Editing SN2 reaction

{{short description|Organic chemistry reaction}}
{{Redirect|SN2|slush nitrogen, the mixture of solid and liquid nitrogen sometimes abbreviated as SN<sub>2</sub>|slush nitrogen}}
{{DISPLAYTITLE:S<sub>N</sub>2 reaction}}
[[File:SN2-MeSH-MeI-montage-3D-balls.png|thumb|right|[[Ball-and-stick model|Ball-and-stick representation]] of the S<sub>N</sub>2 reaction of [[methanethiol|CH<sub>3</sub>SH]] with [[iodomethane|CH<sub>3</sub>I]] yielding dimethylsulfonium. Note that the attacking group attacks from the backside of the leaving group]]

The '''bimolecular nucleophilic substitution''' ('''S<sub>N</sub>2''') is a type of [[reaction mechanism]] that is common in [[organic chemistry]]. In the S<sub>N</sub>2 reaction, a strong [[nucleophile]] forms a new bond to an [[orbital hybridisation|sp<sup>3</sup>]]-hybridised carbon atom via a backside attack, all while the [[leaving group]] detaches from the reaction center in a [[Concerted reaction|concerted]] (i.e. simultaneous) fashion.

The name S<sub>N</sub>2 refers to the [[Hughes-Ingold symbol]] of the mechanism:  "S<sub>N</sub>" indicates that the reaction is a [[nucleophilic substitution]], and "2" that it proceeds via a [[bimolecular]] mechanism, which means both the reacting species are involved in the [[rate-determining step]]. What distinguishes S<sub>N</sub>2 from the other major type of nucleophilic substitution, the [[SN1 reaction|S<sub>N</sub>1 reaction]], is that the displacement of the leaving group, which is the rate-determining step, is separate from the nucleophilic attack in S<sub>N</sub>1.

The S<sub>N</sub>2 reaction can be considered as an organic-chemistry analogue of the [[associative substitution]] from the field of [[inorganic chemistry]].

==Reaction mechanism==
The reaction most often occurs at an [[aliphatic]] [[orbital hybridisation|sp<sup>3</sup>]] carbon center with an [[electronegative]], stable leaving group attached to it, which is frequently a [[halogen]] (often denoted X). The formation of the C–Nu bond, due to attack by the nucleophile (denoted Nu), occurs together with the breakage of the C–X bond. The reaction occurs through a [[transition state]] in which the reaction center is [[coordination number|pentacoordinate]] and approximately sp<sup>2</sup>-hybridised.
[[File:SN2 reaction.svg|center|450px]]

The S<sub>N</sub>2 reaction can be viewed as a [[HOMO and LUMO|HOMO–LUMO interaction]] between the nucleophile and substrate. The reaction occurs only when the occupied lone pair orbital of the nucleophile donates electrons to the unfilled [[Antibonding molecular orbital|σ* antibonding orbital]] between the central carbon and the [[leaving group]]. Throughout the course of the reaction, a p orbital forms at the reaction center as the result of the transition from the [[molecular orbitals]] of the reactants to those of the products.<ref name="Clayden-2012">{{cite book |last1=Clayden |first1=Jonathan |last2=Greeves |first2=Nick |last3=Warren |first3=Stuart |title=Organic chemistry |date=2012 |publisher=Oxford University Press |location=Oxford |isbn=978-0-19-927029-3 |page=330 |edition=2nd}}</ref>
[[File:SN2 reaction orbitals and transition state.svg|center|550px]]

To achieve optimal orbital overlap, the nucleophile attacks 180° relative to the leaving group, resulting in the leaving group being pushed off the opposite side and the product formed with [[Inversion in a point|inversion]] of tetrahedral geometry at the central atom.

For example, the synthesis of macrocidin A, a fungal [[metabolite]], involves an intramolecular ring closing step via an S<sub>N</sub>2 reaction with a [[phenoxide]] group as the nucleophile and a halide as the leaving group, forming an [[ether]].<ref>{{cite journal|title=Synthesis of the Bioherbicidal Fungus Metabolite Macrocidin A|last1=Hasse|first1=Robert|last2=Schobert|first2=Rainer|date=November 28, 2016|url=https://doi.org/10.1021/acs.orglett.6b03240|journal=[[Organic Letters]]|volume=18|issue=24|pages=6352–6355|doi=10.1021/acs.orglett.6b03240|access-date=December 30, 2023|url-access=subscription}}</ref> Reactions such as this, with an alkoxide as the nucleophile, are known as the [[Williamson ether synthesis]].
[[File:Macrocidin A intramolecular etherification.svg|center|Synthesis of macrocidin A via S<sub>N</sub>2 etherification.]]

