Leaving group

In chemistry, a leaving group is a molecular fragment that departs with a pair

of electrons in heterolytic bond cleavage. Leaving groups can be anions, cations or neutral
molecules, but in either case it is crucial that the leaving group be able to stabilize the
additional electron density that results from bond heterolysis. Common anionic leaving
groups are halides such as Cl−, Br−, and I−, and sulfonate esters such as tosylate (TsO−).
Fluoride (F−) functions as a leaving group in the nerve agent sarin gas. Common neutral
molecule leaving groups are water and ammonia. Leaving groups may also be positively
charged cations (such as H+ released during the nitration of benzene); these are also known
specifically as electrofuges.[1][2]

Leaving group ability

The physical manifestation of leaving group ability is the rate at which a reaction takes
place. Good leaving groups give fast reactions. By transition state theory, this implies that
reactions involving good leaving groups have low activation barriers leading to relatively
stable transition states.
It is helpful to consider the concept of leaving group ability in the case of the first step of an
SN1/E1 reaction with an anionic leaving group (ionization), while keeping in mind that this
concept can be generalized to all reactions that involve leaving groups. Because the leaving
group bears a larger negative charge in the transition state (and products) than in the starting
material, a good leaving group must be able to stabilize this negative charge, i.e. form
stable anions. A good measure of anion stability is the pKa of an anion's conjugate acid, and
leaving group ability indeed generally follows this trend, with a lower pKaH being associated
with better leaving group ability.

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

The correlation between pKaH and leaving group ability, however, is not perfect. Leaving
group ability represents the difference in energy between starting materials and a transition
state (ΔG‡) and differences in leaving group ability are reflected in changes in this quantity
(ΔΔG‡). The quantity pKaH, however, represents the difference in energy between starting
materials and products (ΔG) with differences in acidity reflected in changes in this quantity
(ΔΔG). Also, the starting materials in these cases are different. In the case of pKa, the
"leaving group" is bound to a proton in the starting material, while in the case of leaving
group ability, the leaving group is bound to (usually) carbon. It is with these important
caveats in mind that one must consider pKaH to be reflective of leaving group ability, but
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nevertheless the trends in each tend to correlate well with each other. Consistent with this
picture, strong bases such as OH−, OR− and NR2− tend to make poor leaving groups, due their
inability to stabilize a negative charge.

Leaving groups ordered approximately in decreasing ability to leave[3]

R-N2+ dinitrogen

R-OR'2+ dialkyl ether

R-OSO2RF perfluoroalkylsulfonates (e.g. triflate)

R-OTs, R-OMs, etc. tosylates, mesylates and similar

R-I iodide

R-Br bromide

R-OH2+, R'-OHR+ water, alcohols

R-Cl chloride

R-ONO2, R-OPO(OH)2 nitrate, phosphate, and other inorganic esters

R-SR'2+ thioether

R-NR'3+, R-NH3+ amines, ammonia

R-F fluoride

R-OCOR carboxylate

R-OAr phenoxides

R-OH, R-OR hydroxide, alkoxides

2
 R-NR2 amides

It is exceedingly rare for groups such as H− (hydrides) and R3C− (alkyl anions, R=alkyl or H)
to depart with a pair of electrons because of the instability of these bases.

Contextual differences in leaving group ability

It is important to note that the list given above is qualitative and describes trends. The ability
of a group to leave is contextual. For example, in SNAr 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. This effect is general to conjugate base eliminations.
Even when the departure of the leaving group is involved in the rate limiting step of a
reaction there can still exist contextual differences that can change the order of leaving group
ability. In Friedel-Crafts alkylations, the normal halogen leaving group order is reversed so
that the rate of the reaction follows RF > RCl > RBr > RI. This effect is due to their greater
ability to complex the Lewis acid catalyst, and the actual group that leaves is an "ate"
complex between the Lewis acid and the departing leaving group.[4] This situation is broadly
defined as leaving group activation
There can still exist contextual differences in leaving group ability in the purest form, that is
when the actual group that leaves is not affected by the reaction conditions (by protonation
or Lewis acid complexation) and the departure of the leaving group occurs in the rate
determining step. In the situation where other variables are held constant (nature of the alkyl
electrophile, solvent, etc.), a change in nucleophile can lead to a change in the order of
reactivity for leaving groups. In the case below, tosylate is the best leaving group when
ethoxide is the nucleophile, but iodide and even bromide become better leaving groups in the
case of the thiolate nucleophile.[5]

