Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups. Part 2 / 0893 948

20. The synthesis and uses of amino and quaternary ammonium salts

933

The very large carbon-11/carbon-14 isotope effect of 1.202 š 0.008 is almost twice the magnitude of the carbon-12/carbon-14 isotope effect of 1.12š 0.01 measured for the same reaction at 48.5 °C. This clearly illustrates the usefulness of this new type of very large heavy-atom isotope effect. A comparison of these two isotope effects is possible using the Swain Schaad equation33. If one estimates the value of the k11/k14 isotope effect using the Swain Schaad equation33 and the k12/k14 D 1.12, the k11/k14 isotope effect should be 1.21. Given that the Swain Schaad equation is only approximate, the agreement with the observed k11/k14 D 1.0202 is excellent and it is safe to conclude that the Menshutkin reaction has a very large alpha carbon isotope effect and a fairly symmetrical transition state. Matsson and coworkers also used BEBOVIB IV calculations to model the transition state for this reaction46. The calculations and their observed k11/k14 D 1.0202 suggested that the transition state is early with a nitrogen alpha carbon bond order of approximately 0.3 and an alpha carbon iodide bond order of approximately 0.7.

It is worth noting that Yamataka and coworkers47 also found large (near the theoretical maximum) alpha carbon kinetic isotope effects for the Menshutkin reactions between 3,5-disubstituted pyridines and methyl iodide (equation 38, Table 6).

Although the alpha carbon kinetic isotope effects increase slightly as more electronwithdrawing substituents are added to the nucleophile, they are all large and effectively constant for a wide range of nucleophiles. For example, the isotope effect only changes by 0.013 when the rate constant decreases 340 times, i.e. the rate of the reaction with 3,5- dimethylpyridine is 340 times larger than the rate of the reaction with 3,5-dichloropyridine. This suggests that the transition state for the Menshutkin reaction is not very susceptible to changes in the structure of the reactants.

Other types of kinetic isotope effects have been measured in an attempt to determine the structure of the transition states of Menshutkin reactions. For example, Bourns and Hayes1 and Kurz and coworkers48,49 found very small incoming nucleophile nitrogen kinetic isotope effects in Menshutkin reactions (Table 7). These very small isotope effects, which are only slightly larger than the error of the measurements, are not affected significantly by a change in the leaving group, the solvent or even the substrate. It is important to note, however, that these very small incoming nucleophile nitrogen kinetic isotope effects indicate that the transition state is early with only a small amount of nitrogen alpha carbon bond formation. In fact, BEBOVIB IV calculations suggest that the nitrogen alpha carbon bond order in these transition states is between 0.2 and 0.3. This is in excellent agreement with the results from Matsson’s BEBOVIB IV calculations46.

Other workers have concluded that the transition state for the Menshutkin reaction is late with more nitrogen alpha carbon bond formation than alpha carbon leaving group bond rupture. For instance, Harris and coworkers51 found that the secondary alpha deuterium kinetic isotope effects (Table 8) decreased when a poorer nucleophile was used in the SN2 reactions between 3,5-disubstituted pyridines and methyl iodide in 2-nitropropane at 25 °C (equation 38, Table 8).

X

N + CH3 I	+	I −	(38)
	CH3 N

Y

934 Kenneth C. Westaway

TABLE 6. The alpha carbon-12-carbon-13 kinetic isotope effects for the Menshutkin reaction between 3,5-disubstituted pyridines and methyl iodide in 2-nitropropane at 25 °C

3-X	5-Y	(k12/k13)˛
CH3	CH3	1.063 š 0.004
CH3	H	1.062 š 0.002
H	H	1.066 š 0.005
Cl	H	1.074 š 0.002
Cl	Cl	1.076 š 0.016

TABLE 7. The incoming nucleophile nitrogen kinetic isotope effects in Menshutkin reactions with various amines in several solvents

