6.3: \(\mathrm{O}\), \(\mathrm{S}\), and \(\mathrm{N}\) as Leaving Groups
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- 354420
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\(\newcommand{\avec}{\mathbf a}\) \(\newcommand{\bvec}{\mathbf b}\) \(\newcommand{\cvec}{\mathbf c}\) \(\newcommand{\dvec}{\mathbf d}\) \(\newcommand{\dtil}{\widetilde{\mathbf d}}\) \(\newcommand{\evec}{\mathbf e}\) \(\newcommand{\fvec}{\mathbf f}\) \(\newcommand{\nvec}{\mathbf n}\) \(\newcommand{\pvec}{\mathbf p}\) \(\newcommand{\qvec}{\mathbf q}\) \(\newcommand{\svec}{\mathbf s}\) \(\newcommand{\tvec}{\mathbf t}\) \(\newcommand{\uvec}{\mathbf u}\) \(\newcommand{\vvec}{\mathbf v}\) \(\newcommand{\wvec}{\mathbf w}\) \(\newcommand{\xvec}{\mathbf x}\) \(\newcommand{\yvec}{\mathbf y}\) \(\newcommand{\zvec}{\mathbf z}\) \(\newcommand{\rvec}{\mathbf r}\) \(\newcommand{\mvec}{\mathbf m}\) \(\newcommand{\zerovec}{\mathbf 0}\) \(\newcommand{\onevec}{\mathbf 1}\) \(\newcommand{\real}{\mathbb R}\) \(\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}\) \(\newcommand{\laspan}[1]{\text{Span}\{#1\}}\) \(\newcommand{\bcal}{\cal B}\) \(\newcommand{\ccal}{\cal C}\) \(\newcommand{\scal}{\cal S}\) \(\newcommand{\wcal}{\cal W}\) \(\newcommand{\ecal}{\cal E}\) \(\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}\) \(\newcommand{\gray}[1]{\color{gray}{#1}}\) \(\newcommand{\lgray}[1]{\color{lightgray}{#1}}\) \(\newcommand{\rank}{\operatorname{rank}}\) \(\newcommand{\row}{\text{Row}}\) \(\newcommand{\col}{\text{Col}}\) \(\renewcommand{\row}{\text{Row}}\) \(\newcommand{\nul}{\text{Nul}}\) \(\newcommand{\var}{\text{Var}}\) \(\newcommand{\corr}{\text{corr}}\) \(\newcommand{\len}[1]{\left|#1\right|}\) \(\newcommand{\bbar}{\overline{\bvec}}\) \(\newcommand{\bhat}{\widehat{\bvec}}\) \(\newcommand{\bperp}{\bvec^\perp}\) \(\newcommand{\xhat}{\widehat{\xvec}}\) \(\newcommand{\vhat}{\widehat{\vvec}}\) \(\newcommand{\uhat}{\widehat{\uvec}}\) \(\newcommand{\what}{\widehat{\wvec}}\) \(\newcommand{\Sighat}{\widehat{\Sigma}}\) \(\newcommand{\lt}{<}\) \(\newcommand{\gt}{>}\) \(\newcommand{\amp}{&}\) \(\definecolor{fillinmathshade}{gray}{0.9}\)Recall that a good leaving group should be able to accept (in a stable form) the pair of electrons from the bond that breaks. Typically, good leaving groups are weak bases. For this reason, hydroxide (\({}^{-}\mathrm{OH}\)) and amide (\({}^{-}\mathrm{NH}_{2}\)) are unlikely to be produced during a nucleophilic substitution reaction. However, as noted earlier, alcohols can be converted into good leaving groups by protonation, which results in \(\mathrm{H}_{2}\mathrm{O}\) as the leaving group.
Alcohols can also be modified (or derivatized) to produce better leaving groups. This is particularly useful when we need to carry out a reaction that is sensitive to acidic conditions when the method we have used earlier (protonation of the \(\mathrm{OH}\)) cannot be used. The most common derivative used to make the \(\mathrm{OH}\) group into a good leaving group is the Tosyl group (para-toluenesulphonate). It can be formed by reacting an alcohol with p-toluenesulfonylchloride (\(\mathrm{TosCl}\)) in the presence of a base (such as pyridine) that acts to remove the \(\mathrm{HCl}\) that is produced).
We can consider the derivatization reaction as mechanistically similar to other nucleophilic substitutions we have considered, except that it takes place at an \(\mathrm{S}\) instead of a \(\mathrm{C}\).
The resulting \(\mathrm{OTos}\) group is a very good leaving group, making the molecule reactive to nucleophilic substitution reactions. In effect, we have changed the leaving group from \({}^{-}\mathrm{OH}\), which is a relatively strong base, to \({}^{-}\mathrm{OTos}\) which is a very weak base—it is the organic equivalent of sulfate, the conjugate base of sulfuric acid. The negative charge on \({}^{-}\mathrm{OTos}\) becomes delocalized to the other oxygens bound to the \(\mathrm{S}\), thereby stabilizing the base.
In a similar manner, sulfides can be transformed into leaving groups, most commonly through the methylation of the sulfide, which produces a powerful reagent that can be used to methylate other species.
In biological systems, a common methylating agent, S-adenosylmethionine (\(\mathrm{SAM} \rightarrow\)), uses this mechanism