If the substrate that is undergoing S<sub>N</sub>2 reaction has a [[Stereocenter|chiral centre]], then inversion of [[Molecular configuration|configuration]] ([[stereochemistry]] and [[optical activity]]) may occur; this is called the [[Walden inversion]]. For example, 1-bromo-1-fluoroethane can undergo nucleophilic attack to form 1-fluoroethan-1-ol, with the nucleophile being an HO<sup>−</sup> group. In this case, if the reactant is levorotatory, then the product would be dextrorotatory, and vice versa.<ref>{{Cite book|last=CURTIS|first=CLIFF. MURGATROYD, JASON. SCOTT, DAVE|url=https://www.worldcat.org/oclc/1084791738|title=Edexcel international a level chemistry student book.|date=2019|publisher=EDEXCEL Limited|isbn=978-1-292-24472-3|location=[Place of publication not identified]|oclc=1084791738}}</ref>
[[File:SN2 Walden inversion example.svg|500px|center|S<sub>N</sub>2 mechanism of 1-bromo-1-fluoroethane with one of the carbon atoms being a chiral centre.]]

==Factors affecting the rate of the reaction==
The four factors that affect the rate of the reaction, in the order of decreasing importance, are:<ref>{{March6th}}</ref><ref>{{Cite journal|last1=Hamlin|first1=Trevor A.|last2=Swart|first2=Marcel|last3=Bickelhaupt|first3=F. Matthias|date=2018|title=Nucleophilic Substitution (SN2): Dependence on Nucleophile, Leaving Group, Central Atom, Substituents, and Solvent|journal=ChemPhysChem|language=en|volume=19|issue=11|pages=1315–1330|doi=10.1002/cphc.201701363|issn=1439-7641|pmc=6001448|pmid=29542853}}</ref>

===Substrate===
The substrate plays the most important part in determining the rate of the reaction. For S<sub>N</sub>2 reaction to occur more quickly, the nucleophile must easily access the sigma antibonding orbital between the central carbon and leaving group.

S<sub>N</sub>2 occurs more quickly with substrates that are more [[Steric effects|sterically accessible]] at the central carbon, i.e. those that do not have as much sterically hindering substituents nearby. Methyl and primary substrates react the fastest, followed by secondary substrates. Tertiary substrates do not react via the S<sub>N</sub>2 pathway, as the greater steric hindrance between the nucleophile and nearby groups of the substrate will leave the S<sub>N</sub>1 reaction to occur first.
[[File:Steric effects on SN2 reactivity.svg|center|750px]]

Substrates with adjacent pi C=C systems can favor both S<sub>N</sub>1 and S<sub>N</sub>2 reactions. In S<sub>N</sub>1, allylic and benzylic carbocations are stabilized by delocalizing the positive charge. In S<sub>N</sub>2, however, the [[Conjugated system|conjugation]] between the reaction centre and the adjacent pi system stabilizes the transition state. Because they destabilize the positive charge in the carbocation intermediate, electron-withdrawing groups favor the S<sub>N</sub>2 reaction. Electron-donating groups favor leaving-group displacement and are more likely to react via the S<sub>N</sub>1 pathway.<ref name="Clayden-2012" />
[[File:Benzylic chloride nucleophilic substitution.svg|center|650px]]

===Nucleophile===
Like the substrate, steric hindrance affects the nucleophile's strength. The [[methoxide]] anion, for example, is both a strong base and nucleophile because it is a methyl nucleophile, and is thus very much unhindered. [[Potassium tert-butoxide|''tert''-Butoxide]], on the other hand, is a strong base, but a poor nucleophile, because of its three methyl groups hindering its approach to the carbon. Nucleophile strength is also affected by charge and [[electronegativity]]: nucleophilicity increases with increasing negative charge and decreasing electronegativity. For example, OH<sup>−</sup> is a better nucleophile than water, and I<sup>−</sup> is a better nucleophile than Br<sup>−</sup> (in polar protic solvents). In a polar aprotic solvent, nucleophilicity increases up a column of the periodic table as there is no hydrogen bonding between the solvent and nucleophile; in this case nucleophilicity mirrors basicity. I<sup>−</sup> would therefore be a weaker nucleophile than Br<sup>−</sup> because it is a weaker base. Verdict - A strong/anionic nucleophile always favours S<sub>N</sub>2 manner of nucleophillic substitution.

