Comparison of Electron Ionization Fragmentation Pathways for Regioisomeric Ethoxy and Methoxymethyl Substituted Benzoate Esters

Rationale

This study compares the EI fragmentation mechanisms for the regioisomeric 2-, 3-, and 4-ethoxy and methoxymethyl substituted methyl benzoates. These compounds represent isomerism in disubstituted aromatic ring and position of oxygen in the ether substituent. These esters are required synthetic intermediates for the design and synthesis of phenethylamine analogs as potential new drug substances. Regioisomerism of substituents and heteroatoms position often plays a significant role in drug action, potency, and MS fragmentations.

Methods

The ethoxy substituted isomers were obtained from commercial source. The methoxymethyl substituted isomers were prepared from 2-, 3-, and 4-(chloromethyl)benzoyl chloride by methoxide displacement using Na/methanol. The D₃-methyl esters were prepared by acid-catalyzed ester exchange using methanol-D₄ and ethyl esters as substrates. The compounds were evaluated using GC, stable isotope, EI, and MS/MS studies.

Results

The major EI-MS fragments for methyl ethoxybenzoates are m/z 152, 149, and a base peak (3- and 4-substituted isomers) at m/z 121 from the loss of ethene, methoxy radical, and carbomethoxy radical, respectively. The ortho effect in methyl 2-ethoxybenzoate yields a base peak at m/z 120 and other unique cations at m/z 133, 147, and 165 due to the interaction of ortho- side chains. The major ortho effect in methyl 2-methoxymethylbenzoate arises from the ease of formation of the hydrogen rearrangement product yielding the m/z 133 base peak and inhibiting the formation of m/z 121 and 179 ions observed in 3- and 4-substituted isomers.

Conclusions

The methoxymethyl substituted isomers yield more fragments than the ethoxy isomers. Thus, the alkyl ether is a more active participant in the fragmentation processes than the aromatic/phenolic ether for the ethoxy series. The major ortho effect in this series favors the distonic molecular radical cation formation yielding the m/z 133 base peak for the 2-substituted isomer and inhibiting the formation of m/z 121 and 179 species.