CHEMISTRY

Corresponding Member of the Academy of Sciences of the USSR D. N. KURSANOV and S. V. VITT

STUDY OF THE MECHANISM OF ALKYLATION OF PHENOLS BY N-TRIMETHYL-$\alpha$-PHENETHYLAMMONIUM IODIDE

Alkylation of phenols and phenolate anions by ammonium compounds containing a benzyl or substituted benzyl radical has been studied by a number of authors ($^{1-3}$).

It was established ($^{4}$) that, in the interaction of N-benzylpyridinium chloride with phenol, a mixture of products of C- and O-alkylation is formed:

\[ \ce{PhCH2-N+ <pyridine> + PhOH ->[9\%] PhOCH2Ph + <pyridinium> +[?] PhCH2-C6H4-OH + <pyridinium>} \]

It should be assumed that this reaction, like other previously studied ($^{5-8}$) processes of alkylation by ammonium salts, belongs to heterolytic substitution reactions of the $S_N$ type.

Alkylation of phenols by an ammonium salt must proceed either by a synchronous mechanism (A), or by an asynchronous mechanism involving intermediate formation of a free carbonium ion (B) ($^{8}$)

\[ \text{(A)}\qquad \ce{ArOH + R-N+ -> ArR-OH + HN+} \]

\[ \text{(B)}\qquad \ce{R-N+ -> R+ + N \quad;\quad R+ + ArOH -> ArR-OH + H+} \]

We investigated the interaction of N-trimethyl-$\alpha$-phenethylammonium iodide with resorcinol and phloroglucinol. It was found that, on heating these phenols with the ammonium salt, substitution of hydrogen atoms of the phenolic nucleus by the $\alpha$-phenethyl radical occurs (C-alkylation reaction):

\[ \ce{ Ph-\overset{*}{CH}(NMe3+)-CH3 + \underset{\text{resorcinol/phloroglucinol nucleus}}{C6H3(OH)3} -> Ph-\overset{*}{CH}(CH3)-C6H2(OH)3 + HNMe3+ } \]

This reaction readily proceeds at a temperature of $150^\circ$ and above. Alkylation of resorcinol and phloroglucinol by optically active iodi-

with N-trimethyl-α-phenethylammonium was carried out at 155–175° in an excess of the phenol being alkylated.

In the case where the reaction proceeds according to scheme (A), the α-phenethylphenols formed should possess optical activity; if, however, the reaction proceeds according to scheme (B), they should not.

It turned out that the α-phenethylphenols obtained in this way do not possess optical activity*. Nor did the α-phenylpropionic acid formed upon their oxidation possess optical activity:

\[ \begin{array}{c} \mathrm{Ph}-\overset{*}{\mathrm{CH}}-\mathrm{CH}_3 \\ \big| \\ \text{phenyl ring bearing } \mathrm{OH},\mathrm{OH} \end{array} \ \xrightarrow[\;25^\circ\;]{\mathrm{KMnO}_4}\ \begin{array}{c} \mathrm{Ph}-\overset{*}{\mathrm{CH}}-\mathrm{CH}_3 \\ \big| \\ \mathrm{COOH} \\ dl \end{array} \]

\[ \begin{array}{c} \mathrm{Ph}-\overset{*}{\mathrm{CH}}-\mathrm{CH}_3 \\ \big| \\ \text{phenyl ring bearing } \mathrm{HO},\mathrm{OH},\mathrm{OH} \end{array} \ \xrightarrow[\;25^\circ\;]{\mathrm{KMnO}_4}\ \begin{array}{c} \mathrm{Ph}-\overset{*}{\mathrm{CH}}-\mathrm{CH}_3 \\ \big| \\ \mathrm{COOH} \\ dl \end{array} \]

These data make it possible to conclude that alkylation of phenols with the N-trimethyl-α-phenethylammonium salt proceeds in such a way that first the ammonium ion decomposes with formation of the α-phenethylcarbonium ion, which then reacts with the phenol, i.e., that the reaction proceeds according to scheme (B).

This conclusion concerning the reaction mechanism found further confirmation in the following.

A reaction was carried out between N-trimethyl-α-phenethylammonium iodide and deuteroresorcinol. In this case deuteroresorcinol was not only the object of alkylation, but also served as a donor of deuterium. The α-phenethylresorcinol formed contained a certain amount (from 6 to 10% of the calculated amount) of deuterium in the phenethyl group.

These figures were obtained as a result of isotopic analysis of the combustion water of α-phenylpropionic acid—the product of mild oxidation of deutero-α-phenethylresorcinol.

