The SN2 Mechanism

The S_N2 Reaction Mechanism

Having gone through the two different types of substitution reactions, and talked about nucleophiles and electrophiles, we’re finally in a position to reveal the mechanism for one of the most important reactions in organic chemistry.

It’s called the S_N2 reaction, and it’s going to be extremely useful for us going forward.

Table of Contents

1. The S_N2 Reaction Proceeds With Inversion of Configuration
2. The Rate Law Of The S_N2 Is Second Order Overall
3. The Reaction Rate Is Fastest For Small Alkyl Halides (Methyl > Primary > Secondary >> Tertiary)
4. The S_N2 Mechanism Proceeds Through A Concerted Backside Attack Of The Nucleophile Upon The Alkyl Halide
5. Notes
6. (Advanced) References and Further Reading

1. The S_N2 Reaction Proceeds With Inversion of Configuration

When we start with a molecule with a chiral center, such as (S)-2-bromobutane, this class of reaction results in inversion of stereochemistry. Note how we start with (S)-2-bromobutane and end up with (R)-2-methylbutanenitrile. 

2. The Rate Law Of The S_N2 Is Second Order Overall

Note how the rate of the reaction is dependent on both the concentration of the nucleophile and that of the substrate. In other words, it’s a second-order reaction.

3. The Reaction Rate Of The S_N2 Reaction Is Fastest For Small Alkyl Halides (Methyl > Primary > Secondary >> Tertiary)

Finally, note how changes in the substitution pattern of the alkyl halide results in dramatic changes in the rate of the reaction.[Note 1] “Smaller” alkyl halides like methyl bromide are fast, while more highly substituted tertiary alkyl bromide doesn’t proceed at all.

Taking all this data into consideration, we refer to this reaction as the S_N2 mechanism. What does S_N2 stand for?

• Substitution
• Nucleophilic
• 2 molecules in the rate determining step

So how does it work?

4. The S_N2 Mechanism Proceeds Through A Concerted Backside Attack Of The Nucleophile Upon The Alkyl Halide

The best explanation we have for what happens in this reaction is that it proceeds through what organic chemists refer to as a backside attack.  The nucleophile approaches the alkyl halide 180° from the C-Br bond, and as the C-(nucleophile) bond forms, the C-(leaving group) bond breaks [Note 2] At the transition state of the reaction, there are partial C-(nucleophile) and C-(leaving group) bonds (denoted by dashed lines). Note the geometry too – instead of tetrahedral, it’s trigonal bipyramidal. This is 5-coordinate carbon – if only for a femtosecond or two.

And in an analogy you’ll no doubt hear many times, then,  like an umbrella in a strong wind, the three groups flip over as the leaving group leaves, resulting in inversion of configuration. Note that inversion happens at carbons without stereocenters too – it’s just that we can’t observe it because there’s no way to detect the change in configuration.

This umbrella metaphor for the backside attack mechanism is so fundamental and well known in organic chemistry that you can tweet about it and people will know exactly what you mean.

In the next post, we’ll show some more examples of this reaction and explain why it’s one of the most useful reactions in chemistry.

P.S. You may remember that Freda also took this awesome picture of an ozonolysis reaction.

Next Post: Why The S_N2 Is Powerful

Notes

Note 1. Numbers are approximate. Source – Smith, M. and March, J. L. “March’s Advanced Organic Chemistry” 5th ed.

Note 2. backside attack, because the nucleophile donates a pair of electrons into the most accessible empty orbital, which is the antibonding (σ*) orbital of the C-(leaving group) bond, which resides at 180° to the bond. Donation of a pair of electrons into the antibonding orbital results in cleavage of the bond. It’s kind of like an “eject button” in that way.

