View source for Leaving group

{{short description|Atom(s) that detach from the substrate during a chemical reaction}}
[[File:Leaving groups-3-types-of-reactions.png|thumb|300x300px|Common mechanistic contexts that involve the departure of a nucleofugal leaving group.  The leaving group (LG) is shown in red. Top: S<sub>N</sub>2 reaction; middle/left: first step of S<sub>N</sub>1 and E1 reactions; middle/right: second step of E1cb, A<sub>AC</sub>2, and B<sub>AC</sub>2 reactions; bottom: E2 reaction.]]In [[organic chemistry]], a '''leaving group''' typically means a [[Chemical species|molecular fragment]] that departs with an [[electron|electron pair]] during a [[reaction step]] with [[heterolysis (chemistry)|heterolytic bond cleavage]].  In this usage, a ''leaving group'' is a less formal but more commonly used synonym of the term ''[[nucleofuge]]''; although [[IUPAC]] gives the term a broader definition.  

A species' ability to serve as a leaving group can affect whether a reaction is viable, as well as what mechanism the reaction takes.  

Leaving group ability depends strongly on context, but often correlates with ability to stabilize additional [[electron density]] from bond heterolysis.  Common anionic leaving groups are {{chem2|Cl-}}, {{chem2|Br-}} and {{chem2|I-}} [[halide]]s and [[sulfonate]] esters such as [[tosyl]]ate ({{chem2|TsO-}}).  Water ({{chem2|H2O}}), [[alcohols]] ({{chem2|R\sOH}}), and [[amines]] ({{chem2|R3N}}) are common neutral leaving groups, although they often require activating catalysts.  Some moieties, such as [[hydride]] (H<sup>&minus;</sup>) serve as leaving groups only extremely rarely.

== Nomenclature ==
[[IUPAC]] defines a leaving group to be any [[Moiety (chemistry)|group of atoms]] that detaches from the main [[Substrate (chemistry)|substrate]] during a [[elementary step|reaction step]].<ref name=":0">{{cite book |title=Gold Book: leaving group |publisher=IUPAC |year=2009 |isbn=978-0-9678550-9-7 |chapter=Leaving group |doi=10.1351/goldbook.L03493 |chapter-url=https://www.iupac.org/goldbook/L03493.pdf |archive-date=2017-11-07 |access-date=2017-06-10 |archive-url=https://web.archive.org/web/20171107010358/https://www.iupac.org/goldbook/L03493.pdf |url-status=dead }}</ref>  The term thus includes groups that depart ''without'' an electron pair in a heterolytic cleavage ([[electrofuge]]s), like {{chem2|[[Hydron (chemistry)|H+]]}} or {{chem2|SiR3+}}, which commonly depart in [[electrophilic aromatic substitution]] reactions.<ref name=":0" /><ref>{{cite web |title=Gold Book: electrofuge |url=https://www.iupac.org/goldbook/E01965.pdf |url-status=dead |archive-url=https://web.archive.org/web/20171107010401/https://www.iupac.org/goldbook/E01965.pdf |archive-date=2017-11-07 |access-date=2017-06-10 |publisher=IUPAC}}</ref>  Similarly, species of high [[thermodynamic stability]] like [[nitrogen]] ({{chem2|N2}}) or [[carbon dioxide]] ({{chem2|CO2}}) commonly act as leaving groups in homolytic bond cleavage reactions of [[Radical (chemistry)|radical species]].  

In [[organic chemistry]], the term leaving group is rarely used for such species, being restricted only to [[Nucleofuge|nucleofugal]] leaving groups.<ref>For example, leaving groups are defined this way in ''Organic Chemistry: Structure and Function'' (8th ed.) by P. Vollhardt and N. Schore (p. 231).</ref>  Leaving groups are generally [[anion]]s or neutral species, departing from neutral or [[cation]]ic substrates, respectively, though in rare cases, cations leaving from a [[dication]]ic substrate are also known.<ref>{{Cite journal |last1=Weiss |first1=Robert |last2=Engel |first2=Stefan |date=February 1992 |title=Electrostatic Activation of Nucleofuges: Cationic Leaving Groups |url=https://onlinelibrary.wiley.com/doi/10.1002/anie.199202161 |journal=Angewandte Chemie International Edition in English |language=en |volume=31 |issue=2 |pages=216–217 |doi=10.1002/anie.199202161 |issn=0570-0833|url-access=subscription }}</ref>  

This article follows the organic chemistry convention.