===Leaving group===
Good leaving groups on the substrate lead to faster S<sub>N</sub>2 reactions. A good leaving group must be able to stabilize the [[electron density]] that comes from breaking its bond with the carbon center. This leaving group ability trend corresponds well to the [[Acid dissociation constant|p''K''<sub>a</sub>]] of the leaving group's conjugate acid (p''K''<sub>aH</sub>); the lower its p''K''<sub>aH</sub> value, the faster the leaving group is displaced.

Leaving groups that are neutral, such as [[water]], [[alcohols]] ({{chem2|R\sOH}}), and [[amines]] ({{chem2|R\sNH2}}), are good examples because of their positive charge when bonded to the carbon center prior to nucleophilic attack. Halides ([[Chloride|{{chem2|Cl-}}]], [[Bromide|{{chem2|Br-}}]], and [[Iodide|{{chem2|I-}}]], with the exception of [[Fluoride|{{chem2|F-}}]]), serve as good anionic leaving groups because electronegativity stabilizes additional electron density; the fluoride exception is due to its strong bond to carbon.

Leaving group reactivity of alcohols can be increased with [[sulfonates]], such as [[Tosyl group|tosylate]] ({{chem2|-OTs}}), [[triflate]] ({{chem2|-OTf}}), and [[mesylate]] ({{chem2|-OMs}}). Poor leaving groups include [[hydroxide]] ({{chem2|-OH}}), [[alkoxides]] ({{chem2|-OR}}), and [[Azanide|amides]] ({{chem2|-NR2}}).
[[File:Alcohol to tosylate.svg|center|450px]]

The [[Finkelstein reaction]] is one S<sub>N</sub>2 reaction in which the leaving group can also act as a nucleophile. In this reaction, the substrate has a halogen atom exchanged with another halogen. As the negative charge is more-or-less stabilized on both halides, the reaction occurs at equilibrium.
[[File:Finkelstein reaction example.svg|center|400px]]

===Solvent===
The solvent affects the rate of reaction because solvents may or may not surround a nucleophile, thus hindering or not hindering its approach to the carbon atom.<ref>{{Cite journal|last1=Hamlin|first1=Trevor A.|last2=van Beek|first2=Bas|last3=Wolters|first3=Lando P.|last4=Bickelhaupt|first4=F. Matthias|date=2018|title=Nucleophilic Substitution in Solution: Activation Strain Analysis of Weak and Strong Solvent Effects|journal=Chemistry – A European Journal|language=en|volume=24|issue=22|pages=5927–5938|doi=10.1002/chem.201706075|issn=1521-3765|pmc=5947303|pmid=29457865}}</ref> [[Polar aprotic solvents]], like [[tetrahydrofuran]], are better solvents for this reaction than polar [[protic solvent]]s because polar protic solvents will [[hydrogen bond]] to the nucleophile, hindering it from attacking the carbon with the leaving group. A polar aprotic solvent with low dielectric constant or a hindered dipole end will favour S<sub>N</sub>2 manner of nucleophilic substitution reaction. Examples: [[dimethylsulfoxide]], [[dimethylformamide]], [[acetone]], etc. In parallel, solvation also has a significant impact on the intrinsic strength of the nucleophile, in which strong interactions between solvent and the nucleophile, found for polar [[protic solvent]]s, furnish a weaker nucleophile. In contrast, polar aprotic solvents can only weakly interact with the nucleophile, and thus, are to a lesser extent able to reduce the strength of the nucleophile.<ref>{{cite journal |last1=Hansen |first1=Thomas |last2=Roozee |first2=Jasper C. |last3=Bickelhaupt |first3=F. Matthias |last4=Hamlin |first4=Trevor A. |title=How Solvation Influences the S N 2 versus E2 Competition |journal=The Journal of Organic Chemistry |date=4 February 2022 |volume=87 |issue=3 |pages=1805–1813 |doi=10.1021/acs.joc.1c02354|pmid=34932346 |pmc=8822482 }}</ref><ref>{{cite journal |last1=Vermeeren |first1=Pascal |last2=Hansen |first2=Thomas |last3=Jansen |first3=Paul |last4=Swart |first4=Marcel |last5=Hamlin |first5=Trevor A. |last6=Bickelhaupt |first6=F. Matthias |title=A Unified Framework for Understanding Nucleophilicity and Protophilicity in the S N 2/E2 Competition |journal=Chemistry – A European Journal |date=December 2020 |volume=26 |issue=67 |pages=15538–15548 |doi=10.1002/chem.202003831|pmid=32866336 |pmc=7756690 }}</ref>

