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 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. 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 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. 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. 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 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. 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. 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. 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. 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 prior to departure that a molecule can formally lose such poor leaving groups as hydroxide.