==Overview==
Leaving group ability manifests physically in a fast [[reaction rate]]. [[Transition state theory|Equivalently]], reactions involving good leaving groups have low activation barriers and relatively stable transition states.  Because different reaction mechanisms have different transition states, leaving group ability depends on the reaction in question.  

For example, consider the first step of an [[SN1 reaction|S<sub>N</sub>1]] or [[E1 reaction]] in neutral media: ionization, with an anionic leaving group.  

[[File:ionization reaction wide.png|center|thumb|350px|In an ionization reaction, as in all reactions that involve leaving group departure, the leaving group bears a larger negative charge in the transition state and products than it does in the starting materials]]Because the leaving group gains negative charge in the transition state (and products), a good leaving group must stabilize this negative charge and form a stable [[anion]].  Strong bases such as {{chem2|OH-, OR-}} and {{chem2|NR2-}} tend to make poor leaving groups, as they cannot stabilize further negative charge; whereas extremely weak bases, such as [[Mesylate|OSO<sub>2</sub>CH{{Su|b=3|p=&minus;}}]], leave easily.  Mathematically, leaving groups typically exhibit [[Bell–Evans–Polanyi principle|Bell–Evans–Polanyi correlation]] between the [[Acid dissociation constant|dissociation constant]] for their [[conjugate acid]] (p''K''<sub>aH</sub>) and lability.{{Cn|date=May 2025}}  

===Context-dependence===
The correlation in S<sub>N</sub>1 and E1 reactions between leaving group ability and p''K''<sub>aH</sub> is not perfect. Leaving group ability reflects the energy difference (Δ''G''<sup>‡</sup>) between neutral starting materials and the partially-charged, partially-bonded transition state. The p''K''<sub>aH</sub>, however, represents net energy difference (Δ''G°'') for the (possibly multi-step) adduction equilibrium between the leaving group and a solvated proton.  [[Hammond's postulate]] explains conceptually when and why the two energy differences correlate.{{Cn|date=May 2025}}    

For reactions with a different transition state, other aspects of the leaving group may govern.  In acid-catalyzed reactions' [[rate-determining step]], only adducts between the formal leaving group and the acid catalyst depart.  In those cases, leaving group ability correlates with bond strength to the catalyst (see {{Slink||Leaving group activation}}).  Even more dramatically, [[benzoic acid|benzoate anions]] decarboxylate when heated with a [[copper]] salt catalyst, in principle expulsing an aryl anion from {{CO2}}.  The true leaving group is most likely an [[Organocopper chemistry|arylcopper compound]] rather than the aryl anion salt.{{Cn|date=May 2025}}    

Even for the same reaction mechanism in the same media, relative lability may depend on the other reagents. In the substitutions tabulated below, [[ethoxide]] displaces tosylate before any halide, but [[Para-Thiocresol|''para''-thiocresolate]] prefers to displace iodide and even bromide before tosylate.<ref name="Hoffman 1965">{{Cite journal |last=Hoffmann |first=H. M. R. |year=1965 |title=1252. The rate of displacement of toluene-p-sulphonate relative to bromide ion. A new mechanistic criterion |journal=Journal of the Chemical Society (Resumed) |volume=1965 |issue= |pages=6753–6761 |doi=10.1039/JR9650006753 |issn=0368-1769}}</ref>  

{| class="wikitable" style="margin: 1em auto 1em auto;"
|+ '''Relative rates for leaving groups (''k''<sub>X</sub>/''k''<sub>Br</sub>) in each reaction'''
|-
! scope="col" width="100px" | Leaving group (X)
! scope="col" width="350px" style="padding-left: 2em" | [[File:Propyl halide toluene thiolate reaction.png|center|332px]]
! scope="col" width="350px" | [[File:Ethyl halide ethoxide reaction.png|center|291px]]
|- align="center"
|Cl || 0.0074 || 0.0024 (at 40&nbsp;°C)
|- align="center"
|Br || 1 || 1
|- align="center"
|I || 3.5 || 1.9
|- align="center"
|OTs || 0.44 || 3.6
|}