Nucleophile (amine)	Substrate	Solvent	k14/k15a
4-Methylpyridine	CH3OMs	H2O	0.9969
	CH3OTf	MeCN	0.9937
Pyridine	CH3OMs	H2O	0.9971
	CH3OTs	H2O	0.9978
	CH3OTf	H2O	0.9965
	CH3OTs	H2O	0.9978
	CH3OTf	H2O	0.9965
	CH3OTs	H2O	0.9978
	CH3OTf	H2O	0.9965
	CH3OTf	MeCN	0.9946
	CH3OTf	DCE	0.9942
	CH3Cl	H2O	0.9960
	CH3Br	H2O	0.9972
	CH3I	H2O	0.9950
	CH3ThC	H2O	0.9976
	CH3ThC	MeCN	0.9964
3-Acetylpyridine	CH3OMs	H2O	0.9972
	CH3OBr	H2O	0.9972
2,6-Dimethylpyridine	CH3OMs	H2O	0.9978
	CH3OTs	H2O	0.9977
	CH3OTf	MeCN	0.9941
Quinuclidine	CH3OMs	H2O	1.0002b
	CH3OMs	MeCN	0.9962b
N,N-Dimethyl-4-toluidine	CH3OMs	MeCN (wet)	1.0024b
	CH3OMs	MeCN	1.0027b
	BzOBs	Me2CDO	c
Et3N			1.0028d
	CH3I	Benzene	1.0009
	CH3CH2I	Benzene	1.0015d
Me3N	CH3CH2Br	Benzene	0.9991d

a Reference 48. b Reference 49. c Reference 50. d Reference 1.

TABLE 8. The secondary alpha hydrogen deuterium kinetic isotope effects for the Menshutkin reaction between 3,5-disubstituted pyridines and methyl iodide in 2-nitropropane at 25 °C

3-X	5-Y	(kH/kD)˛
CH3	CH3	0.908
CH3	H	0.851
H	H	0.850
Cl	H	0.835
Cl	Cl	0.810

20. The synthesis and uses of amino and quaternary ammonium salts

935

The important observation is that all of the isotope effects are large and inverse. Thus, the transition states in these reactions must obviously be very crowded, i.e. the C˛ H(D) out-of-plane bending vibrations in the transition state must be high energy19. As a result, these workers concluded that nitrogen alpha carbon bond formation is more advanced than alpha carbon iodine bond rupture in the transition state. It is interesting, however, that these authors also concluded that the N C˛ bond formation is approximately 30% complete in the transition state.

In another study, Paneth and O’Leary52 measured the incoming nucleophile nitrogen and the secondary alpha hydrogen deuterium kinetic isotope effects for the Menshutkin reaction between N,N-dimethyl-para-toluidine and methyl iodide in methanol at 25 °C. They found a very small nitrogen kinetic isotope effect of 1.0019 š 0.001 in good agreement with the isotope effects reported by Kurz and coworkers48,49. The secondary alpha deuterium kinetic isotope effect for this reaction was 0.83 š 0.04, in good agreement with the isotope effects reported by Harris and coworkers51. This indicated that the transition state was sterically crowded and Paneth and O’Leary concluded that the transition state was symmetrical or slightly late with nitrogen alpha carbon bond formation advanced with respect to alpha carbon iodide bond rupture.

Ando, Tanabe and Yamataka53 measured both the carbon-12/carbon-14 and the secondary alpha hydrogen-tritium kinetic isotope effects for the Menshutkin reactions between substituted N,N-dimethylanilines and substituted benzyl benzenesulfonates in acetone at 35 °C (equation 39). They found large carbon-12/carbon-14 isotope effects and small secondary alpha tritium isotope effects for these reactions (Table 9). The carbon-12/carbon-14 isotope effects for these reactions are all large, i.e. they are near the theoretical maximum for these isotope effects. Thus, these isotope effects agree, in general, with the large k11/k14 isotope effect reported by Matsson and coworkers (vide supra). It is important to note that the carbon isotope effects go through a maximum when the leaving group is changed in the reactions between benzyl para-substituted benzenesulfonates and N,N-dimethyl-para- toluidine. This was the first illustration that alpha carbon kinetic isotope effects in SN2

TABLE 9. The carbon-12/carbon-14 and secondary alpha hydrogen tritium kinetic isotope effects for the SN 2 reactions between Y-substituted N,N-dimethylanilines and Z- substituted benzyl X-substituted benzensulfonates in acetone at 35 °Ca

		Z D m-Br				Z D H
Y	X	k12/k14	(kH/kT)˛		k12/k14	(kH/kT)˛
p-CH3O	p-Cl	1.130	1.033	1.142		1.061
p-CH3O	H			1.140
p-CH3O	p-CH3			1.148
p-CH3	m-NO2	1.151	1.041	1.119		1.056
p-CH3	p-Cl	1.148	1.026	1.149		1.055
p-CH3	H	1.137	1.030	1.162		1.043
p-CH3	p-CH3	1.141	1.031	1.156		1.033
p-CH3	p-CH3O	1.141		1.147		1.035
H	m-NO2			1.158
H	p-Cl			1.143		1.042
H	H			1.135
m-CH3	p-Cl	1.129
p-Br	p-Cl	1.117	1.033	1.139		1.048
m-NO2	m-NO2			1.127

a The errors in the k12/k14 are between š0.003 and š0.005 while those for the (kH/kT)˛ range from š0.008 to š0.012.

