Antihydrophobic Cosolvent Effects for Alkylation Reactions in Water Solution, Particularly Oxygen versus Carbon Alkylations of Phenoxide Ions

Abstract

Antihydrophobic cosolvents such as ethanol increase the solubility of hydrophobic molecules in water, and they also affect the rates of reactions involving hydrophobic surfaces. In simple reactions of hydrocarbons, such as the Diels-Alder dimerization of 1,3-cyclopentadiene, the rate and solubility data directly reflect the geometry of the transition state, in which some hydrophobic surface becomes hidden. In reactions involving polar groups, such as alkylations of phenoxide ions or S(N)1 ionizations of alkyl halides, cosolvents in water can have other effects as well. However, solvation of hydrophobic surfaces is still important. By the use of structure-reactivity relationships, and comparing the effects of ethanol and DMSO as solvents, it has been possible to sort out these effects. The conclusions are reinforced by an ab initio computer model for hydrophobic solvation. The result is a sensible transition state for phenoxide ion as a nucleophile, using its oxygen n electrons to avoid loss of conjugation. The geometry of alkylation of aniline is very different, involving packing (stacking) of the aniline ring onto the phenyl ring of a benzyl group in the benzylation reaction. The alkylation of phenoxide ions by benzylic chlorides can occur both at the phenoxide oxygen and on ortho and para positions of the ring. Carbon alkylation occurs in water, but not in nonpolar organic solvents, and it is observed only when the phenoxide has at least one methyl substituent ortho, meta, or para. The effects of phenol substituents and of antihydrophobic cosolvents on the rates of the competing alkylation processes indicate that in water the carbon alkylation involves a transition state with hydrophobic packing of the benzyl group onto the phenol ring. The results also support our conclusion that oxygen alkylation uses the n electrons of the phenoxide oxygen as the nucleophile and does not have hydrophobic overlap in the transition state. The mechanisms and explanations for competing oxygen and carbon alkylations differ from previous proposals by others.

A Unitary Anesthetic Binding Site at High Resolution

“…Propofol and analogs were purchased from Sigma-Aldrich or Acros (Geel, Belgium); compounds 2, 3, and 5 were synthesized as previously described (21,22). Ligand structures are given in Table 1.…”

Biomimetic Chemistry: Biology as an Inspiration

“…As part of this, we also showed that we could determine the detailed transition state geometries of a number of important chemical reactions, a goal of chemistry that was hitherto completely impossible, by using such denaturants in water solution (22). The magnitude of the denaturant effect on reaction rates proved to be directly related to the amount of exposed hydrocarbon surface in the transition states for the reactions relative to that in the starting materials.…”

Enzymatic C-glycosylation: Insights from the study of a complementary pair of plant O- and C-glucosyltransferases

“…In addition to steric effects that will contribute to the relative positioning of reactive and catalytic groups, it is conceivable that other chemical factors of selectivity in competing O and C alkylations of phenoxide ions might thus have become optimized in each enzyme. Solvent dielectric and polarity, S N 1 or S N 2 character of the transition state, and hydrogen bonding have been discussed in literature as factors affecting the position of alkylations of phenoxide ions [38]. Moreover, the hard-soft character of the phenoxide is considered important in determining the selectivity of oxygen vs. carbon alkylation [39].…”