==Reaction kinetics==
The rate of an S<sub>N</sub>2 reaction is [[second order reaction|second order]], as the [[rate-determining step]] depends on the nucleophile concentration, <nowiki>[</nowiki>Nu<sup>−</sup><nowiki>]</nowiki> as well as the concentration of substrate, <nowiki>[RX]</nowiki>.<ref name="Clayden-2012" />

:[[Reaction rate|r]] = k<nowiki>[RX][</nowiki>Nu<sup>−</sup><nowiki>]</nowiki>

This is a key difference between the S<sub>N</sub>1 and S<sub>N</sub>2 mechanisms. In the S<sub>N</sub>1 reaction the nucleophile attacks after the rate-limiting step is over, whereas in S<sub>N</sub>2 the nucleophile forces off the leaving group in the limiting step. In other words, the rate of S<sub>N</sub>1 reactions depend only on the concentration of the substrate while the S<sub>N</sub>2 reaction rate depends on the concentration of both the substrate and nucleophile.<ref name = "Clayden-2012" />

It has been shown<ref>Absence of S<sub>N</sub>1 Involvement in the Solvolysis of Secondary Alkyl Compounds, T. J. Murphy, J. Chem. Educ.; 2009; 86(4) pp 519-24; (Article) doi: 10.1021/ed041p678</ref> that except in uncommon (but predictable cases) primary and secondary substrates go exclusively by the S<sub>N</sub>2 mechanism while tertiary substrates go via the S<sub>N</sub>1 reaction.  There are two factors which complicate determining the mechanism of nucleophilic substitution reactions at secondary carbons:
# Many reactions studied are solvolysis reactions where a solvent molecule (often an alcohol) is the nucleophile.  While still a second order reaction mechanistically, the reaction is kinetically first order as the concentration of the nucleophile–the solvent molecule, is effectively constant during the reaction. This type of reaction is often called a pseudo first order reaction.
# In reactions where the leaving group is also a good nucleophile (bromide for instance) the leaving group can perform an S<sub>N</sub>2 reaction on a substrate molecule.  If the substrate is chiral, this inverts the configuration of the substrate before solvolysis, leading to a racemized product–the product that would be expected from an S<sub>N</sub>1 mechanism. In the case of a bromide leaving group in alcoholic solvent Cowdrey et al.<ref>{{cite journal|title=Relation of Steric orientation to Mechanism in Substitution Involving Halogen Atoms and Simple or Substituted Hydroxyl Groups|author1=W.A. Cowdrey|author2=E.D. Hughes|author3=C.K. Ingold|author4=S. Masterman|author5=A.D. Scott|journal=J. Chem. Soc.|year=1937|pages=1252–1271|doi=10.1039/JR9370001252}}</ref> have shown that bromide can have an S<sub>N</sub>2 rate constant 100-250 times higher than the rate constant for ethanol.  Thus, after only a few percent solvolysis of an enantiospecific substrate, it becomes racemic.

The examples in textbooks of secondary substrates going by the S<sub>N</sub>1 mechanism invariably involve the use of bromide (or other good nucleophile) as the leaving group have confused the understanding of alkyl nucleophilic substitution reactions at secondary carbons for 80 years<sup>[3]</sup>. Work with the 2-adamantyl system (S<sub>N</sub>2 not possible) by Schleyer and co-workers,<ref>The 2-Adamantyl System, a Standard for Limiting Solvolysis in a Secondary Substrate J. L. Fry, C. J. Lancelot, L. K. M. Lam, J. M Harris, R. C. Bingham, D. J. Raber, R. E. Hill, P. v. R. Schleyer, J. Am. Chem. Soc.; 1970; 92, pp 1240-42 (Article); doi: 10.1021/ja00478a031</ref> the use of azide (an excellent nucleophile but very poor leaving group) by Weiner and Sneen,<ref>A Clarification of the Mechanism of Solvolysis of 2-Octyl Sulfonates. Stereochemical Considerations; H. Weiner, R. A. Sneen, J. Am. Chem. Soc.; 1965; 87 pp 287-91; (Article) doi: 10.1021/ja01080a026</ref><ref>A Clarification of the Mechanism of Solvolysis of 2-Octyl Sulfonates. Kinetic Considerations; H. Weiner, R. A. Sneen, J. Am. Chem. Soc.; 1965; 87 pp 292-96; (Article) doi: 10.1021/ja01080a027</ref> the development of sulfonate leaving groups (non-nucleophilic good leaving groups), and the demonstration of significant experimental problems in the initial claim of an S<sub>N</sub>1 mechanism in the solvolysis of optically active 2-bromooctane by Hughes et al.<ref>Homogeneous Hydrolysis and Alcoholysis of β-n-Octyl halides, E. D. Hughes, C. K. Ingold, S. Masterman, J. Chem. Soc.; 1937; pp 1196–1201; (Article) doi: 10.1039/JR9370001196</ref><sup>[3]</sup> have demonstrated conclusively that secondary substrates go exclusively (except in unusual but predictable cases) by the S<sub>N</sub>2 mechanism.

