Theoretical and Experimental Methods for the Analysis of Reaction Mechanisms in S_NAr Processes

Activation of Electrophile/Nucleophile Pair by a Nucleophilic and Electrophilic Solvation in a SNAr Reaction

“…Electrophilic solvation represents the specific interaction through an HB with the hydrogen atom of the solvent, whereas nucleophilic solvation describes a specific interaction through a HB between an acidic hydrogen atom of the E + / Nu − pair and the solvent (Ormazábal-Toledo et al, 2013c ). The effect of the HB in S N Ar was early studied by Bernasconi et al (Bunnett et al, 1955 ; Bernasconi and De Rossi, 1976 ) and recently by our group (Ormazábal-Toledo et al, 2013a , b , c ; Gallardo-Fuentes et al, 2014 ; Alarcón-Espósito et al, 2015 ; Contreras et al, 2015 ) from experimental and theoretical point of view in order to explain the observed reactivity trends (Parr et al, 1999 ; Contreras et al, 2003 ; Ormazábal-Toledo et al, 2013a ).…”

“…(ii) when k −1 + k 2 ≫ k 3 the formation of the MC intermediate is the rate determining step, where k obs is given by Equation 5: (Banjoko and Babatunde, 2004 ; Um et al, 2007 ; Ormazábal-Toledo et al, 2013a , b , c ; Terrier, 2013 ; Gallardo-Fuentes et al, 2014 ; Gazitúa et al, 2014 ; Alarcón-Espósito et al, 2015 , 2016 , 2017 ; Contreras et al, 2015 ).…”

“…Scheme 1 shows the S N Ar process considered in this work. Note that, the first step on the reaction pathway corresponds to the formation of a zwitterionic complex named Meisenheimer complex (MC) from which two processes for its decomposition have been postulated:(Banjoko and Babatunde, 2004 ; Um et al, 2007 ; Ormazábal-Toledo et al, 2013a , b , c Terrier, 2013 ; Gallardo-Fuentes et al, 2014 ; Gazitúa et al, 2014 ; Alarcón-Espósito et al, 2015 , 2016 , 2017 ; Contreras et al, 2015 ) (a) expulsion of the leaving group (LG) followed by fast proton loss to give the reaction product ( k 2 in Scheme 1 ), and (b) the base-catalyzed deprotonation of the MC that loss the LG to give the reaction product ( k 3 in Scheme 1 ) (Alarcón-Espósito et al, 2017 ).…”

“…Solvent effects studies in S N Ar have been addressed experimentally in order to get detailed information about phenomena that are not observable and occurring at microscopic levels (Ormazábal-Toledo et al, 2013b , c ; Alarcón-Espósito et al, 2015 ; Contreras et al, 2015 ). The model systems are the reactions between the substrate or electrophile named 4-chloroquinazoline and two amines of different nature (aniline and hydrazine), respectively (see Scheme 1 ).…”

How the Nature of an Alpha-Nucleophile Determines a Brønsted Type-Plot and Its Reaction Pathways. An Experimental Study

“…However, α-electron withdrawing group diminishes the α-effect (Evanseck et al, 1987;Yamataka, 2006, 2007;Nigst et al, 2012) Finally, TS structures analysis have shown that there is no difference between nucleophiles with and without α-effect (Ren and Yamataka, 2007) Therefore, it is possible that the α-effect could be related with several factors, and more studies are needed to provide a detailed description about how this significant effect operates. For better understanding the α-effect, in the present work we studied the magnitude of the α-effect of the reacting pair (electrophile/ nucleophile) evaluating the nucleophilic rate coefficients of a nucleophilic aromatic substitution (S N Ar) reaction in aqueous media (Cho et al, 2014) The postulated mechanism for a S N Ar reaction involves a nucleophilic addition followed by elimination of a leaving group (LG) and it requires the presence of at least one strong electron-withdrawing (Bunnett and Morath, 1955;Liebman et al, 1996) substituent in the ring of the electrophile to stabilize the intermediate, called Meisenheimer Complex (MC) and good LG (Bunnett and Zahler, 1951;Banjoko and Babatunde, 2004;Crampton et al, 2004Crampton et al, , 2007Um et al, 2007;Terrier, 2013;Ormazábal-Toledo et al, 2013b;Gallardo-Fuentes et al, 2014;Gazitúa et al, 2014;Contreras et al, 2015;Calfumán et al, 2017;Sánchez et al, 2018b) The first step of the reaction mechanism corresponds to the formation of a MC. In a second step, the LG detaches after an intramolecular proton transfer (RLPT) from the nucleophile (Bernasconi and De Rossi, 1976;Maķosza, 1993;Bernasconi et al, 2004;Nudelman, 2009;Um et al, 2012;Ormazabal-Toledo et al, 2013;Ormazábal-Toledo et al, 2013a;Swager and Wang, 2017) Scheme 1 shows the general reaction mechanism for a S N Ar reaction.…”