Carbonium ions possess proton mobility and, in the presence of deuterium donors, exchange the hydrogen atoms attached to the carbon atom adjacent to the carbonium center \((^9)\).

This property of carbonium ions makes it possible to judge their participation in the chemical transformation. Therefore the formation of α-phenethylresorcinol containing deuterium in the phenethyl group indicates the intermediate formation of the α-phenethylcarbonium ion:

\[ \begin{array}{c} \mathrm{Ph}-\overset{*}{\mathrm{CH}}-\mathrm{CH}_3 \\ \big| \\ {}^{\oplus}\mathrm{NMe}_3 \\ d \end{array} \rightarrow \mathrm{Ph}-\overset{\oplus}{\mathrm{CH}}-\mathrm{CH}_3 \xrightarrow[\;- \mathrm{H}^{\oplus}\;]{+\mathrm{D}^{\oplus}} \mathrm{Ph}-\overset{\oplus}{\mathrm{CH}}-\mathrm{CD}_3 \rightarrow \begin{array}{c} \mathrm{Ph}-\overset{*}{\mathrm{CH}}-\mathrm{CD}_3 \\ \big| \\ \text{resorcinol ring bearing } \mathrm{OH},\mathrm{OH} \\ dl \end{array} \rightarrow \]

\[ \xrightarrow{\mathrm{KMnO}_4} \begin{array}{c} \mathrm{Ph}-\overset{*}{\mathrm{CH}}-\mathrm{CD}_3 \\ \big| \\ \mathrm{COOH} \\ dl \end{array} \]

* α-Phenethylphloroglucinol could not be isolated in pure form; therefore, after removal of ammonium salts and unreacted phloroglucinol, the reaction mixture was oxidized directly to α-phenylpropionic acid.

A small depth of exchange in percentage terms (but significant in absolute magnitude) apparently indicates the short lifetime of the α-phenethylcarbonium ion. From the data on the depth of exchange it follows that the rate of the deuterium-exchange reaction of the α-phenethylcarbonium ion is at least ten times smaller than the rate of interaction of this ion with resorcinol.

Experimental Part

1. Interaction of d-N-trimethyl-α-phenethylammonium iodide with resorcinol. A mixture of 0.1 mole of d-N-trimethyl-α-phenethylammonium iodide \(^{(8)}\) and 0.2 mole of resorcinol was heated in a nitrogen atmosphere for 6 hr at \(175 \pm 2^\circ\).

The reaction products were treated with water and extracted with ether. The ether solution was extracted with \(4 N\) NaOH; the resulting alkaline solution was acidified with sulfuric acid.

The oil that separated was extracted with ether and dried over magnesium sulfate. After removal of the solvent, the residue was fractionated using a fir-tree dephlegmator 8 cm high. This gave α-phenethylresorcinol, b.p. \(189—192^\circ\) (2 mm). Yield 9.68 g. On standing, the substance crystallized. Colorless needles from benzene–n-hexane, m.p. \(78.0—79.0^\circ\). The substance had no optical activity.

Found, %: C 78.47; H 6.55
\(\mathrm{C}_{14}\mathrm{H}_{14}\mathrm{O}_{2}\). Calculated, %: C 78.51; H 6.59

Bis-p-nitrobenzoate, m.p. \(143.5—144^\circ\) from a mixture of benzene with n-hexane.

2. Oxidation of α-phenethylresorcinol to α-phenylpropionic acid. The reaction was carried out under the conditions described by Hart \(^{(10)}\).

To a solution of 4.57 g of α-phenethylresorcinol in 350 ml of acetone, with stirring, was added a solution cooled to \(10—12^\circ\) of 25.6 g of \(\mathrm{KMnO}_{4}\) in 1.2 l of water. The rate of addition of the solution was regulated so that the temperature of the reaction mass remained within \(24—26^\circ\). After addition of the entire permanganate solution, stirring was continued for 30 min, after which the reaction mixture was carefully acidified with \(4 N\) sulfuric acid and sodium bisulfite solution was added to dissolve the precipitated manganese dioxide.

The reaction mixture was extracted with methylene chloride; the extract was washed with water and then shaken with \(2 N\) sodium carbonate solution. After filtration, the alkaline solution was acidified with \(4 N\) sulfuric acid. The acid that separated was extracted with methylene chloride; the resulting extract was dried over \(\mathrm{MgSO}_{4}\).