936	Kenneth C. Westaway

reactions pass through a maximum as the theoretical calculations suggested10,11.

N(CH3 )2	+	CH2 O	SO2
Y	Z		X
			(39)
	+		O SO2
	CH2 N(CH3 )2
Z		Y	X

The secondary alpha tritium isotope effects, on the other hand, are small. Benzyl substrates have looser SN2 transition states than methyl substrates (vide infra) and thus these reactions would be expected to have slightly larger isotope effects than methyl substrates. Thus, these tritium isotope effects are in general agreement with those found by Paneth and O’Leary52 and by Harris and coworkers51 in other Menshutkin reactions (vide supra). It is worth nothing that the tritium isotope effects are smaller for the meta-bromobenzyl benzenesulfonates than for the benzyl benzenesulfonates. This is expected because the transition state is invariably tighter with a shorter nucleophile-leaving group distance, when a more electron-withdrawing substituent is on the phenyl ring on the alpha carbon. Finally, although the transition states in these Menshutkin reactions appear to be slightly looser than those found for the methyl substrates in other studies, these isotope effects are consistent with a transition state with significant nitrogen alpha carbon bond formation and less alpha carbon oxygen bond rupture.

The newest type of isotope effect that has been used to characterize the transition state of the Menshutkin reaction is a secondary incoming nucleophile hydrogen deuterium kinetic isotope effect54. These isotope effects involve using primary amines labelled with deuterium at the nitrogen as the nucleophile (equation 40). In fact, Lee and collaborators54 measured both the secondary alpha hydrogen deuterium and the secondary hydrogen deuterium incoming nucleophile kinetic isotope effects for four different Menshutkin reactions (Table 10). The secondary alpha deuterium isotope effects for the benzyl benzenesulfonate reactions are fairly large and normal, indicating that these reactions have a loose transition state with long nucleophile alpha carbon and alpha carbon leaving group bonds. The methyl and ethyl substrate reactions, on the other hand, have inverse secondary alpha deuterium isotope effects like those found in the other Menshutkin reactions (vide supra). These inverse isotope effects indicate that these reactions have tight transition states with short nucleophile alpha carbon and alpha carbon leaving group bonds.

Y

NL2 + RCH2 OSO2

Z

(40)

+	Y OSO2	Z
RCH2 NL2

L = H, D

20. The synthesis and uses of amino and quaternary ammonium salts

937

TABLE 10. The secondary alpha deuterium and secondary incoming nucleophile deuterium kinetic isotope effects found for the SN 2 reactions between para-substituted anilines and benzylamines with benzyl, methyl and ethyl para-substituted benzensulfonates in acetonitrile at 30 °C

Substituent	para-Substituent				(kH/kD)a
on the nucleophile	on the leaving group	(kH/kD)˛
						Nucl
Benzyl para-substituted benzenesulfonates with para-substituted anilines
m-NO2	CH3	1.089 š 0.005			0.973
p-CH3O	CH3	1.096 š 0.009			0.955
m-NO2	NO2	1.095 š 0.010			0.951
p-CH3O	NO2	1.102 š 0.010			0.898
Benzyl para-substituted benzenesulfonates with para-substituted benzylamines
m-NO2	CH3				0.966
p-CH3O	CH3				0.952
m-NO2	NO2				0.953
p-CH3O	NO2				0.940
Methyl para-substituted benzenesulfonates with para-substituted anilines
		0.971 š 0.009				b
m-NO2	CH3				0.963	š 0.009b
p-CH3O	CH3	0.990 š 0.008			0.978	š 0.008b
m-NO2	NO2	0.974 š 0.007			0.968	š 0.009b
p-CH3O	NO2	0.993 š 0.007			0.984	š 0.007
Ethyl para-substituted benzenesulfonates with para-substituted anilines
m-NO2	CH3	0.963 š 0.009			b
					0.851b
p-CH3O	CH3	0.978 š 0.008			0.862b
m-NO2	NO2	0.968 š 0.009			0.858b
p-CH3O	NO2	0.984 š 0.007			0.869

a The authors did not give error limits for most of these isotope effects. They imply that the error is less than 1%.

b At 65 °C.