==E2 competition==
A common [[side reaction]] taking place with S<sub>N</sub>2 reactions is [[elimination reaction|E2 elimination]]: the incoming anion can act as a base rather than as a nucleophile, abstracting a proton and leading to formation of the [[alkene]]. This pathway is favored with sterically hindered nucleophiles. Elimination reactions are usually favoured at elevated temperatures<ref>{{cite web|url=http://www.masterorganicchemistry.com/2012/09/10/elimination-reactions-are-favored-by-heat/|title=Elimination Reactions Are Favored By Heat — Master Organic Chemistry|website=www.masterorganicchemistry.com|access-date=13 April 2018}}</ref> because of increased [[entropy]]. This effect can be demonstrated in the gas-phase reaction between a [[phenolate]] and a simple [[alkyl halide|alkyl bromide]] taking place inside a [[mass spectrometer]]:<ref>''Gas Phase Studies of the Competition between Substitution and Elimination Reactions'' Scott Gronert [[Accounts of Chemical Research]]; '''2003'''; 36(11) pp 848 - 857; (Article) {{doi|10.1021/ar020042n}}</ref><ref>The technique used is [[electrospray ionization]] and because it requires charged reaction products for detection the nucleophile is fitted with an additional sulfonate anionic group, non-reactive and well separated from the other anion. The product ratio of substitution and elimination product can be measured from the intensity their relative molecular ions.</ref>

:[[File:SN2 E2 gas phase competition.svg|center|650px|Competition experiment between SN2 and E2]]

With [[ethyl bromide]], the reaction product is predominantly the substitution product. As [[steric hindrance]] around the electrophilic center increases, as with [[isobutyl]] bromide, substitution is disfavored and elimination is the predominant reaction. Other factors favoring elimination are the strength of the base. With the less basic [[benzoate]] substrate, isopropyl bromide reacts with 55% substitution. In general, gas phase reactions and solution phase reactions of this type follow the same trends, even though in the first, [[solvent effects]] are eliminated.

==Roundabout mechanism==
A development attracting attention in 2008 concerns a S<sub>N</sub>2 '''roundabout mechanism''' observed in a gas-phase reaction between chloride ions and [[methyl iodide]] with a special technique called ''crossed molecular beam imaging''. When the chloride ions have sufficient velocity, the initial collision of it with the methyl iodide molecule causes the methyl iodide to spin around once before the actual S<sub>N</sub>2 displacement mechanism takes place.<ref>''Imaging Nucleophilic Substitution Dynamics'' J. Mikosch, S. Trippel, C. Eichhorn, R. Otto, U. Lourderaj, J. X. Zhang, W. L. Hase, M. Weidemüller, and R. Wester Science 11 January '''2008''' 319: 183-186 {{doi| 10.1126/science.1150238}} (in Reports)</ref><ref>''PERSPECTIVES CHEMISTRY: Not So Simple'' John I. Brauman (11 January 2008) Science 319 (5860), 168. {{doi|10.1126/science.1152387}}</ref><ref>''Surprise From SN2 Snapshots Ion velocity measurements unveil additional unforeseen mechanism'' Carmen Drahl [[Chemical & Engineering News]] January 14, '''2008''' Volume 86, Number 2 p. 9 http://pubsapp.acs.org/cen/news/86/i02/8602notw1.html, video included</ref>

==See also==
* [[Arrow pushing]]
* [[Christopher Kelk Ingold]]
* [[Finkelstein reaction]]
* [[Neighbouring group participation]]
* [[Nucleophilic acyl substitution]]
* [[Nucleophilic aromatic substitution]]
* [[SN1 reaction|S<sub>N</sub>1 reaction]]
* [[SNi|S<sub>N</sub>i]]
* [[Substitution reaction]]

==References==
{{Reflist}}

{{Reaction mechanisms}}

{{DEFAULTSORT:Sn2 Reaction}}
[[Category:Nucleophilic substitution reactions]]
[[Category:Reaction mechanisms]]