Reaction of the Ambident Electrophile Dimethyl Carbonate with the Ambident Nucleophile Phenylhydrazine

Abstract

To explore the ambident electrophilic reactivity of dimethyl carbonate (DMC), reactions with the ambident nucleophile phenylhydrazine were investigated. When a Brönsted base was used, selective carboxymethylation occurred at N-1, after that several other compounds were produced selectively utilizing various conditions. Formation of these compounds was explained by using the Hard-Soft Acid-Base (HSAB) theory. Catalysis by some metal salts altered the reactivity of phenylhydrazine, which effected selective carboxymethylation at N-2 of phenylhydrazine instead.Dimethyl carbonate (DMC) is a well-known nontoxic reagent and solvent that has been used for many Green applications, namely the substitution of toxic reagents such as methyl halides and phosgene for the selective methylation and carboxymethylation, respectively, of numerous nucleophiles. 1 Both transformations are possible owing to the two nonequivalent electrophilic centers of DMC, making it an ambident electrophile. Selectivity toward either center can be attributed to the HardSoft Acid-Base (HSAB) theory, introduced by Pearson. 2 In the context of DMC, the theory can be simply applied by suggesting DMC will carboxymethylate (hard reaction) hard nucleophiles or methylate (soft reaction) soft nucleophiles. It should be pointed out that this classification is a relative assignment for the differing reactivities of the two electrophilic centers of DMC.A prime example that demonstrates both hard and soft nucleophilicity in a tandem reaction, and is also relevant to this report, is the reaction of arylacetonitriles with DMC. 3 From the starting material, e.g., phenylacetonitrile, an anion is generated with a Brönsted base; the anion is a hard nucleophile and thus reacts with DMC to produce the carboxymethylated arylacetonitrile 2. Bearing the carboxylate group, the reactive carbon anion is rendered a soft nucleophilic center and undergoes methylation to produce the methyl carboxymethylated arylacetonitrile 3. Reaction between MeOH and 3 results in the formation of 2-methyl-2-phenylacetonitrile (4), which does not readily undergo methylation because the loss of the carboxymethyl moiety renders the carbon a hard nucleophilic center, which only permits the carboxymethylation to reproduce 3. Significantly, the reaction was carried out with DMC as a solvent/reagent; after complete conversion the selectivity for the mono-methylated product 4 was >99%.DMC has also been shown to react analogously with other nucleophiles, such as amino compounds. 4 In an effort to explore this concept further, a more complex class of nucleophile was sought. In particular, ambident nucleophiles were of interest due to the appealing concept of exploring reactions of ambident nucleophiles with ambident electrophiles.Phenylhydrazine was our first choice for an ambident nucleophile. On face value, it is a relatively simple molecule. It possesses two adjacent nitrogens; however, they differ in reactivity due to the phenyl substituent at N-1. In the literature there are some reports of alkylati...

Isosorbide and dimethyl carbonate: a green match

“…It is also noteworthy that in general alkylation reactions promoted by DMC chemistry are conducted at temperatures above 150 °C [24–35], but in this case study the intramolecular cyclisation step leading to isosorbide, which is an alkylation reaction (Scheme 2), takes place at the DMC refluxing temperature (90 °C).…”

“…This compound has been extensively employed as green substitute of highly toxic phosgene in carboxymethylation reactions and methyl halides or other noxious methylating agents in methylation reactions [24–35]. …”

5-Membered cyclic ethers via phenonium ion mediated cyclization through carbonate chemistry

“…In fact, DMC acts as methoxycarbonylation agent with harder nucleophiles via a B Ac 2 mechanism at reflux temperature (T = 90 °C) and as methylating agent with softer nucleophiles via a B Al 2 mechanism, at higher temperature (T > 150 °C) [15][16][17][18][19][20][21][22][23] (Fig. 1).…”

Cyclization reaction of amines with dialkyl carbonates to yield 1,3-oxazinan-2-ones

“…In the last 20 years, dimethyl carbonate (DMC) and its derivatives have become well-known substitutes for phosgene and alkyl halides [25] and have been shown to effectively react with aliphatic [26,27] and aromatic [27,28] amines and hydrazines [29] to give a wide range of carbamates and methyl amines. DMC is a green reagent and solvent produced industrially by CO 2 insertion into an epoxide, followed by cleavage of the resulting cyclic carbonate with methanol [30].…”