Nucleophilic Substitution: SN2 and SN1 reactions and Stereochemistry

There is large amount of evidence that S_N2 reactions proceed with a backside attack of the nucleophile Nu at the carbon atom attached to the leaving group X^1-3.

Fig. 1: Mechanism for the S_N2 reaction

In a previous post entitled “The S_N2 reaction: Substitution Nucleophilic Bimolecular” the kinetic evidence for the S_N2 mechanism was shown.

However, much more convincing evidence is obtained from the fact that the mechanism of the  S_N2 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

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 S_N2 reaction occurs. When (+)-malic acid reacts with SOCl₂ the substitution reaction proceeds with retention of configuration – an S_N1 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. 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 S_N2 mechanism comes from compounds with leaving groups at bridgehead carbons⁴ (Fig. 5). These compounds do not react with ethoxide ion – under S_N2 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.

Another evidence for the S_N2 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 S_N2 reactions do not occur. As a matter of fact the reactivity of carbon atoms, attached to a potential leaving group, towards S_N2 reactions follow the order shown in Fig. 6

Fig. 6: Steric effects and reactivity on the S_N2 reaction. Reactivity increases as the atoms attached to the C-X carbon are less bulky. The tertiary carbon atom is nonreactive towards S_N2 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 S_N2 reactions is shown in Fig. 7. The reaction is S_N2 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 - S_N2 reaction- even though is a secondary halide. 1-chloro-2,2-dimethylpropane does not react under S_N2 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”, 2^nd Edition, Elsevier, 2002

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

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