Introduction of Substitution of the Hydroxyl Group

As a reference, using the chemical behaviour of alkyl halides, we are encouraged to look for analogous elimination and substitution reactions of alcohols. Obviously, the major difference is a change in the leaving anion to hydroxide from halide. Because oxygen is little more electronegative than chlorine (3.5 vs. 2.8 on the Pauling scale), we suppose the C-O bond to be more polar than a C-Cl bond. Additionally, a free measure of the electrophilic character of carbon atoms from their nmr chemical shifts (both ¹³C & alpha protons), indicates that oxygen and chlorine substituents exert a similar electron-withdrawing influence when bonded to sp³ hybridized carbon atoms. Despite this promising background evidence, alcohols do not go through similar S_N2 reactions generally observed with alkyl halides. For an instance, the fast S_N2 reaction of 1-bromobutane with sodium cyanide, displayed below, has no parallel when 1-butanol is treated with sodium cyanide. Actually ethyl alcohol is frequently employed as a solvent for alkyl halide substitution reactions like this.

CH₃CH₂CH₂CH₂-Br + Na⁽⁺⁾ CN^(-)      CH₃CH₂CH₂CH₂-CN +  Na⁽⁺⁾ Br^(-)

CH₃CH₂CH₂CH₂-OH + Na⁽⁺⁾ CN^(-)      No Reaction

The main factor here is the stability of the leaving anion (bromide vs. hydroxide). We know that than the water (by more than 18 powers of ten), HBr is a much stronger acid and this variation will be reflected in reactions that generate their conjugate bases. The weaker base, the is bromide anion, is more stable and its free in a elimination or substitution reaction will be much more favorable than that of hydroxide ion, a stronger and less stable base.
Visibly, an obvious step in the direction of enhancing the reactivity of alcohols in S_N2 reactions would be to alter the -OH functional group in a way that improves its stability as a leaving anion. In strong acid One such type of alteration is to conduct the substitution reaction so that -OH is converted to -OH₂⁽⁺⁾. Because the hydronium ion (H₃O⁽⁺⁾) is a much stronger acid than water, than hydroxide ion, its conjugate base (H₂O) is a better leaving group. The single problem with this approach is that several nucleophiles, which include cyanide, in strong acid, are deactivated by protonation, successfully removing the nucleophilic co-reactant required for the substitution. The strong acids HI, HCl and HBr are not subject to this complexity because their conjugate bases are good nucleophiles and are even weaker bases than alcohols. The following equations demonstrated some substitution reactions of alcohols that may be influenced by these acids. Because was true for alkyl halides, nucleophilic substitution of 1º-alcohols proceeds with an S_N2 mechanism, where 3º-alcohols react by an S_N1 mechanism. Reactions of 2º-alcohols might be take place by both mechanisms and frequently produce some rearranged products. Numbers in parentheses next to the mineral acid formulas stand for the weight percentage of a concentrated aqueous solution, the type wherein these acids are generally used.

CH₃CH₂CH₂CH₂-OH +  HBr (48%)      CH₃CH₂CH₂CH₂-OH₂⁽⁺⁾ Br^(-)      CH₃CH₂CH₂CH₂-Br +  H₂O       S_N2

(CH₃)₃C-OH +  HCl (37%)   (CH₃)₃C-OH₂⁽⁺⁾ Cl^(-)      (CH₃)₃C⁽⁺⁾ Cl^(-) +  H₂O (CH₃)₃C-Cl +  H₂O S_N1

Even though these reactions are sometimes considered as "acid-catalyzed" this is not firmly correct. In the entire transformation a strong HX acid is converted to water, a very weak acid, so at least a stoichiometric quantity of HX is required for a total conversion of alcohol to alkyl halide. The requirement of using equal quantities of very strong acids in this reaction limits its helpfulness to simple alcohols of the form displayed above. Obviously, Alcohols having acid sensitive groups would, not accept such type of treatment. However, the idea of altering the -OH functional group to enhance its stability as a leaving anion can be followed in other directions. The following picture displays some alterations that have proven effective. In each case the hydroxyl group is converted to an ester of a strong acid. The first two illustrations show the sulfonate esters described earlier. The third and fourth examples display the formation of a phosphite ester (X represents remaining bromines or additional alcohol substituents) and a chlorosulfite ester respectively. All of these leaving groups (colored blue) have conjugate acids that are much stronger than water (by 13 to 16 powers of ten) so the leaving anion is respectively more stable than hydroxide ion. The tosylate and mesylate compounds are specifically helpful in that they may be used in substitution reactions with a wide range of nucleophiles. The intermediates formed in reactions of alcohols with phosphorus tribromide and thionyl chloride (last two examples) are rarely isolated, and these reactions carry on to alkyl chloride and bromide products.

The significance of sulfonate ester intermediates in common nucleophilic substitution reactions of alcohols may be demonstrated by the following conversion of 1-butanol to pentanenitrile (butyl cyanide), a reaction that does not take place with the alcohol alone. The thionyl and phosphorus halides, alternatively, only act to convert alcohols to the related alkyl halides.

Some illustrations of alcohol substitution reactions employing this approach to activating the hydroxyl group are displayed in the diagram. The first two cases provide to reinforce the fact that sulfonate ester derivatives of alcohols may change alkyl halides in a range of S_N2 reactions. The next two cases illustrate the use of phosphorus tribromide in converting alcohols to bromides. This reagent may be employed without added base (for example pyridine), since = the phosphorous acid result is a weaker acid than HBr. Phosphorous tribromide is best employed with 1º-alcohols, since 2º-alcohols frequently give rearrangement by-products resulting from competing S_N1 reactions. Note: the ether oxygen in reaction 4 is not influenced by this reagent; where, another synthesis using concentrated HBr cleaves ethers. Phosphorus trichloride (PCl₃) converts alcohols to alkyl chlorides in an identical way but thionyl chloride is generally preferred for this transformation because the inorganic products are gases (SO₂ & HCl). Phosphorus triiodide is not stable, but might be from a mixture of red iodine and phosphorus, generated in situ , and performs to convert alcohols to alkyl iodides. The last illustration displays the reaction of thionyl chloride with a chiral 2º-alcohol. The existence of an organic base like pyridine is important, since it provides a substantial concentration of chloride ion needed for the final S_N2 reaction of the chlorosufite intermediate. In the nonexistence of base chlorosufites decompose on heating to give the supposed alkyl chloride with retention of configuration
Tertiary alcohols are not usually used for substitution reactions of the type discussed here, because S_N1 and E1 reaction paths are dominant and are hard to control.

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