Organic reaction mechanism

(ör′gan·ik rē′ak·shən ′mek·ə′niz·əm)

(organic chemistry) A pathway of chemical states traversed by an organic chemical system in its passage from reactants to products.

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A complete, step-by-step account of how a reaction of organic compounds takes place. A fully detailed mechanism would correlate the original structure of the reactants with the final structure of the products and account for changes in structure and energy throughout the progress of the reaction. It would also account for the formation of any intermediates and the rates of interconversions of all of the various species. Because it is not possible to detect directly all of these details, evidence for a reaction mechanism is always indirect. Experiments are designed to produce results that provide logical evidence for (but can never unequivocally prove) a mechanism. For most organic reactions, there are mechanisms that are considered to be well established based on bodies of experimental evidence. Nevertheless, new data often become available that provide further insight into new details of a mechanism or that occasionally require a complete revision of an accepted mechanism.

Classification of organic reactions

The description of an organic reaction mechanism typically includes designation of the overall reaction (for example, substitution, addition, elimination, oxidation, reduction, or rearrangement), the presence of any reactive intermediates (that is, carbocations, carbanions, free radicals, radical ions, carbenes, or excited states), the nature of the reagent that initiates the reaction (such as electrophilic or nucleophilic), the presence of any catalysis (such as acid or base), and any specific stereochemistry. For example, reaction (1)
1

would be described as a concerted nucleophilic substitution of an alkyl halide that proceeds with inversion of stereochemistry. A reaction that proceeds in a single step, without intermediates, is described as concerted or synchronous. Reaction (1) is an example of the S_N2 mechanism (substitution, nucleophilic, bimolecular).

Potential energy diagrams

A common method for illustrating the progress of a reaction is the potential energy diagram, in which the free energy of the system is plotted as a function of the completion of the reaction (see illustration).

Potential energy–reaction coordinate diagram for a typical nucleophilic substitution reaction that proceeds by the S_N2 mechanism. E_a = activation energy.

The reaction coordinate is intended to represent the progress of the reaction, and it may or may not correlate with an easily observed or measurable feature. In reaction (1), the reaction coordinate could be considered to be the increasing bond length of the carbon-bromine (C-Br) bond as it is broken, or the decreasing separation of C and iodine (I) as they come together to form a bond. In fact, a complete potential energy diagram should illustrate the variation in energy as a function of both of these (and perhaps several other relevant structural features), but this would require a three- dimensional (or higher) plot.

Besides identifying the energy levels of the original reactants and the final products, the potential energy diagram indicates the energy level of the highest point along the reaction pathway, called the transition state. Because the transition state represents the highest energy that the molecules must attain as they proceed along the reaction pathway, the energy level of the transition state is a key indication of how easily the reaction can occur. Features that tend to make the transition state more stable (lower in energy) make the reaction more favorable. Such stabilizing features could be intramolecular, such as electron donation or withdrawal by substituents, or intermolecular, such as stabilization by solvent. See also Chemical bonding; Energy.

Kinetics

Another way to illustrate the various steps involved in a reaction mechanism is as a kinetic scheme that shows all of the individual steps and their rate constants. The S_N2 mechanism is a single step, so the kinetics must represent that step; the rate is observed to depend on the concentrations of both the organic substrate and the nucleophile. However, for multistep mechanisms the kinetics can be a powerful tool for distinguishing the presence of alternative pathways. For example, when more highly substituted alkyl halides undergo nucleophilic substitution, the rate is independent of the concentration of the nucleophile. This evidence suggests a two-step mechanism, called the S_N1 mechanism, as shown in reaction scheme (2), where the k terms represent rate constants.
2a

2b

The S_N1 mechanism accomplishes the same overall nucleophilic substitution of an alkyl halide, but does so by initial dissociation of the leaving group (Br⁻) to form a carbocation, step (2a). The nucleophile then attaches to the carbocation to form the final product, step (2b). Alkyl halides that have bulky groups around the carbon to be substituted are less likely to be substituted by the direct S_N2 mechanism, because the nucleophile encounters difficulty in making the bond to the inaccessible site (called steric hindrance). If those alkyl groups have substituents that can support a carbocation structure, generally by electron donation, then the S_N1 mechanism becomes preferable.

A crucial feature of a multistep reaction mechanism is the identification of the rate-determining step. The overall rate of reaction can be no faster than its slowest step. In the S_N1 mechanism, the bond-breaking reaction (2a) is typically much slower than the bond-forming reaction (2b). Hence, the observed rate is the rate of the first step only. Thus, kinetics can distinguish the S_N1 and S_N2 mechanisms, as shown in Eqs. (3) and (4),
3.

4.
where R is an alkyl group, X is a halogen or other leaving group, Nu is a nucleophile, and the terms in the brackets represent concentrations.

A more complete description of the S_N1 mechanism was recognized when it was observed that the presence of excess leaving group [for example, Br⁻ in reaction (2)] can affect the rate (called the common ion rate depression). This indicated that the mechanism should include a reverse step [k₋₁ in reaction step (2a)] in which the leaving group returns to the cation, regenerating starting material. In this case, the rate depends in a complex manner on the competition of nucleophile and leaving group for reaction with the carbocation. See also Chemical dynamics; Reactive intermediates; Steric effect (chemistry).

Activation parameters

The temperature dependence of the rate constant provides significant information about the transition state of the rate-determining step. The Arrhenius equation (5)
5.
expresses that dependence in terms of an exponential function of temperature and an activation energy, E_a; A is called the Arrhenius or preexponential factor, and R is the gas constant. See also Gas.

The activation energy represents the energy difference between the reactants and the transition state, that is, the amount of energy that must be provided in order to proceed along the reaction pathway successfully from reactant to product.

Stereochemistry

Careful attention to the stereochemistry of a reaction often provides crucial insight into the specific orientation of the molecules as they proceed through the reaction mechanism. The complete inversion of stereochemistry observed in the S_N2 mechanism provides evidence for the backside attack of the nucleophile. Alkyl halides that undergo substitution by the S_N1 mechanism do not show specific stereochemistry, since the loss of the leaving group is completely uncorrelated with the bonding of the necleophile.

In addition reactions, possible stereochemical outcomes are addition of the new bonds to the same or opposite sides of the original pi bond, called syn and anti addition, respectively. The anti addition of bromine to double bonds provides evidence for the intermediacy of a bridged bromonium ion, as shown in reaction (6).
6

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