Relative rates for leaving groups (kX/kBr) in each reaction

3
 Leaving
group (X)

Cl 0.0074 0.0024 (at 40 °C)

Br 1 1

I 3.5 1.9

OTs 0.44 3.6

Activation
It is common in E1 and SN1 reactions for a poor leaving group to be transformed into a good
one by protonation or complexation with a Lewis acid. Thus, it is by protonation before
departure that a molecule can formally lose such poor leaving groups as hydroxide.
The same principle is at work in the Friedel-Crafts reaction. Here, a strong Lewis acid is
required to generate either a carbocation from an alkyl halide in the Friedel-Crafts alkylation
reaction or an acylium ion from an acyl halide.

In the vast majority of cases, reactions that involve leaving group activation generate a
cation in a separate step, before either nucleophilic attack or elimination. For example, SN1
and E1 reactions may involve an activation step, whereas SN2 and E2 reactions generally do
not.

In conjugate base eliminations

The requirement for a good leaving group is relaxed in conjugate base elimination reactions.
These reactions include loss of a leaving group in the β position of an enolate as well as the
regeneration of a carbonyl group from the tetrahedral intermediate in nucleophilic acyl
substitution. Under forcing conditions, even amides can be made to undergo basic
hydrolysis, a process that involves the expulsion of an extremely poor leaving group, R2N−.
Even more dramatic, decarboxylation of benzoate anions can occur by heating
with copper or Cu2O, involving the loss of an aryl anion. This reaction is facilitated by the
fact that the leaving group is most likely an arylcopper compound rather than the much more
basic alkali metal salt.

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This dramatic departure from normal leaving group requirements occurs mostly in the realm
of C=O double bond formation where formation of the very strong C=O double bond can
drive otherwise unfavorable reactions forward. The requirement for a good leaving group is
still relaxed in the case of C=C bond formation via E1cB mechanisms, but because of the
relative weakness of the C=C double bond, the reaction still exhibits some leaving group
sensitivity. Notably, changing the leaving group's identity (and willingness to leave) can
change the nature of the mechanism in elimination reactions. With poor leaving groups, the
E1cB mechanism is favored, but as the leaving group's ability changes, the reaction shifts
from having a rate determining loss of leaving group from carbanionic
intermediate B via TS BC‡ through having a rate determining deprotonation step via TS
AB‡ (not pictured) to a concerted E2 elimination. In the latter situation, the leaving group X
has become good enough that the former transition state connecting
intermediates B and C has become lower in energy than B, which is no longer a stationary
point on the potential energy surface for the reaction. Because only one transition state
connects starting material A and product C, the reaction is now concerted (albeit very
asynchronous in the pictured case) due to the increase in leaving group ability of X.

"Super" and "hyper" leaving groups

The prototypical super leaving group is triflate, and the term has come to mean any leaving
group of comparable ability. Compounds where loss of a super leaving group can generate a
stable carbocation are usually highly reactive and unstable. Thus, the most commonly
encountered organic triflates are methyl triflate and alkenyl or aryl triflates, all of which
cannot form stable carbocations on ionization, rendering them relatively stable. It has been
noted that steroidal alkyl nonaflates (another super leaving group) generated from alcohols
and perfluorobutanesulfonyl fluoride were not isolable as such but immediately formed the
products of either elimination or substitution by fluoride generated by the reagent. Mixed
acyl-trifluoromethanesulfonyl anhydrides smoothly undergo Friedel-Crafts acylation without
a catalyst,[6] unlike the corresponding acyl halides, which require a strong Lewis acid.

