetic isotope effect will be smaller) when the a-carbon-nucleophile and a-carbon-leaving group bonds are short in the transition state

(8). Applying this rationale to the experimental isotope effects in the two reactions indicates that the contact ion pair complex transition state must be tighter, with shorter nucleophile-a- carbon and (or) a-carbon-leaving group bonds than the solvent- separated ion pair complex transition state.

The tighter SN2 transition state for the reaction with the contact ion pair complex seems probable because the small lithium cation has a large charge density and will tie up (reduce) the electron density on the sulfur atom of the nucleophile. This, in turn, would mean that the sulfur nucleophile would have to come closer to the a-carbon before it disturbed the a-carbon- chlorine bond sufficiently to cause reaction. If this occurred, the transition state would have a shorter S---C, bond and, presum- ably, a tighter transition state. The smaller secondary a - deuterium kinetic isotope effect that is observed is consistent with this hypothesis.

Harnmett p values were determined for the SN2 reactions between n-butyl chloride andpara-substituted lithium thiophen- oxides in 1 % and in 4% aqueous diglyme where the nucleophile is the contact ion pair complex and the solvent-separated ion pair complex, respectively. These p values were measured in an attempt (i) to determine the structure of the SN2 transition states in more detail and (ii) to determine if the length of the sulfur- a-carbon bond is indeed shorter in the contact ion pair complex transition state. The Hamrnett p value of - 1.39 found in the contact ion pair complex reaction is much larger than the p value of -0.56 found for the solvent-separated ion pair complex reaction, Table 4. Negative p values are found in both reactions because the sulfur of the nucleophile becomes less negative when the reactants are converted into the transition state. The addition of water to the solvent would be expected to alter the magnitude of the Hammett p value. If this effect were significant, it could alter the conclusions drawn about the rela- tive lengths of the sulfur-a-carbon transition state bonds in 1 and 4% aqueous diglyme. However, the most aqueous solvent only contains 4% water rather than 1% water and the rate constants are only slightly (from 6% to 2.7 times) different in the two solvents. In contrast, the rate constant in a protic solvent (MeOH) is more than 100 times smaller than the rate constant in diglyme (1,6). As a result, the effect of the change in solvent on the magnitude of the p value should be reasonably small. Since the change in the p value with the change from 1% water to 4% water is large, i.e., the p value is 2.5 times larger in the case where the nucleophile is the solvent-separated ion pair complex, it is probably safe to conclude that the change in p is related to a change in transition state ~tructure.~ If this is the case, the larger p value in the contact ion pair complex reaction indicates that more charge density has been lost from the sulfur atom in going

'A referee suggested that the Hammett p value could be affected by the change in solvent in another way. He proposed that the interaction between the nucleophile and the developing chloride ion in the transi- tion state would be greater when the developing chloride ion is not solvated with hydrogen-bonded water molecules. If this interaction were different, the p value in 4 and 1% aqueous diglyme would be different because of a change in solvent rather than a change in transi- tion state structure. However, it is not clear whether the interaction between the negative sulfur and the negative chloride ion would affect the magnitude of the p value. Presumably, the nucleophile would inter- act much more strongly with the partially positively charged a-carbon than with the leaving group. As a result, the proposed effect should be small. Since the p value in 1 % aqueous diglyme is 2.5 times that in 4% aqueous diglyme, it seems probable that the sulfur-a-carbon bond is shorter in the transition state of the contact ion pair reaction.

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FANG AND WESTAWAY 1021

Experimental Preparation of reagents

Diglyme Two litres of spectroscopic grade diglyme were purified by stirring

with 50 g of ferrous sulfate dihydrate and 50 g of potassium hydroxide for 2 h at room temperature. After the solvent had been filtered, it was distilled at atmospheric pressure. The fraction boiling between 160 and 162°C was collected and dried over sodium metal for 8 h before use.

Buy1 chloride The preparation of the undeuterated and deuterated substrates is

described elsewhere (1).

Kinetic measurements The concentration of the unreacted thiophenoxide ion was deter-

mined by titrating 1 rnL aliquots of the reaction mixture electrochemi- cally with a standard silver nitrate solution (1, 11). The substrate concentration varied from 1.6 to 2.7 X lo-' M and the alkali metal thiophenoxide (nucleophile) concentration ranged from 3.6 to 6.6 x 1(r3 M in these experiments. The rate constants were obtained from the slope of the normal second-order plot (12). The reactions were fol- lowed to between 50 and 75% of completion. Good second-order plots, linear up to at least 75% of completion, were found for all the reactions. The correlation coefficients of the least-squares line for individual rate constants varied from 0.998 to 0.9999. Over 90% of the reactions had a correlation coefficient greater than 0.999.

Acknowledgement The authors gratefully acknowledge the financial support

provided by the Natural Sciences and Engineering Research Council of Canada.

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