Quantification of Electrophilic Activation by Hydrogen-Bonding Organocatalysts

Abstract

A spectrophotometric sensor is described that provides a useful assessment of the LUMO-lowering provided by catalysts in Diels–Alder and Friedel–Crafts reactions. A broad range of 33 hydrogen-bonding catalysts was assessed with the sensor, and the relative rates in the above reactions spanned 5 orders of magnitude as determined via 1H- and 2H NMR spectroscopic measurements, respectively. The differences between the maximum wavelength shift of the sensor with and without catalyst (Δλmax–1) were found to correlate linearly with ln(krel) values for both reactions, even though the substrate feature that interacts with the catalyst differs significantly (ketone vs nitro). The sensor provides an assessment of both the inherent reactivity of a catalyst architecture as well as the sensitivity of the reaction to changes within an architecture. In contrast, catalyst pKa values are a poor measure of reactivity, although correlations have been identified within catalyst classes.

Experimental and Theoretical Studies in Hydrogen-Bonding Organocatalysis

“…However, the analysis of p K a values do not take into account various secondary interactions, mainly steric effects, and binding geometry. A different approach to assessment of H-bond catalysts relies on a spectrophotometric sensor 16a and its ability to respond to LUMO-lowering imparted by hydrogen bonding of the carbonyl group by shifting its λ max [28]. This change in electronic properties of the sensor is, therefore, detectable by UV-Vis spectroscopy (Figure 4).…”

CF3-groups critically enhance the binding of thiourea catalysts to ketones – a NMR and FT-IR study

“…13 Despite the importance of hydrogen-bonding, other contributions including dual activation, secondary interactions, and steric effects have been suggested to affect catalytic activity. 14 Since catalyst-substrate aggregates are the relevant reactive intermediates, which determine amongst others e.g. reaction rates, energetic barriers etc., the binding strength between these thiourea catalysts and the substrates is important for catalytic activity.…”

Organocatálise Enantiosseletiva: Evolução E Aspectos Recentes

“…Em 2014, Kozlowski e colaboradores realizaram a quantificação da ativação eletrofílica via ligação de hidrogênio por organocatalisadores, por meio de análises de espectroscopia UV/vis de reações de Diels-Alder e Friedel-Crafts. 40 Os ácidos fosfóricos derivados de BINOL também são amplamente utilizados como organocatalisadores em diversas reações. 38 Em 2011, List e colaboradores reportaram a primeira indolização de Fischer enantiosseletiva promovida pelo ácido fosfórico derivado de BINOL 37 de uma série de cicloexanonas 4-substituídas derivadas de fenilidrazonas 36 levando a tetraidrocarbazóis 3-substituídos 38 em altos rendimentos e boas enantiosseletividades (Esquema 11, superior).…”

“…Na etapa organocatalisada, o hidrogênio ácido da malonitrila(40) interage com o catalisador bifuncional 44, que atua como base de Lewis, enquanto a quinona 41 é ativada por 44 por meio de ligação de hidrogênio, promovendo a adição de Michael.…”