Inorganic chemistry, aleaving group typically means amolecular fragment that departs with anelectron pair during areaction step withheterolytic bond cleavage. In this usage, aleaving group is a less formal but more commonly used synonym of the termnucleofuge; althoughIUPAC 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 additionalelectron density from bond heterolysis. Common anionic leaving groups areCl−,Br− andI−halides andsulfonate esters such astosylate (TsO−). Water (H2O),alcohols (R−OH), andamines (R3N) are common neutral leaving groups, although they often require activating catalysts. Some moieties, such ashydride (H−) serve as leaving groups only extremely rarely.
IUPAC defines a leaving group to be anygroup of atoms that detaches from the mainsubstrate during areaction step.[1] The term thus includes groups that departwithout an electron pair in a heterolytic cleavage (electrofuges), likeH+ orSiR+3, which commonly depart inelectrophilic aromatic substitution reactions.[1][2] Similarly, species of highthermodynamic stability likenitrogen (N2) orcarbon dioxide (CO2) commonly act as leaving groups in homolytic bond cleavage reactions ofradical species.
Inorganic chemistry, the term leaving group is rarely used for such species, being restricted only tonucleofugal leaving groups.[3] Leaving groups are generallyanions or neutral species, departing from neutral orcationic substrates, respectively, though in rare cases, cations leaving from adicationic substrate are also known.[4]
This article follows the organic chemistry convention.
Leaving group ability manifests physically in a fastreaction 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 anSN1 orE1 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 stableanion. Strong bases such asOH−, OR− andNR−2 tend to make poor leaving groups, as they cannot stabilize further negative charge; whereas extremely weak bases, such asOSO2CH−
3, leave easily. Mathematically, leaving groups typically exhibitBell–Evans–Polanyi correlation between thedissociation constant for theirconjugate acid (pKaH) and lability.[citation needed]
The correlation in SN1 and E1 reactions between leaving group ability and pKaH is not perfect. Leaving group ability reflects the energy difference (ΔG‡) between neutral starting materials and the partially-charged, partially-bonded transition state. The pKaH, however, represents net energy difference (ΔG°) 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.[citation needed]
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§ Leaving group activation). Even more dramatically,benzoate anions decarboxylate when heated with acopper salt catalyst, in principle expulsing an aryl anion from CO2. The true leaving group is most likely anarylcopper compound rather than the aryl anion salt.[citation needed]
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, butpara-thiocresolate prefers to displace iodide and even bromide before tosylate.[5]
| Leaving group (X) |  |  |
|---|---|---|
| Cl | 0.0074 | 0.0024 (at 40 °C) |
| Br | 1 | 1 |
| I | 3.5 | 1.9 |
| OTs | 0.44 | 3.6 |
Many organic chemistry textbooks offer a table comparing typical leaving groups' ability across common reactions:
| Leaving groups ordered approximately in decreasing ability to leave[6] | |
|---|---|
| R−N+2 | dinitrogen |
| R−OR'+2 | dialkyl ether |
| R−OSO2RF | perfluoroalkylsulfonates (e.g.triflate) |
| R–I | iodide |
| R–OTs, R–OMs, etc. | tosylates,mesylates and similar sulfonates |
| R–Br | bromide |
| R−OH+2,R'−OHR+ | water,alcohols |
| R–Cl | chloride |
| R−ONO2,R−OPO(OR')2 | nitrate,phosphate, and other inorganic esters |
| R−SR'+2 | thioether |
| R−NR'+3,R−NH+3 | amines,ammonia |
| R–F | fluoride |
| R–OCOR | carboxylate |
| R–OAr | phenoxides |
| R–OH, R–OR | hydroxide,alkoxides |
| R–NR2 | amides |
| R–H | hydride |
| R–R' | arenide, alkanide |
It is exceedingly rare for groups such asH− (hydrides),R3C− (alkyl anions, R = alkyl or H), orAr− (aryl anions, Ar = aryl) to depart with a pair of electrons because of the high energy of these species. TheChichibabin reaction provides an example of hydride as a leaving group, while theWolff-Kishner reaction andHaller-Bauer reaction feature unstabilized carbanion leaving groups.
For SN2 reactions, typical synthetically-useful leaving groups includeCl−, Br−, I−,−OTs,−OMs,−OTf, andH2O. 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 likePh2P− orEtS− demethylateanisole derivatives through SN2 displacement at the methyl group. Hydroxide, alkoxides, amides, hydride, and alkyl anions do not serve as leaving groups in SN2 reactions.[citation needed]
When anionic or dianionictetrahedral 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.[citation needed] For example, evenamides expulse R2N−, an extremely poor leaving group, innucleophilic acyl substitution.
This elimination of poor leaving groups also extendsvinylogously to conjugate base eliminations. ManyE1cb reactions (e.g. thealdol condensation) commonly involve a hydroxide leaving group from anenolate β position.
Likewise, inSNAr 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 energyMeisenheimer complex, and since the departure is not involved in the rate limiting step, it does not affect the overall rate of the reaction.[7][page needed]
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.
Poor leaving groups favor the E1cB mechanism, but as the leaving group improves, transition stateBC‡ becomes lower in energy. First, the rate-determining step shifts: initially leaving-group elimination from intermediateB; it becomes deprotonation via transition stateAB‡ (not pictured). Eventually,BC‡ is no longerstationary on the potential energy surface, and the reaction becomes a concerted E2 elimination (albeit very asynchronous in the diagrammed case).[citation needed]
InSN1 andE1 reactions, protonation or complexation with aLewis 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 inFriedel-Crafts reactions. There, a strong Lewis acid is required to generate acarbocation from an alkyl halide or anacylium ion from an acyl halide.
InFriedel-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 theLewis acid catalyst. The actual group that leaves is an "ate" complex between the Lewis acid and the formal leaving group.[8]
Any leaving group comparable totriflate is called asuper leaving group; such compounds generallyautoionize if the electrofuge can form a stable carbocation.[citation needed] Thus, the most commonly encountered organic triflates are alkenyl, aryl, andmethyl triflates, of which none can form stable carbocations. Conversely, mixed acyl-triflyl anhydrides smoothly undergo Friedel-Crafts acylation,[9] 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 withreductive elimination. Prominent hyper leaving groups include varioushalonium ions,[10] such as diaryl iodonium salts; and otherλ3-iodanes.
Hyper leaving groups can be displaced by extraordinarily weak nucleophiles, in part becauseentropy favors splitting one molecule into three.[citation needed] Heating neat samples of(CH3)2Cl+ [CHB11Cl11]− under reduced pressure methylated the very poorly nucleophilic carborane anion, with concomitant expulsion of theCH3Cl leaving group.[11] Likewise, dialkylhalonium hexafluoroantimonate salts alkylate other alkyl halides to give exchanged products.[12]
In one study, reactivities increased in the order chloride (krel = 1), iodide (krel = 91), tosylate (krel = 3.7×104), triflate (krel = 1.4×108), phenyliodonium tetrafluoroborate (PhI+ BF−4, krel = 1.2×1014).[citation needed] In general, leaving groups from dialkylhalonium ions increase in lability asRI < RBr < RCl.[citation needed]