The secondary incoming nucleophile deuterium kinetic isotope effects are all inverse. This is because both the N H(D) bending and stretching vibrations become higher in energy in the transition state as the steric crowding increases (the nitrogen alpha carbon bond forms). Obviously, when the nitrogen alpha carbon bond formation is more complete in the transition state, the steric crowding around the N H(D) bonds will be greater and the isotope effect will be more inverse. Thus, these new isotope effects are useful because they indicate the degree of nitrogen alpha carbon bond formation in the transition state.

The authors concluded that the transition states for the Menshutkin reactions of the benzyl substrates were early (reactant-like) with nitrogen alpha carbon bond formation lagging behind alpha carbon oxygen bond rupture. The transition states for the Menshutkin reactions with the methyl and ethyl substrates, on the other hand, are tight (product-like) with nitrogen alpha carbon bond formation greater than alpha carbon oxygen bond rupture.

Finally, it is worth noting that the substituent effects are different on the two types of Menshutkin reactions as well. For the benzyl substrates, changing to a better nucleophile, i.e. changing the substituent on the nucleophile from the meta-nitro to a para-methoxy substituent, leads to a later, more product-like transition state with more inverse secondary incoming nucleophile deuterium kinetic isotope effects. However, the same change in nucleophile in the reactions with the methyl and ethyl substrates leads to an earlier transition state and less inverse secondary incoming nucleophile deuterium kinetic isotope effects.

938 Kenneth C. Westaway

TABLE 11. The carbon-11/carbon-14 kinetic isotope effects for the SN 2 reactions between several amine nucleophiles and the labelled methyl iodide in dimethoxyethane or acetonitrile at 15 °C and 30 °C, respectively

Nucleophile	Solvent	Temperature	k11/k14	pKa
(CH3CH2)3N	DME	15.00	1.221 š 0.006	10.65
Quinuclidine	DME	15.00	1.220 š 0.005	10.95
2,6-Lutidine	acetonitrile	30.00	1.220 š 0.009	6.77
2,4-Lutidine	acetonitrile	30.00	1.189 š 0.012	6.72

Finally, Persson, Berg and Matsson55 measured the k11/k14 isotope effects for the SN2 reactions between several amine nucleophiles and labelled methyl iodide in dimethoxyethane or acetonitrile at 15 °C and 30 °C, respectively, to determine how sterically crowded nucleophiles affected the structure of the transition state of a Menshutkin reaction. The results in Table 11 show that the k11/k14 isotope effects for these reactions are large. In fact, they are all near the theoretical maximum value for these isotope effects. Secondly, the isotope effect for the reaction with the more sterically hindered amine, 2,6-lutidine, is larger than that for the less sterically hindered 2,4-lutidine. It is worth noting that 2,6-lutidine and 2,4-lutidine have almost the same pKa, so there is little or no electronic effect in these reactions. Le Noble and Miller56

found a larger chlorine			leaving group isotope effect (k35/k37 D 1.0038 š 0.0003) for
the 2,6-lutidine		methyl	chloride reaction than for the corresponding pyridine reaction

(k35/k37 D 1.00355 š 0.00008) in bromobenzene at 100 °C. Thus, it appears that the carbon chlorine bond rupture is more advanced in the reaction with the more sterically crowded nucleophile, although the difference could be due to the fact that 2,6-lutidine is also a better nucleophile than pyridine. Also, the nitrogen incoming nucleophile kinetic isotope effects measured by Kurz and coworkers48,49 and by Bourns and Hayes1 (see above) indicated that nitrogen alpha carbon bond formation is not well advanced in the transition state. These isotope effects suggest that the transition state for the reaction with the more sterically hindered nucleophile is loose with longer nitrogen-alpha carbon and alpha carbon-chlorine bonds. Finally, theoretical calculations also suggested a looser transition state should be found when a more sterically crowded nucleophile was used in this reaction, and the authors concluded that the transition state for these reactions were early but that the reaction, with the more sterically crowded nucleophile and the larger alpha carbon k11/k14 isotope effect, was looser.