5
Methyl triflate, however, does not participate in Friedel-Crafts alkylation reactions with
electron-neutral aromatic rings.
Beyond super leaving groups in reactivity lie the "hyper" leaving groups. Prominent among
these are λ3-iodanes, which include diaryl iodonium salts, and other halonium ions. In one
study, a quantitative comparison of these and other leaving groups was conducted. Relative
to chloride (krel=1), reactivities increased in the order bromide (krel=14), iodide (krel=91),
tosylate (krel=3.7 x 104), triflate (krel=1.4 x 108), phenyliodonium tetrafluoroborate (PhI+ BF4−,
krel=1.2 x 1014). Along with the criterion that a hyper leaving group be a stronger leaving
group than triflate is the necessity that the leaving group undergo reductive elimination. In
the case of halonium ions this involves reduction from a trivalent halonium to a monovalent
halide coupled with the release of an anionic fragment. Part of the exceptional reactivity of
compounds of hyper leaving groups has been ascribed to the entropic favorability of having
one molecule split into three.

The ability of hyper leaving groups is enhanced by entropic factors

Dialkyl halonium ions have also been isolated and characterized for simple alkyl groups.
These compounds, despite their extreme reactivity towards nucleophiles, can be obtained
pure in the solid state with very weakly nucleophilic counterions such as SbF-
[7][8]
6  and CHB11Cl11−.[9] The strongly electrophilic nature of these compounds engendered by
their attachment to extremely labile R-X (R = alkyl, X = Cl, Br, I) leaving groups is
illustrated by their propensity to alkylate very weak nucleophiles. Heating neat samples of
(CH3)2Cl+ [CHB11Cl11]− under reduced pressure resulted in methylation of the very poorly
nucleophilic carborane anion with concomitant expulsion of the CH3Cl leaving group.
Dialkyl halonium hexafluoroantimonate salts alkylate excess alkyl halides to give exchanged
products. Their strongly electrophilic nature, along with the instability of primary
carbocations generated from ionization of their alkyl groups, points to their possible
involvement in Friedel-Crafts alkylation chemistry.[7] The order of increasing lability of
these leaving groups is R-I < R-Br < R-Cl.

References

1. ^ "Leaving group" (PDF). Gold Book: leaving group. IUPAC.

2009. doi:10.1351/goldbook.L03493. ISBN 978-0-9678550-9-7.
2. ^ "Gold Book: electrofuge" (PDF). IUPAC. Archived from the
original (PDF) on 2017-11-07. Retrieved 2017-06-10.
3. ^ Smith, March. Advanced Organic Chemistry 6th ed. (501-502)

6
4. ^ Brown, Herbert C.; Hans Jungk (1955). "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
Compounds1,2". Journal of the American Chemical Society. 1955, 77 (21): 5584–
5589. doi:10.1021/ja01626a039. ISSN 0002-7863.
5. ^ Hoffmann, H. M. R. (1965). "1252. The rate of displacement of toluene-p-
sulphonate relative to bromide ion. A new mechanistic criterion". Journal of the
Chemical Society (Resumed). 1965: 6753–
6761. doi:10.1039/JR9650006753. ISSN 0368-1769.
6. ^ Martínez, A. Garcia; A. Herrera Fernandez; D. Molero Vilchez; M. L.
Laorden Gutiérrez; L. R. Subramanian (1993). "A New Easy One-Step Synthesis of
Isoquinoline Derivatives from Substituted Phenylacetic Esters". Synlett. 1993 (3):
229–230. doi:10.1055/s-1993-22413. ISSN 0936-5214.
7. ^ Jump up to:a b George A. Olah; John R. DeMember (1969). "Friedel-Crafts
chemistry. IV. Dialkylhalonium ions and their possible role in Friedel-Crafts
reactions". Journal of the American Chemical Society. 1969, 91 (8): 2113–
2115. doi:10.1021/ja01036a044. ISSN 0002-7863.
8. ^ Olah, George A.; John R. DeMember (1970). "Friedel-Crafts chemistry. V.
Isolation, carbon-13 nuclear magnetic resonance, and laser Raman spectroscopic
study of dimethylhalonium fluoroantimonates". Journal of the American Chemical
Society. 1970, 92 (3): 718–720. doi:10.1021/ja00706a058. ISSN 0002-7863.
9. ^ Stoyanov, Evgenii S.; Irina V. Stoyanova; Fook S. Tham; Christopher A.
Reed (2010). "Dialkyl Chloronium Ions". Journal of the American Chemical
Society. 132 (12): 4062–4063. doi:10.1021/ja100297b. ISSN 0002-
7863. PMID 20218556.