The SN1 Mechanism

The SN1 Reaction Mechanism

• There are two important classes of nucleophilic substitution mechanisms – the S_N1 and S_N2 mechanisms (See article – Two Types of Substitution Reactions)
• The S_N1 mechanism is distinct from the S_N2 in three distinct ways.
• The reaction is fastest for tertiary alkyl halides and slowest for primary (and methyl) halides
• The rate law is unimolecular – it is only dependent on the concentration of substrate (i.e. alkyl halide) and not the nucleophile
• Alkyl halides with a chiral center at the “alpha-carbon” will give a product that provides a mixture of retention of configuration and inversion of configuration. [Note 2] Sometimes this is described as “racemization” .
• The best explanation for how this reaction works is that it begins with a (rate-determining) loss of a leaving group to give a carbocation, which can then undergo attack by a weak nucleophile at either face, resulting in the loss of stereochemistry.
• The S_N1 reaction is sometimes accompanied by carbocation rearrangements. (See article – Substitution With Rearrangement)

Table of Contents

1. Stereochemistry Of The SN1 Reaction: A Mixture of Retention and Inversion is Observed
2. The Rate Law Of The SN1 Reaction Is First-Order Overall
3. The Reaction Rate Increases With Substitution At Carbon (Tertiary >> Secondary > Primary)
4. The Stepwise Reaction Mechanism of the SN1 Reaction
5. Notes
6. Quiz Yourself! 
7. (Advanced) References and Further Reading

1. Stereochemistry Of The SN1 Reaction: A Mixture of Retention and Inversion is Observed

If we start with an enantiomerically pure product, (that is, one enantiomer), these reactions tend to result in a mixture of products where the stereochemistry is the same as the starting material (retention) or opposite (inversion). In other words, some degree of racemization will take place (See post: What Is A Racemic Mixture?)

Compare this to the S_N2, which always results in inversion of stereochemistry! Clearly something different must be going on here.

2. The Rate Law Of The SN1 Reaction Is First-Order Overall

We can also measure the rate law of these reactions. When we do so, we notice that the rate is only dependent on the concentration of the substrate, but not on the concentration of nucleophile.

Weird. Remember that the S_N2 depends on both. Why might this reaction only depend on the concentration of substrate?

3. The Reaction Rate Increases With Substitution At Carbon

When we subtly change the types of substrates (e.g. alkyl halides) we use in these reactions, we find that tertiary substrates (for instance, t-butyl bromide) are considerably faster than secondary alkyl bromides, which are in turn faster than primary [Note 1]

Compare that to the case for S_N2, where primary was faster than secondary and tertiary hardly reacted at all. Mysterious!

4. The Stepwise Reaction Mechanism of the S_N1 Reaction

The best hypothesis we have for this reaction is a stepwise mechanism.

• In the first step, the leaving group leaves, forming a carbocation.
• In the second, a nucleophile attacks the carbocation, forming the new product.

This explains all of our observations nicely. First of all, the slow step should be formation of the (unstable) carbocation – which only depends on the substrate, not the nucleophile.

Furthermore, since the stability of carbocations depends tremendously on substitution pattern (tertiary carbocations are more stable than secondary, which are more stable than primary) this also conveniently explains the dependence of the reaction rate on substitution pattern  (See post: Carbocation Stability)

Any factor which stabilizes the carbocation, increases the rate at which the leaving group can leave. 

It also helps us understand the stereochemistry. Since the electrophile is flat, attack could occur from either face; which means that we obtain a mixture of retention and inversion products.

This is therefore called the S_N1 mechanism – Substitution, Nucleophilic, Unimolecular – to contrast with the S_N2 (Substitution, Nucleophilic, Bimolecular).

It all seems to work if you’ve got a good leaving group present (like a halogen). But what if you don’t have a good leaving group? In the next post we’ll talk about how to make a poor leaving group into a good one.

Next Post: The Conjugate Acid Is A Better Leaving Group

Notes

Note 1.  – the primary alkyl halide shown here is certainly reacting solely through an S_N2 mechanism.

Note 2.  Athough it’s often said that the S_N1 proceeds with “racemization” of stereocenters, in practice a 50/50 split of stereocenters may not be obtained due to “ion pairing” effects.

In other words, the leaving group could leave, but not fully dissociate from the vicinity of the carbocation, which could block a nucleophile from attacking the electrophile from that face. For that reason it’s a little bit more correct to say that it proceeds with a  “mixture of retention and inversion” rather than “racemization”.

Quiz Yourself!

Click to Flip

(Advanced) References and Further Reading

1. 56. Mechanism of substitution at a saturated carbon atom. Part V. Hydrolysis of tert.-butyl chloride. 
   Edward D. Hughes.
   J. Chem. Soc. 1935, 235
   DOI: 10.1039/JR9350000255
   Original study where the hydrolysis of t-butyl chloride was found to be first-order in alkyl halide and zero order in base, giving rise to the mechanism we now know as SN1.