Unfortunately, the same trend in the k11/k14 isotope effects is not observed in the triethylamine/quinuclidine reactions with methyl iodide, although it is possible that the identical isotope effects may be due to the cancellation of two effects, a steric effect and an electronic effect, i.e. triethylamine is both a stronger base and a more sterically crowded nucleophile. It is interesting that the chlorine leaving group kinetic isotope effects are also different for these two reactions. Swain and Hershey57 found a larger chlorine leaving group isotope effect in the reaction of the less sterically hindered nucleophile, quinuclidine

(k35/k37 D 1.0071 š 0.0001), than for the corresponding triethylamine methyl chloride reaction (k35/k37 D 1.00640 š 0.00009).

B. The SN 2 Reactions of Quaternary Ammonium Salts

Westaway and coworkers have measured the secondary alpha deuterium and nitrogen leaving group kinetic isotope effects for the SN2 reactions between thiophenoxide ions and benzyldimethylphenylammonium ion to learn how ion-pairing, a change in solvent or substituents in the nucleophile, the substrate and the leaving group affect the structure of SN2 transition states.

20. The synthesis and uses of amino and quaternary ammonium salts

939

In one study to determine how a change in nucleophile affected the structure of the SN2 transition state, the secondary alpha deuterium and nitrogen leaving group kinetic isotope effects for the SN2 reactions between several para-substituted thiophenoxide ions and benzyldimethylphenylammonium ion (equation 41) were measured at 0 °C in DMF containing a high concentration of sodium nitrate to keep the ionic strength constant, so accurate rate constants could be determined58. Surprisingly, the nitrogen leaving group and the secondary alpha deuterium kinetic isotope effects for these reactions (Table 12) were identical. Two explanations for the identical secondary alpha deuterium and nitrogen kinetic isotope effects are possible. One possibility is that the transition states do not change when the substituent on the nucleophile is altered. This suggestion seems highly unlikely, however, because no one has observed this behavior in any study, and it is unreasonable to conclude that a change in nucleophile, which changes the rate constant by a factor of 6.4, would not alter the energy (structure) of the transition state, thereby causing a change in the isotope effects. The second, more likely, possibility is that the change in nucleophile changes the transition state but that the changes that occur in transition state structure do not cause a change in the isotope effect. If one assumes that the nitrogen leaving group kinetic isotope effects can be interpreted in the usual fashion, i.e. that the magnitude of the isotope effect increases with the percent C˛- - -N bond rupture in the SN2 transition state10, then all three reactions have identical amounts of C˛ - - -N bond rupture in the transition state. If this is the case, interpreting the secondary alpha hydrogen deuterium isotope effects is not straightforward. If a SN2 transition state were unsymmetrical and the bond to one of the nucleophiles was very long, the magnitude of the isotope effect would be determined by the length of the shorter reacting bond, because the second nucleophile in the SN2 transition state is too far away to affect the C˛ H(D) out-of-plane bending vibrations that determine the magnitude of the isotope effect19 (Figure 4).

	S− +	+
Z		C6 H5CH2		N(CH3 )2 C6 H5

(41)

Z	S CH2 C6 H5 + (CH3 )2 NC6 H5

The nitrogen (leaving group) kinetic isotope effects indicate that there is no change in the amount of C˛- - -N bond rupture in the SN2 transition state when the substitutent in the

TABLE 12. The nitrogen (leaving group) and secondary alpha hydrogen deuterium kinetic isotope effects for the SN 2 reactions between several para-substituted sodium thiophenoxide and benzyldimethylphenylammonium nitrate in DMF at 0 °C

para-Substituent on	k14/k15
the thiophenoxide ion			(kH/kD)˛
CH3O	1.0162	š 0.0007a	1.221	š 0.012b
H	1.0166	š 0.0004	1.215	š 0.011
Cl	1.0166	š 0.0005	1.215	š 0.013

a The standard deviations of the mean of at least four separate experiments.

b The error in the isotope effect D 1/kD[ kH 2 C kH/kD 2 ð kD 2]1/2 where kH and kD are the standard deviations for the rate constants for the undeuterated and deuterated substrates, respectively.