After removal of the solvent, α-phenylpropionic acid was distilled. Yield 1.34 g, b.p. \(147—9^\circ\) (14 mm) (after two distillations), \(n_{D}^{20}\) 1.5228 (according to the literature \(^{(10)}\), α-phenylpropionic acid has b.p. \(145—8^\circ\) (15 mm), \(n_{D}^{20}\) 1.5210). The acid obtained proved to be optically inactive \(([\alpha]_{D}^{20}\ 0 \pm 0.2^\circ)\).

Neutralization equivalent: found 150.6; calculated 151.1.

Found, %: C 71.46; H 6.65
\(\mathrm{C}_{9}\mathrm{H}_{10}\mathrm{O}_{2}\). Calculated, %: C 71.97; H 7.71

S-Benzylthiuronium salt, m.p. \(143—4^\circ\).
p-Bromophenacyl ester, m.p. \(62—3^\circ\).

Found, %: C 59.22; H 4.14
\(\mathrm{C}_{17}\mathrm{H}_{15}\mathrm{O}_{3}\mathrm{Br}\). Calculated, %: C 58.91; H 4.35

3. Interaction of dl-N-trimethyl-α-phenethylammonium iodide with deuteroresorcinol. 27.5 g of resorcinol

and 6.0 ml of deuterium oxide was placed in a distillation flask. The contents of the flask were homogenized by gentle heating. The water was distilled off under vacuum and collected in a receiver cooled with liquid nitrogen. After removal of all the water, deuterioresorcinol was distilled. B.p. 163–6° (17 mm). Yield 26.8 g.

The water obtained on combustion of the deuterioresorcinol had an excess density of 18500 γ/ml.

A mixture of 29.1 g of \(dl\)-\(N\)-trimethyl-\(\alpha\)-phenethylammonium iodide and 18.5 g of deuterioresorcinol was heated in nitrogen at \(172 \pm 2^\circ\) for 3 hr. There was obtained 8.42 g of deutero-\(\alpha\)-phenethylresorcinol with b.p. 197–8° (4 mm), m.p. 77.5–78.5° (from a benzene–\(n\)-hexane mixture). 7.13 g of deutero-\(\alpha\)-phenethylresorcinol was oxidized to \(\alpha\)-phenylpropionic acid. 1.55 g of substance was obtained, b.p. 154–6° (18 mm), \(n_D^{20}\) 1.5229.

The water obtained on combustion of the \(\alpha\)-phenylpropionic acid had an excess density of 416 γ/ml, which amounts to 9.6% of the value calculated for exchange equilibrium.

The incorporation of deuterium into the phenethyl group indicates the intermediate formation of an \(\alpha\)-phenethylcarbonium ion in the alkylation of resorcinol by the ammonium salt.

1. Interaction of \(d\)-\(N\)-trimethyl-\(\alpha\)-phenethylammonium iodide with phloroglucinol. A mixture of 0.03 mole of \(d\)-\(N\)-trimethyl-\(\alpha\)-phenethylammonium iodide and 0.04 mole of phloroglucinol was heated in nitrogen for 6 hr at \(155 \pm 1^\circ\).

The reaction mixture was treated with 30 ml of 0.5 \(N\) \(\mathrm{H_2SO_4}\) and 30 ml of ether. Phloroglucinol was filtered off; the ethereal solution was washed with water and dried over \(\mathrm{MgSO_4}\).

After removal of the solvent, a thick, noncrystallizing residue was obtained (5.75 g).

Since attempts to isolate pure \(\alpha\)-phenethylphloroglucinol from this residue were unsuccessful, it was directly oxidized to \(\alpha\)-phenylpropionic acid. In this way 1.64 g of \(\alpha\)-phenylpropionic acid was obtained, b.p. 146–8° (12 mm), \(n_D^{20}\) 1.5210.

Investigation of the rotatory power showed that the substance was completely devoid of optical activity (\([\alpha]_D^{20}\ 0 \pm 0.2^\circ\)). It follows from this that \(\alpha\)-phenethylphloroglucinol also was optically inactive.

In an analogous experiment, from 29.0 g of \(dl\)-\(N\)-trimethyl-\(\alpha\)-phenethylammonium and 17.3 g of phloroglucinol, 6.21 g of \(dl\)-\(\alpha\)-phenylpropionic acid was obtained, b.p. 159–160° (20 mm), \(n_D^{21}\) 1.5225.

Institute of Organoelement Compounds
Academy of Sciences of the USSR

Received
14 XI 1956

CITED LITERATURE

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