Introduction to Substitution of (X)

The features that we seen above lead us to anticipate specific sorts of reactions that are expected to occur with alkyl halides. In illustrating these, it is helpful to entitle the halogen-bearing carbon as alpha and the carbon atom(s) adjacent to it as beta, as noticed in the first four equations displayed below. Substitution or Replacement of the halogen on the α-carbon (colored maroon) from a nucleophilic reagent is a usually observed reaction, as displayed in equations 1, 2, 5, 6 & 7 in the below diagram. Also, because the electrophilic character that is introduced by the halogen expands to the β-carbons, and because nucleophiles are also bases, the possibility of base persuaded H-X elimination must also be measured, as demonstrated by equation 3. At last, there are some combinations of nucleophiles and alkyl halides that fail to display any reaction over a 24 hour period, like the example in equation 4. For uniformity, alkyl bromides have been employed in these examples. Identical reactions occur when alkyl iodides or chlorides are used, but the speed of the reactions and the exact distribution of products will change.

In the direction to know why some combinations of alkyl nucleophiles and halides give a substitution reaction, where other combinations give elimination, and yet others give no observable reaction, we must examine systematically the way in which changes in reaction variables perturb the course of the reaction. The following general equation shortened the issues that will be significant in such an investigation.

One conclusion, relating to the R-group's structure to possible products, should be directly obvious. An elimination reaction is not possible if R- has no beta-hydrogens, unless a structural rearrangement takes place first. The first four halides displayed below do not give elimination reactions on treatment with base, since they have no β-hydrogens. The two halides on the right do not usually go through such type of reactions because the potential elimination products have highly strained double or triple bonds.

It is also worth noting that sp² hybridized C-X compounds, like the three on the right, do not usually go through nucleophilic substitution reactions, unless other functional groups perturb the double bond(s).

Using the general reaction displayed above as our reference, we can identify the following observables and variables.

The S_N2 Mechanism

As depicted in the earlier section, a majority of the reactions so far depicted appear to proceed by a common single-step technique. This technique is considered as the S_N2 mechanism, whereas S stands for Substitution, N refers to Nucleophilic and 2 stands for bimolecular. At the alpha-carbon, other characteristics of the S_N2 mechanism are inversion, increased reactivity with increasing nucleophilicity of the nucleophilic steric and reagent hindrance to rear-side bonding, particularly in neopentyl and tertiary halides. Even though reaction 3 exhibits second order kinetics, it is an elimination reaction and must so proceed by a very distinct mechanism, which will be explained later.

The S_N1 Mechanism

Reaction 7, displayed at the end of the earlier part, is visibly distinct from the other cases we have examined. It not only displays first order kinetics, but the chiral 3º-alkyl bromide reactant goes through substitution with the modest nucleophile water with extensive racemization. In all of these characteristics this reaction fails to meet the features of the S_N2 mechanism. An identical instance is found in the hydrolysis of tert-butyl chloride, displayed below. Note: The primary substitution product in this reaction is in fact a hydronium ion, which quickly transfers a proton to the chloride anion. This 2^nd acid-base proton transfer is frequently omitted in writing the entire equation, like in the case of reaction 7 above.

(CH₃)₃C-Cl   +   H₂O   -->  (CH₃)₃C-OH₂⁽⁺⁾   +   Cl^(-)   -->  (CH₃)₃C-OH   +   HCl

Even though the hydrolysis of tert-butyl chloride, as displayed above, may be interpreted like an S_N2 reaction in which the constant and high concentration of solvent water does not show up in the rate equation, there is good proof this is not the case. First, the equal hydrolysis of ethyl bromide is over a thousand times slower, while authentic S_N2 reactions visibly display a large rate increase for 1º-alkyl halides. Second, a modest increase of hydroxide anion concentration has no influence on the rate of hydrolysis of tert-butyl chloride, in spite of the much greater nucleophilicity of hydroxide anion compared with water.

The first order kinetics of these reactions suggests a two-step techniques in which the rate-determining step contains the ionization of the alkyl halide, as displayed on the right. In this technique, a carbocation is created as a high-energy intermediate and this species bonds instantly to nearby nucleophiles. If the nucleophile is a neutral molecule, the primary result is an "onium" cation, as displayed above for t-butyl chloride, and supposed in the energy diagram. In evaluating this technique, we may infer various results from its function.
First, the only reactant that is going through change in the first (rate-determining) step is the alkyl halide, so we suppose such type of reactions would be unimolecular and follow a first-order rate equation. Therefore for this mechanism, the name S_N1 is applied. 

Second, because nucleophiles alone participate in the fast second step, their comparative molar concentrations rather than their nucleophilicities should be the initial product-determining factor. If a nucleophilic solvent like water is employed, its high concentration will guarantee that alcohols are the important product. Recombination of the halide anion with the carbocation intermediate just reforms the starting compound. Note: S_N1 reactions wherein the nucleophile is also the solvent are usually called solvolysis reactions. Hydrolysis of t-butyl chloride is an instance.

Third, the Hammond postulate implies that the activation energy of the rate-determining first step will be inversely proportional to the stability of the carbocation intermediate. The stability of carbocations was considered previous and a qualitative relationship is given in the equation below.

Subsequently, we suppose that 3º-alkyl halides will be more reactive than their 2º and 1º-counterparts in reactions that follow an S_N1 mechanism. This is opposed to the reactivity order observed for the S_N2 mechanism. benzylic and Allylic and halides are extremely reactive by either mechanism.
Fourth, in order to make possible the charge separation of an ionization reaction, same as needed by the 1^st step, a good ionizing solvent will be needed. Two solvent features will be specifically significant in this respect. The first is the capability of solvent molecules to orient themselves among ions so as to attenuate the electrostatic force one ion exerts on the other. This feature is associated to the dielectric constant, ε, of the solvent. The Solvents having high dielectric constants, like dimethyl sulfoxide (ε=45), water (ε=81), formic acid (ε=58), & acetonitrile (ε=39) are usually referred as better ionizing solvents than are some general organic solvents like acetone (ε=21), methylene chloride (ε=9), ethanol (ε=25), & ether (ε=4). The second issue is solvation, which considers to the solvent's capability to stabilize ions by encasing them in a sheath of weakly bonded solvent molecules. By hydrogen-bonding solvents, Anions are solvated. Cations are frequently best solvated by nucleophilic sites on a solvent molecule (for example nitrogen & oxygen atoms), but these nucleophiles may form strong covalent bonds to carbon, in the case of carbocations, so converting the intermediate to a substitution product. This is what occurs in the hydrolysis reactions explained above. 

Fifth, the Stereospecificity of these reactions may change. The carbon atoms that are positively-charged of a carbocation has a trigonal (flat) configuration (it prefers to be sp² hybridized) and can bond to a nucleophile evenly well from either face. To come across a random environment If the intermediate from a chiral alkyl halide survives long enough, the results are supposed to be racemic (a 50:50 mixture of enantiomers). Alternatively, if the departing halide anion temporarily blocks front side, or if a nucleophile is oriented selectively at one or the other face, then the substitution might happen with predominant inversion or even retention of configuration.

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