== Table ==
Many organic chemistry textbooks offer a table comparing typical leaving groups' ability across common reactions:

{| class="wikitable" style="margin: 1em auto 1em auto;"
! colspan="2" | Leaving groups ordered approximately in decreasing ability to leave<ref>Smith, March. ''Advanced Organic Chemistry'' 6th ed. (501-502)</ref>
|-
|{{chem2|R\sN2+}}
|[[nitrogen|dinitrogen]]
|-
|{{chem2|R\sOR'2+}}
|[[ether|dialkyl ether]]
|-
|{{chem2|R\sOSO2R^{F} }}
|perfluoroalkylsulfonates (e.g. [[triflate]])
|-
|R–I
|[[iodide]]
|-
|R–OTs, R–OMs, etc.
|[[tosylate]]s, [[mesylate]]s and similar sulfonates
|-
|R–Br
|[[bromide]]
|-
|{{chem2|R\sOH2+}}, {{chem2|R'\sOHR+}}
|[[water]], [[Alcohol (chemistry)|alcohol]]s
|-
|R–Cl
|[[chloride]]
|-
|{{chem2|R\sONO2}}, {{chem2|R\sOPO(OR')2}}
|[[nitrate]], [[phosphate]], and other inorganic esters
|-
|{{chem2|R\sSR'2+}}
|[[thioether]]
|-
|{{chem2|R\sNR'3+}}, {{chem2|R\sNH3+}}
|[[amine]]s, [[ammonia]]
|-
|R–F
|[[fluoride]]
|-
|R–OCOR
|[[carboxylic acid|carboxylate]]
|-
|R–OAr
|[[phenoxide]]s
|-
|R–OH, R–OR
|[[hydroxide]], [[alkoxide]]s
|-
|R–NR<sub>2</sub>
|[[metal amides#alkali metal amides|amides]]
|-
|R–H
|[[hydride]]
|-
|R–R'
|[[Carbanion|arenide, alkanide]]
|}
It is exceedingly rare for groups such as {{chem2|H-}} ([[hydride]]s), {{chem2|R3C-}} ([[Carbanion|alkyl anions]], R = alkyl or H), or {{chem2|Ar-}} (aryl anions, Ar = aryl) to depart with a pair of electrons because of the high energy of these species.  The [[Chichibabin reaction]] provides an example of hydride as a leaving group, while the [[Wolff–Kishner reduction|Wolff-Kishner reaction]] and [[Ketone#Reactions|Haller-Bauer reaction]] feature unstabilized carbanion leaving groups.

== S<sub>N</sub>2 reactions ==
For S<sub>N</sub>2 reactions, typical synthetically-useful leaving groups include {{chem2|Cl-, Br-, I-}}, {{chem2|-OTs, -OMs, -OTf}}, and {{chem2|H2O}}.  Phosphate and carboxylate substrates are more likely to react by competitive addition-elimination, while sulfonium and ammonium salts generally form ylides or undergo E2 elimination.  Phenoxides ({{chem2|-OAr}}) constitute the lower limit for feasible S<sub>N</sub>2 leaving groups: very strong nucleophiles like {{chem2|Ph2P-}} or {{chem2|EtS-}} demethylate [[anisole]] derivatives through S<sub>N</sub>2 displacement at the methyl group.  Hydroxide, alkoxides, amides, hydride, and alkyl anions do not serve as leaving groups in S<sub>N</sub>2 reactions.{{Cn|date=May 2025}}

== Basic eliminations ==
When anionic or dianionic [[Tetrahedral carbonyl addition compound|tetrahedral intermediates]] collapse, the high electron density of the neighboring heteroatom facilitates the expulsion of even a very poor leaving group.  This dramatic departure occurs because forming a very strong C=O double-bond can drive an otherwise unfavorable reaction forward.{{cn|date=May 2025}}  For example, even [[Amide|amides]] expulse R<sub>2</sub>N<sup>−</sup>, an extremely poor leaving group, in [[nucleophilic acyl substitution]].  

