In organic chemistry, a leaving group typically means a molecular fragment that departs with an electron pair during a reaction step with 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 proceeds at a meaningful rate, as well as what mechanism the reaction takes. Leaving group ability depends strongly on context, but correlates with ability to stabilize additional electron density from bond heterolysis. Common anionic leaving groups are Cl−, Br− and I− halides and sulfonate esters such as tosylate (TsO−). Water (H2O), alcohols (R−OH), and amines (R3N) are common neutral leaving groups. Some moieties, such as hydride (H−) serve as leaving groups only extremely rarely.
Nomenclature IUPAC defines a leaving group to be any group of atoms that detaches from the main substrate during a reaction step. The term thus includes groups that depart without an electron pair in a heterolytic cleavage (electrofuges), like H+ or SiR+3, which commonly depart in electrophilic aromatic substitution reactions. Similarly, species of high thermodynamic stability like nitrogen (N2) or carbon dioxide (CO2) commonly act as leaving groups in homolytic bond cleavage reactions of radical species. In organic chemistry, the term leaving group is rarely used for such species, being restricted only to nucleofugal leaving groups. Leaving groups are generally anions or neutral species, departing from neutral or cationic substrates, respectively, though in rare cases, cations leaving from a dicationic substrate are also known. This article follows the organic chemistry convention.
Overview Leaving group ability manifests physically in a fast reaction rate. 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 or E1 reaction in neutral media: ionization, with an anionic leaving group.
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 OH−, OR− and NR−2 tend to make poor leaving groups, as they cannot stabilize further negative charge; whereas extremely weak bases, such as OSO2CH−3, leave easily. As such, leaving groups typically exhibit correlation between their reactivity and the dissociation constant for their conjugate acid (pKaH). The correlation between leaving group ability and pKaH is not perfect. Leaving group ability is a kinetic phenomenon, so it reflects the difference between the energy of a transition state and reactants (ΔG‡). Acidity is a thermodynamic phenomenon reflecting energy difference between products and reactants (ΔG). Additionally, the bonds being broken are different: loss of a leaving group breaks a bond to (usually) carbon, and ionization of an acid breaks a bond to hydrogen. Many organic chemistry textbooks offer a table comparing typical leaving groups' ability across common reactions:
It is exceedingly rare for groups such as H− (hydrides), R3C− (alkyl anions, R = alkyl or H), or 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 reaction and Haller-Bauer reaction feature unstabilized carbanion leaving groups.
Context-dependence For reactions with a different transition state, other aspects of the leaving group may govern. In acid-catalyzed reactions' rate-determining step, 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 § Leaving group activation). 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. Even for the same reaction mechanism in the same media, relative reactivity of a leaving group may depend on the other reagents. In the substitutions tabulated below, ethoxide displaces tosylate faster than any halide, but para-thiocresolate displaces iodide and even bromide faster than tosylate.
SN2 reactions For SN2 reactions, typical synthetically-useful leaving groups include Cl−, Br−, I−, −OTs, −OMs, −OTf, and 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 (−OAr) constitute the lower limit for feasible SN2 leaving groups: very strong nucleophiles like Ph2P− or EtS− demethylate anisole derivatives through SN2 displacement at the methyl group. Hydroxide, alkoxides, amides, hydride, and alkyl anions do not serve as leaving groups in SN2 reactions.
Base eliminations When anionic or dianionic 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. For example, even amides expulse R2N−, an extremely poor leaving group, in nucleophilic acyl substitution. This elimination of poor leaving groups also extends to conjugate base eliminations. Many E1cb reactions (e.g. the aldol condensation) commonly involve a hydroxide leaving group from an enolate β position.
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.
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