Reactions of Glycolonitrile with Ammonia and Water: A Free Energy Map

Abstract

Glycolonitrile, the product of combining CHO and HCN, is an intermediate in the Strecker reaction leading to the synthesis of the amino acid glycine. However, besides glycine, a plethora of other compounds are also generated when CHO and HCN react in the presence of ammonia and water. As a starting point to analyze the possible components of this complex mixture, we have employed density functional theory to construct a free energy map of all two-carbon (C2) species that may be present when glycolonitrile participates in addition or elimination reactions with ammonia and water. By identifying thermodynamic sinks and kinetic barriers, we find that the myriad C2 species can be grouped into three broad regions across the free energy landscape. This allows us to trace possible routes to glycine and other molecules of interest in the reaction mixture. The present map also extends our previous work on one-carbon (C1) species. We had previously found one issue with our computational protocol in the C1 map; however, our present C2 map provides a larger data set that supports using an empirical correction to our original protocol for imidic acid to amide transformations, without increasing the computational cost, while retaining the original protocol for other classes of reactions.

Early Steps of Glycolonitrile Oligomerization: A Free-Energy Map

“…Our map shows the multitude of dimers and trimers that may be present in the complex mixture and why it is unlikely that glycine can be formed under mild conditions if glycolonitrile (in the absence of ammonia and therefore no aminoacetonitrile) is the sole starting material. The free energies are calculated for neutral conditions (pH 7) at 25 °C, in line with extending our previous work 7 and providing a baseline for future work.…”

“…Potential issues stemming from the approximations and assumptions made in our protocol are discussed more extensively in previous work. 7,9 ■ RESULTS AND DISCUSSION Orientation to the Energy Maps. The aqueous free energies in our maps are relative to the reference molecules (glycolonitrile, water, ammonia), as described in the Computational Methods.…”

“…Tautomer 26, with its pendant aldehyde group, is of interest because hydrolysis of the ring to monomeric species (following the dashed purple lines) leads to glycolic acid and an aminated glyoxal; deamination of the latter (although endergonic) leads to glyoxal as shown in our previous work. 7 A similar pendant aldehyde compound can be formed through the route 13 → 36 → 37 → 38 where hydrolysis of 38 to its monomeric species leads to glyoxal (monohydrate) and glycolic acid. However, this route is also overall energetically unfavorable and suffers from the same issues described by 10 → 33 → 34 → 35.…”

“…5 One possible reason: in aqueous solution, glycolamidine easily hydrolyzes to glycolamidethe reaction is exergonic and kinetically facile. 7 Arrhenius et al also proposed a route to glycolamide and glycolic acid. In our map, this route runs 1 → 2 → 22 → 29 → 41 → 12 → glycolamide + glycolic acid.…”

Thermodynamics of Potential CHO Metabolites in a Reducing Environment

“…That being said, our protocol does show systematic errors when calculating barriers, but since quantitative kinetics is not part of the present study, this is not an issue. When extended to include nitrogen-containing species, our protocol still does well but systematic errors do crop up for specific functional groups [26]. Going to a higher level of theory and/or including dispersion corrections does not improve the results (see Table S1); this may seem surprising but quantum chemistry is about error cancellation, and our protocol (with its foibles) seems to work well, at least for the compounds in this study.…”