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Nucleophilic Substitution: SN2 and SN1 reactions and Stereochemistry





There is large amount of evidence that SN2 reactions proceed with a backside attack of the nucleophile Nu at the carbon atom attached to the leaving group X1-3.

Fig. 1: Mechanism for the SN2 reaction

Fig. 1: Mechanism for the SN2 reaction

In a previous post entitled “The SN2 reaction: Substitution Nucleophilic Bimolecular” the kinetic evidence for the SN2 mechanism was shown.

However, much more convincing evidence is obtained from the fact that the mechanism of the  SN2 reaction predicts inversion of configuration when substitution occurs at a chiral carbon. This inversion of configuration that proceeds through transition state 1 (Fig. 1) is called Walden inversion.

Walden presented a number of examples in which inversion must have taken place such as the one shown in Fig. 2
 
Fig. 2: Inversion of configuration is observed when (+)-malic acid is treated with PCl5 while retention of configuration when treated with SOCl2


Fig. 2: Inversion of configuration is observed when (+)-malic acid is treated with PCl5 while retention of configuration when treated with SOCl2

When (+)-malic acid reacts with PCl5 the substitution reaction (OH is replaced by Cl) proceeds with inversion of configuration and (-)-chlorosuccinic acid is produced – an SN2 reaction occurs. When (+)-malic acid reacts with SOCl2 the substitution reaction proceeds with retention of configuration – an SN1 type of mechanism is involved.

At that point of time Walden was not able to explain the above findings in terms of reaction mechanisms.
In 1923, Phillips and coworkers carried out a series of experiments in order to prove where inversion takes place. The following experiment was carried out. (+)-1-phenyl-2-propanol was converted to its ethyl ether by the two routes shown in Fig. 3. Path AB gave the (-) ether while path CD gave the (+) ether. Therefore, at least one of the four steps must be an inversion. It is extremely unlikely that there is inversion in steps A, C, D since in all these steps the C-O bond is unbroken. Therefore, only in step B inversion occurred. 

A number of such experiments were carried out and they showed that certain specific reactions proceed with inversion.

For example, when (+)-(S)-sec-butanol is treated with TsCl/pyridine followed by Bu4N AcO/DMF – SN2 reaction conditions – inversion is observed at the chiral carbon where the substitution takes place. However, when the same alcohol is treated with SOClF/SbF5 and H2O – SN1 reaction conditions – a racemic mixture is obtained (Fig. 4)

 
Fig. 3: Inversion of configuration is observed when (+)-1-phenyl-2-propanol  is treated with TsCl and K2CO3 / EtOH

Fig. 3: Inversion of configuration is observed when (+)-1-phenyl-2-propanol  is treated with TsCl and K2CO3 / EtOH 















Fig. 4: The SN2 reaction goes with inversion of configuration at the carbon atom under attack but the  SN1 reaction gives a racemic product.


Fig. 4: The SN2 reaction goes with inversion of configuration at the carbon atom under attack but the  SN1 reaction gives a racemic product.


Another kind of evidence for the SN2 mechanism comes from compounds with leaving groups at bridgehead carbons4 (Fig. 5). These compounds do not react with ethoxide ion – under SN2 conditions - while their open-chain analogs react readily. However, this is what it is expected for bridge-head carbons since there is no possibility for the nucleophile to approach from the rear.
Fig. 5: Compounds with leaving groups at bridgehead carbons do not react with ethoxide ion under SN2 reaction conditions. The nucleophile cannot attack from the back and therefore an SN2 type of reaction is not possible.

Fig. 5: Compounds with leaving groups at bridgehead carbons do not react with ethoxide ion under SN2 reaction conditions. The nucleophile cannot attack from the back and therefore an SN2 type of reaction is not possible.

Another evidence for the SN2 mechanism comes from the fact that as the carbon atom under attack becomes substituted with bulkier groups the approach for the nucleophile is more difficult due to steric hindrance and as a result SN2 reactions do not occur. As a matter of fact the reactivity of carbon atoms, attached to a potential leaving group, towards SN2 reactions follow the order shown in Fig. 6
Fig. 6: Steric effects and reactivity on the SN2 reaction. Reactivity increases as the atoms attached to the C-X carbon are less bulky. The tertiary carbon atom is nonreactive towards SN2 reactions due to steric hindrance – the nucleophile cannot approach the C-X atom  because of the bulky CH3 groups.

Fig. 6: Steric effects and reactivity on the SN2 reaction. Reactivity increases as the atoms attached to the C-X carbon are less bulky. The tertiary carbon atom is nonreactive towards SN2 reactions due to steric hindrance – the nucleophile cannot approach the C-X atom  because of the bulky CH3 groups.
Another example of steric hindrance on SN2 reactions is shown in Fig. 7. The reaction is SN2 and 2-chloropropane reacts with hydrogen carbide even though it is a secondary halide while 1-chloro-2,2-dimethylpropane - a primary halide - does not react. This is due to the difficulty that the nucleophile has to approach the carbon atom due to the bulky substituent group attached. 
Fig. 7: 2-chloropropane reacts with the nucleophile - SN2 reaction- even though is a secondary halide. 1-chloro-2,2-dimethylpropane does not react under SN2 conditions even though it is a primary halide because it is sterically hindered.

Fig. 7: 2-chloropropane reacts with the nucleophile - SN2 reaction- even though is a secondary halide. 1-chloro-2,2-dimethylpropane does not react under SN2 conditions even though it is a primary halide because it is sterically hindered.


References



1. L. Sun et al., J.A.C.S., 123, 5753 (2001)

2. R. Bruckner, “Advanced Organic Chemistry – Reaction Mechanisms”, 2nd Edition, Elsevier, 2002

3. M.B. Smith & J. March “March’s Advanced Organic Chemistry”, 6th Edition, Wiley-Interscience, 2007

4. P. Muller, J. Mareda in G.A. Olah “Cage Hydrocarbons”, Wiley, 1990













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