940	Kenneth C. Westaway

H

S

Cα

N

FIGURE 4. Showing how the magnitude of a secondary alpha hydrogen deuterium kinetic isotope effect can be determined by the length of the shorter reacting bond rather than by the nucleophile leaving group distance in an unsymmetrical SN 2 transition state

nucleophile is altered. Moreover, the amount of C˛- - -N bond rupture in the SN2 transition state is not large because the nitrogen isotope effect is only approximately one-third of the theoretical maximum nitrogen leaving group kinetic isotope effect of 1.04459. Also, the nitrogen isotope effects found when thiophenoxide ion was the nucleophile in these reactions (k14/k15 D 1.0166 š 0.0004) is significantly smaller than the 1.0200 š 0.0007 found for the same reaction in DMF at an ionic strength of 0.64 (Table 13)60. Thus, it appears that C˛- - -N bond rupture is not well advanced in these transition states (the transition states are reactant-like).

The secondary alpha hydrogen deuterium kinetic isotope effects for these reactions, on the other hand, are very large, indicating the transition states are very loose with long S- - -N distances. Since the C˛ - - -N bonds are short, the S- - -C˛ bonds must be very long in these transition states. This conclusion is warranted because the secondary alpha hydrogen deuterium kinetic isotope effects found for the reaction with thiophenoxide ion in this study [ kH/kD ˛ D 1.22 š 0.01] is the largest that has been found for an SN2 reaction of a quaternary ammonium ion. Moreover, the kH/kD ˛ of 1.22 š 0.01 found in this study is significantly larger than that [ kH/kD ˛ D 1.179 š 0.0071] found for the same reaction at an ionic strength of 0.640 (Table 13). The Hammett D 1.62 š 0.01 in the reaction where kH/kD ˛ D 1.22, whereas a larger Hammett value of 1.76 š 0.19 was found in the reaction with kH/kD ˛ D 1.179. Since a larger value is observed when the change in charge on going from the reactants to the transition state is larger, i.e. when there is more nucleophile alpha carbon bond formation in the transition state, the reaction with the larger (kH/kD)˛ must have the longer S- - -C˛ transition state bond.

TABLE 13. The secondary alpha hydrogen deuterium and primary nitrogen kinetic isotope effects for the SN 2 reaction between sodium thiophenoxide and benzyldimethylphenylammonium nitrate at different ionic strengths in DMF at 0 ° C

Ionic strength	(kH/kD)˛		k14/k15		Hammett
		a		b	1.62	c
0.904	1.215	š 0.011a	1.0166	š 0.0004b		š 0.01c
0.64	1.179	š 0.007	1.0200	š 0.0007	1.79	š 0.19
a The error in the isotope effect D 1/kD[ kH 2 C kH/kD 2 ð kD 2]1/2					where kH and kD

are the standard deviations for the rate constants for the undeuterated and deuterated substrates, respectively.

b The standard deviation of the mean of five different measurements.

c The correlation coefficients for the Hammett plots found by changing the para-substituent in the nucleophile are 1.000 for the reaction at an ionic strength of 0.904 and 0.994 for the reaction at an ionic strength of 0.64.

20. The synthesis and uses of amino and quaternary ammonium salts

941

The most reasonable explanation for the constant nitrogen and secondary alpha deuterium kinetic isotope effects found in these reactions is that changing the substituent in the nucleophile does not affect the amount of C˛- - -N bond rupture in the transition state but changes the length of the S- - -C˛ transition state bond significantly. However, these changes in the length of the S- - -C˛ transition state bond occur too far from the alpha carbon to affect the C˛ (H)D out-of-plane bending vibrations (the magnitude of the secondary alpha hydrogen deuterium kinetic isotope effect). As a result, the magnitude of the secondary alpha deuterium kinetic isotope effect is only determined by what happens to the shorter C˛- - -N bond when the substituent is changed and, since the C˛- - -N bond does not change when the substituent in the nucleophile is altered, the magnitude of the secondary alpha deuterium kinetic isotope effect does not change when the substituent on the nucleophile is altered.

These conclusions are interesting because they are consistent with the predictions of the ‘Bond Strength Hypothesis’61 which suggests that ‘there will be a significant change in the weaker reacting bond but little or no change in the stronger reacting bond in an SN2 transition state when a substitutent in the nucleophile, the substrate, or the leaving group is altered in an SN2 reaction’. Since the carbon sulfur bond is weaker than the carbon nitrogen bond in these SN2 reactions61, the ‘Bond Strength Hypothesis’ would predict that adding an electron-withdrawing group to the nucleophile should not affect the alpha carbon-leaving group (C˛- - -N) bond significantly but should lead to a significant change in the length of the weaker S- - -C˛ bond. It is interesting that these are the exact changes suggested on the basis of the isotope effects. Finally, another interesting conclusion is that the shortest bond in these SN2 transition states is the strongest bond, i.e. the stronger C˛ - - -N bond is the shorter reacting bond and the weaker S- - -C˛ bond is longer in the transition state.