This elimination of poor leaving groups also extends [[Vinylogy|vinylogously]] to conjugate base eliminations.  Many [[E1cB-elimination reaction|E1cb]] reactions (e.g. the [[aldol condensation]]) commonly involve a hydroxide leaving group from an [[enol]]ate β position. 

Likewise, in [[nucleophilic aromatic substitution|S<sub>N</sub>Ar]] reactions, the rate is generally increased when the leaving group is fluoride relative to the other halogens. This effect is due to the fact that the highest energy transition state for this two step addition-elimination process occurs in the first step, where fluoride's greater electron withdrawing capability relative to the other halides stabilizes the developing negative charge on the aromatic ring. The departure of the leaving group takes place quickly from this high energy [[Meisenheimer complex]], and since the departure is not involved in the rate limiting step, it does not affect the overall rate of the reaction.<ref>Warren, S.; Wyatt, P. ''Organic Synthesis: The Disconnection Approach'', 2nd ed.; Wiley: Chichester, U.K., 2008.</ref>{{page needed|date=May 2025}} 

=== E1cb reactions ===
E1cb reactions proceed with poor leaving groups, but because the C=C double bond is weaker than a C=O bond, the leaving group affects the elimination mechanism.  

[[File:E1cB reaction.png|center|350px]]

[[File:Elimination continuum.png|center|650px]]

Poor leaving groups favor the E1cB mechanism, but as the leaving group improves, transition state '''''BC''<sup>‡</sup>''' becomes lower in energy.  First, the rate-determining step shifts: initially leaving-group elimination from intermediate '''''B'''''; it becomes deprotonation via transition state '''''AB''<sup>‡</sup>''' (not pictured).  Eventually, '''''BC''<sup>‡</sup>''' is no longer [[Stationary point|stationary]] on the potential energy surface, and the reaction becomes a concerted E2 elimination (albeit very asynchronous in the diagrammed case).{{cn|date=May 2025}}

==Activation==
In [[substitution reaction|S<sub>N</sub>1]] and [[elimination reaction#E1 mechanism|E1]] reactions, protonation or complexation with a [[Lewis acid]] commonly transform a poor leaving group into a good one.  Then the reaction proceeds with (respectively) nucleophilic attack or elimination.  For example, protonation before departure allows a molecule to formally lose such poor leaving groups as hydroxide.

The same principle is applies in [[Friedel-Crafts reaction]]s. There, a strong Lewis acid is required to generate a [[carbocation]] from an alkyl halide or an [[acyl#acylium cations, anions, and radicals|acylium ion]] from an acyl halide.

[[File:Leaving group activation by lewis acid complexation png.png|center|500px]]

In [[Friedel-Crafts reaction|Friedel-Crafts alkylations]], the normal halogen leaving group order is reversed, and the reaction rate follows RF > RCl > RBr > RI. This effect is due to their greater ability to complex the [[Lewis acid]] catalyst.  The actual group that leaves is an "ate" complex between the Lewis acid and the formal leaving group.<ref name="Brown 1955">{{Cite journal |last=Brown |first=Herbert C. |author2=Hans Jungk |year=1955 |title=The Reaction of Benzene and Toluene with Methyl Bromide and Iodide in the Presence of Aluminum Bromide; Evidence for a Displacement Mechanism in the Methylation of Aromatic Compounds |journal=Journal of the American Chemical Society |volume=1955, 77 |issue=21 |pages=5584–5589 |doi=10.1021/ja01626a039 |bibcode=1955JAChS..77.5584B |issn=0002-7863}}</ref>

==Spontaneous departures==
Any leaving group comparable to [[triflate]] is called a '''super leaving group'''; such compounds generally [[Molecular_autoionization|autoionize]] if the electrofuge can form a stable carbocation.{{Cn|date=May 2025}} Thus, the most commonly encountered organic triflates are alkenyl, aryl, and [[methyl trifluoromethanesulfonate|methyl triflates]], of which none can form stable carbocations.  Conversely, mixed acyl-triflyl anhydrides smoothly undergo Friedel-Crafts acylation,<ref>{{Cite journal |last=Martínez |first=A. Garcia |author2=A. Herrera Fernandez |author3=D. Molero Vilchez |author4=M. L. Laorden Gutiérrez |author5=L. R. Subramanian |year=1993 |title=A New Easy One-Step Synthesis of Isoquinoline Derivatives from Substituted Phenylacetic Esters |journal=Synlett |volume=1993 |issue=3 |pages=229–230 |doi=10.1055/s-1993-22413 |issn=0936-5214}}</ref> where the corresponding acyl halides would require a strong Lewis acid catalyst. 

