Formamide-Catalyzed Nucleophilic Substitutions: Mechanistic Insight and Rationalization of Catalytic Activity

Abstract

Herein, detailed mechanistic investigations into formamide-catalyzed nucleophilic substitution (S N ) of alcohols are reported. Alkoxyiminium chlorides and hexafluorophosphates were synthesized and characterized as a key intermediate of the catalytic cycle. The determination of reaction orders and control experiments indicated that the nucleophilic attack of the formamide catalyst onto the reagent BzCl is the rate-determining step. Linear free energy relationship revealed a correlation between the quantified Lewis basicity strength of formamides by means of 11B NMR spectroscopy and their catalytic activity in S N -transformations. The observed difference in catalytic ability was attributed to the natural bond order charge, dipole moment, and Sterimol parameter B5. Importantly, this rationalization enables the prediction of the capacity of formamides to promote S N -type transformations in general.

Hydrogen-bond donor and acceptor cooperative catalysis strategy for cyclic dehydration of diols to access O-heterocycles

“…Moreover, an inverse deuterium kinetic isotope effect ( k H / k D = 0.89) was observed by comparing the rate of dehydrative etherification of 1c with that of CD 3 OH ( 1c′ ), which supports the idea that the reaction mainly follows an S N 2-like pathway (fig. S14, B and C) ( 7 , 9 , 39 ). In addition, tertiary alcohol (e.g., 5a ) was also tolerant to this IL catalyst but showed a low reactivity with a 36% yield of 5b under the similar reaction conditions.…”

Mechanistic Inference from Statistical Models at Different Data-Size Regimes

“…Moreover, a recent review by Norrby and co-workers provides an excellent computational chemistry assessment of how the mechanistic study of organic reactivity has been affected by machine learning . Herein, we also set mechanistic inference as our mainstay; however, our specific aim is to demonstrate through selected examples that a careful experimental design not only enables efficient reaction optimization but can concurrently generate uniquely suitable data sets for mechanistic investigation. − …”

A method of mild deoxydichlorination of aldehydes catalyzed by Triphenylphosphine oxide

“…The development of methods for nucleophilic substitution (SN) in sp 3 -hybridized carbon centers is the most significant and widespread problem of chemical transformations in organic synthesis [1][2][3][4][5]. Nucleophilic substitutions are general chemical transformations, as they allow, for example, strategic building of C-Cl, C-O, C-N and C-C bonds [6][7][8][9][10][11][12][13][14][15]. At the same time, compounds such as geminal dihalides are important intermediates in the chemical synthesis of useful natural substances, including active biological compounds.…”