The nucleophile in the SN2 reactions between benzyldimethylphenylammonium nitrate and sodium para-substituted thiophenoxides in methanol at 20 °C (equation 42) can exist as a free thiophenoxide ion or as a solvent-separated ion-pair complex (equation 43)62,63. The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects for these SN2 reactions were determined to learn how a substituent on the nucleophile affects the structure of the SN2 transition state for the free ion and ion-pair reactions64.

Z	S− +			+
				C6 H5CH2			N(CH3 )2 C6 H5	(42)
	Z						S CH2 C6 H5 +	(CH3 )2 NC6 H5
xM+ +	x −SC6 H5				[M+(solvent)y −SC6 H5]x			(43)

The secondary alpha deuterium kinetic isotope effects for both the ion pair and the free ion reactions (Table 14) decrease when a more electron-withdrawing para-substituent is on the nucleophile. Since the magnitude of the secondary alpha deuterium kinetic isotope effect is directly related to the S- - -N distance in the SN2 transition state19, adding a more electron-withdrawing substituent to the nucleophile leads to a transition state with a shorter S- - -N distance. The primary leaving group nitrogen kinetic isotope effects for the free ion and the ion-pair reactions (Table 14), on the other hand, increase very slightly when a more electron-withdrawing substituent is added to the nucleophile. Therefore, the

942	Kenneth C. Westaway

TABLE 14. The secondary alpha deuterium kinetic isotope effects and primary leaving group nitrogen kinetic isotope effects for the free ion and ion-pair SN 2 reactions between benzyldimethylphenylammonium nitrate and para-substituted thiophenoxide ions in methanol at 20 °C

para-Substituent	(kH/kD)˛		k14/k15
The nucleophile is the free thiophenoxide ion
CH3O	1.271 š 0.013a		1.0162 š 0.0005b
H	1.222 š 0.013		1.0166 š 0.0008
Cl	1.121	š 0.014	1.0169	š 0.0005
The nucleophile is a solvent-separated ion-pair complex
CH3O	1.216	š 0.012a	1.0161	š 0.0005b
H	1.207	š 0.008	1.0162	š 0.0010
Cl	1.150	š 0.009	1.0166	š 0.0003

a The error in the isotope effect is 1/kD[ kH 2 C kH/kD 2 ð kD 2]1/2, where kH and kD are the standard deviations for the rate constants for the reactions of the undeuterated and deuterated substrates, respectively. b Standard deviation for the average kinetic isotope effect.

C˛- - -N transition state bond length increases slightly as a more electron-withdrawing substituent is added to the nucleophile. The relative length of the S- - -C˛ transition state bond can be deduced from the primary nitrogen and the secondary alpha deuterium kinetic isotope effects. When a more electron-withdrawing substituent is added to the nucleophile, the C˛- - -N transition state bond increases slightly while the S- - -N distance shortens. Therefore, the S- - -C˛ transition state bond must be much shorter when a more electronwithdrawing substituent is added to the nucleophile in both the free ion and the ion-pair reactions. The relative transition state structures are shown in Figure 5 using the free ion as the nucleophile.

The earlier transition states, found when a more electron-donating substituent is added to the nucleophile, may be found because a better nucleophile would not have to come as close to the alpha carbon to distort the C˛ NC bond and cause reaction.

The greater change in the S- - -C˛ bond with substituent can be understood in terms of the Bond Strength Hypothesis61. The S C˛ bond is weaker than the C˛ NC bond and the Bond Strength Hypothesis predicts that the greatest change will occur in the weaker

δ−						Cα		δ+		/ k ) = 1.27
CH3 OC6 H4 S								N(CH3 )2 C6 H5	(k
									H	D α
									k14 /k15 = 1.0162
		δ−						δ+	(kH / kD)α = 1.22
HC6 H4 S						Cα		N(CH3 )2 C6 H5
									k14 /k15 = 1.0166
				δ−		Cα		δ+	(kH / kD)α = 1.12
ClC6 H4 S								N(CH3 )2 C6 H5

k14 /k15 = 1.0169

FIGURE 5. The relative transition state structures for the SN 2 reactions between benzyldimethylphenylammonium ion and free para-substituted thiophenoxide ions in methanol at 20 °C