2. Mechanism of substitution at a saturated carbon atom. Part IX. The rôle of the solvent in the first-order hydrolysis of alkyl halides
   Leslie C. Bateman and Edward D. Hughes
   J. Chem. Soc. 1937, 1187-1192
   DOI: 10.1039/JR9370001187
   In the hydrolysis of alkyl bromides by water in formic acid, the relative rates at 100° are MeBr 1.00, EtBr 1.71, iPrBr 44.7, and tBuBr ca. 10^8.
3. Reaction kinetics and the Walden inversion. Part I. Homogeneous hydrolysis and alcoholysis of β-n-octyl halides
   Edward D. Hughes, Christopher K. Ingold and Standish Masterman
   J. Chem. Soc. 1937, 1196-1201
   DOI: 10.1039/JR9370001196
4. Reaction kinetics and the Walden inversion. Part IV. Action of silver salts in hydroxylic solvents on β-n-octyl bromide and α-phenylethyl chloride
   Edward D. Hughes, Christopher K. Ingold and Standish Masterman
   J. Chem. Soc., 1937, 1236-1243
   DOI: 10.1039/JR9370001236
   These two papers examine reactions of 2-octyl halides in an attempt to see if pure S_N1 or S_N2 pathways on the same substrate can be favored simply by varying the reaction conditions.
5. The Correlation of Solvolysis Rates
   Ernest Grunwald and S. Winstein
   Journal of the American Chemical Society 1948, 70 (2), 846-854
   DOI: 1021/ja01182a117
   This is a very important paper, discussing the ‘Grunwald-Winstein equation’ for the first time. This equation is an extension of the Hammett equation, taking solvent effects (i.e. ‘ionizing power’) into consideration.
6. The Reactivity of Bridgehead Compounds of Adamantane
   Paul von R. Schleyer and Robert D. Nicholas
   Journal of the American Chemical Society 1961, 83 (12), 2700-2707
   DOI: 1021/ja01473a024
   Bridgehead carbocations are generally quite unstable since they cannot achieve the planar geometry necessary for good hyperconjugative stabilization. Somewhat surprisingly, in this paper it is found that the SN1 reaction of 1-bromoadamantane proceeds only about 1000 times slower than that of t-butyl bromide, albeit (of course) only with retention of configuration.
7. The Common Basis of Intramolecular Rearrangements. VI.1 Reactions of Neopentyl Iodide
   Frank C. Whitmore, E. L. Wittle, and A. H. Popkin
   Journal of the American Chemical Society 1939, 61 (6), 1586-1590
   DOI: 1021/ja01875a073
   An early paper demonstrating that S_N1 reactions can be induced by reaction of an alkyl halide with silver salts. In this case, the neopentyl cation quickly rearranges to the significantly more stable t-amyl cation, and those products are obtained.
8. Mechanism of substitution at a saturated carbon atom. Part XXIX. The rôle of steric hindrance. (Section D) the mechanism of the reaction of neopentyl bromide with aqueous ethyl alcohol
   I. Dostrovsky and E. D. Hughes
   J. Chem. Soc., 1946, 166-169
   DOI: 10.1039/JR9460000166
   This is an example of an S_N1 reaction with rearrangement. Neopentyl bromide in aqueous ethyl alcohol gives t-amyl alcohol (and t-amyl ethyl ether).
9. Mechanism of substitution at a saturated carbon atom. Part XXXV. Effect of temperature on the competition between unimolecular solvolytic and non-solvolytic substitutions of di-p-tolylmethyl chloride. Activation in the fast step of unimolecular non-solvolytic substitution
   Audrey R. Hawdon, E. D. Hughes and C. K. Ingold
   J. Chem. Soc., 1952, 2499-2503
   DOI: 10.1039/JR9520002499
   It is possible to run S_N1 reactions in the presence of added nucleophile, such as in the hydrolysis of benzyl chlorides in the presence of added sodium azide. The separate rates of formation of the carbocation and production of the azide can thus be measured.
10. Methanolysis of Optically Active Hydrogen 2,4-Dimethylhexyl-4-phthalate
    von E. Doering and Harold H. Zeiss
    Journal of the American Chemical Society 1953, 75 (19), 4733-4738
    DOI: 10.1021/ja01115a035
    An early example of an S_N1 reaction without full racemization. Prof. Doering proposes a mechanism in the paper, interesting read.
11. Quaternary stereocentres via an enantioconvergent catalytic S_N1 reaction
    Wendlandt, A.E., Vangal, P. & Jacobsen, E.N.
    Nature 556, 447–451 (2018)
    DOI: 1038/s41586-018-0042-1
    This is a rare example of an asymmetric S_N1 reaction – normally the S_N1 reaction is taught as giving achiral products, but in this particular case it is possible to induce chirality because the carbocation is so highly stabilized (tertiary, benzylic, and propargylic).