Even more reactive are the hyper leaving groups, which are stronger than triflate and react with [[reductive elimination]]. Prominent hyper leaving groups include various [[halonium ion]]s,<ref name="Olah 1969">{{Cite journal |author1=George A. Olah |author-link=George A. Olah |author2=John R. DeMember |year=1969 |title=Friedel-Crafts chemistry. IV. Dialkylhalonium ions and their possible role in Friedel-Crafts reactions |journal=Journal of the American Chemical Society |volume=1969, 91 |issue=8 |pages=2113–2115 |doi=10.1021/ja01036a044 |bibcode=1969JAChS..91.2113O |issn=0002-7863}}</ref> such as diaryl iodonium salts; and other [[iodane|λ<sup>3</sup>-iodanes]].  

Hyper leaving groups can be displaced by extraordinarily weak nucleophiles, in part because [[entropy]] favors splitting one molecule into three.{{Cn|date=May 2025}}  Heating neat samples of {{chem2|(CH3)2Cl+ [CHB11Cl11]-}} under reduced pressure methylated the very poorly nucleophilic carborane anion, with concomitant expulsion of the {{chem2|CH3Cl}} leaving group.<ref>{{Cite journal |last=Stoyanov |first=Evgenii S. |author2=Irina V. Stoyanova |author3=Fook S. Tham |author4=Christopher A. Reed |year=2010 |title=Dialkyl Chloronium Ions |journal=Journal of the American Chemical Society |volume=132 |issue=12 |pages=4062–4063 |doi=10.1021/ja100297b |issn=0002-7863 |pmid=20218556 |bibcode=2010JAChS.132.4062S |s2cid=207048412}}</ref>  Likewise, dialkylhalonium hexafluoroantimonate salts alkylate other alkyl halides to give exchanged products.<ref>{{Cite journal |last=Olah |first=George A. |author2=John R. DeMember |year=1970 |title=Friedel-Crafts chemistry. V. Isolation, carbon-13 nuclear magnetic resonance, and laser Raman spectroscopic study of dimethylhalonium fluoroantimonates |journal=Journal of the American Chemical Society |volume=1970, 92 |issue=3 |pages=718–720 |doi=10.1021/ja00706a058 |bibcode=1970JAChS..92..718O |issn=0002-7863}}</ref> 

[[File:Leaving group reductive elimination png.png|center|thumb|277px|The ability of hyper leaving groups is enhanced by entropic factors]]

In one study, reactivities increased in the order chloride (k<sub>rel</sub> = 1), iodide (k<sub>rel</sub> = 91), tosylate (k<sub>rel</sub> = 3.7{{x10^|4}}), triflate (k<sub>rel</sub> = 1.4{{x10^|8}}), phenyliodonium tetrafluoroborate ({{chem2|PhI+ BF4-}}, k<sub>rel</sub> = 1.2{{x10^|14}}).{{Cn|date=May 2025}}  In general, leaving groups from dialkylhalonium ions increase in lability as {{chem2|RI < RBr < RCl}}.{{Cn|date=May 2025}}

==See also==
{{Div col}}
*'''Entering group''' (a relatively uncommon term)&nbsp;&mdash; a species that bonds to a substrate-derived intermediate.
*[[Electrofuge]]
*[[Electrophile]]
*[[Elimination reaction]]
*[[Nucleofuge]]
*[[Nucleophile]]
*[[Substitution reaction]]
{{Div col end}}

==References==
{{Reflist}}

{{Authority control}}

[[Category:Leaving groups| ]]
[[Category:Organic reactions]]
[[Category:Reaction mechanisms]]