(Advanced) References and Further Reading

1. Ueber die gegenseitige Umwandlung optischer Antipoden
   Walden
   Chem. Ber. 1896, 29 (1), 133-138
   DOI: 10.1002/cber.18960290127
   The inversion of stereochemistry observed in an S_N2 reaction is also called Walden inversion, after the chemist Paul Walden. In this paper, he converts (+)-chlorosuccinic acid to the opposite enantiomer and back.  This process of double inversion resulting in retention is called a Walden cycle.
2. Influence of poles and polar linkings on the course pursued by elimination reactions. Part XVI. Mechanism of the thermal decomposition of quaternary ammonium compounds
   E. D. Hughes, C. K. Ingold, and C. S. Patel
   J. Chem. Soc. 1933, 526-530
   DOI: 10.1039/JR9330000526
   At the end of this paper, the authors make an important point: “When the various series can be more fully filled in, what has been described as a “ point ” of mechanistic change will probably appear as a region, and thus, just as with reaction (A), we now generalise the original conception of reaction (B) by the contemplation of a range of mechanisms, (Bl)-(B2), both extremes of which have been experimentally exemplified”. Basically, the S_N1 and S_N2 mechanisms as taught are two extremes of a continuum, and in practice most reactions lie somewhere in between.
3. Mechanism of substitution at a saturated carbon atom. Part III. Kinetics of the degradations of sulphonium compounds
   John L. Gleave, Edward D. Hughes and Christopher K. Ingold
   J. Chem. Soc. 1935, 234-244
   DOI: 10.1039/JR9350000236
   This is a useful paper – in the beginning the terms “S_N1” and “S_N2” are introduced and defined, and Figs. 1 and 2 depict how the two mechanisms can compete depending on the structure of the substrate.
4. Aliphatic substitution and the Walden inversion. Part I
   E. D. Hughes, F. Juliusburger, S. Masterman, B. Topley, and J. Weiss
   J. Chem. Soc. 1935, 1525-1529
   DOI: 10.1039/JR9350001525
   Classic study correlating the rate of racemization with rate of uptake of radioactive iodide ion. Because this experiment was conducted in the early 20^th century when nuclear chemistry was in its infancy, the iodide ion was made radioactive by exposure to a neutron source (Ra/Be) and the exact isotope was not determined.
5. Mechanism of substitution at a saturated carbon atom. Part XLII. Introductory remarks, and kinetics of the interaction of chloride ions with simple alkyl chlorides in acetone
   B. D. de la Mare
   J. Chem. Soc. 1955, 3169-3173
   DOI: 10.1039/JR9550003169
   Table 2 in this paper demonstrates the rate decrease of a simple S_N2 reaction (Finkelstein displacement of Cl with ³⁶Cl^– in this case) upon going from methyl -> ethyl -> isopropyl. The rate decreases 50-80 fold upon going from methyl -> ethyl or ethyl -> isopropyl.
6. Mechanism of substitution at a saturated carbon atom. Part XXVI. The rôle of steric hindrance. (Section A) introductory remarks, and a kinetic study of the reactions of methyl, ethyl, n-propyl, isobutyl, and neopentyl bromides with sodium ethoxide in dry ethyl alcohol
   I. Dostrovsky and E. D. Hughes
   J. Chem. Soc. 1946, 157-161
   DOI: 10.1039/JR9460000157
   Table I in this paper shows the reduction in reaction rate for the S_N2 reaction of R-Br with OEt- when R goes from methyl -> ethyl -> n-propyl -> isobutyl -> t-amyl. This can be attributed to sterics, as backside attack of the substituted carbon becomes increasingly challenging.
7. Bicyclic Structures Prohibiting the Walden Inversion. Further Studies on Triptycene and its Derivatives, Including 1-Bromotriptycene
   Paul D. Bartlett and Edward S. Lewis
   Journal of the American Chemical Society 1950, 72 (2), 1005-1009
   DOI: 1021/ja01158a094
   1-bromotriptycene is inert under a wide variety of conditions due to the structure – backside access to the C-Br bond is basically impossible, and due to the bridgehead geometry, forming a sp² carbon at that position is strongly disfavored, precluding the formation of a cation or radical there. In the first paragraph, Prof. Bartlett mentions, “Work which was then under way to extend this study to the carbonium ion and the free radical was interrupted by World War II and is here reported.”
8. Reaction kinetics and the Walden inversion. Part VI. Relation of steric orientation to mechanism in substitutions involving halogen atoms and simple or substituted hydroxyl groups
   W. A. Cowdrey, E. D. Hughes, C. K. Ingold, S. Masterman, and A. D. Scott
   J. Chem. Soc. 1937, 1252-1271
   DOI: 10.1039/JR9370001252
   The points listed in the summary are worth reading for understanding what influences the S_N1 and S_N2 pathways.
9. Conformational Analysis. IV. Bimolecular Displacement Rates of Cyclohexyl p-Toluenesulfonates and the Conformational Equilibrium Constant of the p-Toluenesulfonate Group
   Ernest L. Eliel and Rolland S. Ro
   Journal of the American Chemical Society 1957, 7i9 (22), 5995-6000
   DOI: 1021/ja01579a040
   This paper describes a classic S_N2 experiment on cis- and trans-4-t-butylcyclohexyltosylate. The trans ester reacts 19 times faster than cis because of the chair flip. Due to the t-butyl group, the barrier for ring inversion is extremely high (t-butyl is basically ‘locked’ in the equatorial position), and this is described further in the section on A-values.
10. Nucleophilic Substitution (S_N2): Dependence on Nucleophile, Leaving Group, Central Atom, Substituents, and Solvent
    Trevor A. Hamlin, Marcel Swart, F. Matthias Bickelhaupt
    ChemPhysChem 2018, 19 (11), 1315-1330
    DOI: 1002/cphc.201701363
    A more recent paper computationally examining the effects of various variables on S_N2 reaction energetics.
11. Solvolytic Displacement Reactions At Saturated Carbon Atoms
    Andrew Streitwieser, Jr.
    Chemical Reviews 1956 56 (4), 571-75
    DOI: 10.1021/cr50010a001
    This early review by Prof. Streitwieser (U.C. Berkeley) is a comprehensive review of the early literature of the SN1 and SN2 reactions.