Regio- and Stereochemistry of Gas-Phase Acid-Induced Nucleophilic Substitutions on Chiral Allylic Alcohols¹

Abstract

The regio- and stereochemistry of the nucleophilic attack of (S)-trans-3-hexen-2-ol (MS ) and (S)-trans-4-hexen-3-ol (ES ) on the corresponding O-protonated (L = H) and -methylated (L = CH3) derivatives (MSL+ and ESL+ ) are investigated in the gas phase at 40 °C (720 Torr). The MSL+ and ESL+ intermediates are produced in the gas phase by the attack of the ionic Brønsted and Lewis acids, formed by stationary γ-radiolysis of bulk CH3Cl, on the corresponding chiral alcohols, i.e., MS and ES . In these systems, firm evidence in favor of the concerted SN2‘ pathway, accompanying the classical SN2 one, is obtained by excluding the following: (i) the isomerization of MSL+ (or ESL+ ) before the attack by the nucleophile NuH = MS (or ES ); (ii) the isomerization of the (C6H11)2OH+ substitution intermediates before neutralization; (iii) the intermediacy of allylic cations. The regioselectivity factors (SN2‘/SN2 = 1.4 (MS ), 1.1 (ES )) confirm previous experimental and theoretical evidence about the prevalence in the gas phase of the SN2‘ pathway, over the competing SN2 one. Orientation of NuH by MSL+ (or ESL+ ) determines the regiochemistry of the allylic substitution. When NuH approaches the oxonium intermediate from the direction syn to the leaving moiety LOH, a frontside SN2 displacement takes places favored by preliminary proton bonding between LOH and NuH. The SN2‘ reaction instead follows attack on the π-LUMO of the oxonium ion by the NuH juxtaposed anti to the leaving LOH group. Observation of a predominant anti-SN2‘ orientation provides the first experimental basis of modern concepts pointing to Coulombic interactions as the main intrinsic factors governing the SN2‘ stereochemistry and to solvation and ion pairing as the factors determining the low efficiency of SN2‘ reactions and their preferred syn stereochemistry in solution.

Unusual atmospheric pressure chemical ionization conditions for detection of organic peroxides

“…Although the aim of this study was not to describe closely the nature of the mechanism involved in the acid‐induced intramolecular nucleophilic substitution or α–β elimination reaction, some remarks should be made. Consistent with many studies reported previously, such behavior could be induced by an elongation of the peroxide O δ+ —C bond and driven by a carbocation stabilization which will decrease the energy level of the transition state of the reaction 21–33. Prior to dissociation, this activated ion undergoes isomerization into an ion–neutral complex which evolves towards two possible a and b pathways (Scheme ) 34.…”

“…for a microcanonical system (for a given value of energy e ), the magnitude of the microcanonical rate constant k (e) of the reaction yielding [ II + H] + from [ II + CH 3 OH 2 ] + , appears so tenuous that the reactive species is involved in another competing processes such as intramolecular internal nucleophilic substitution and α–β elimination (Scheme ). These kinds of reactions are known to proceed via a highly organized transition state and require a very specific orientation of groups involved in the reaction 32, 33. Such a competition illustrates low values of the microcanonical rate constant for the dissociation of the complex [ II + CH 3 OH 2 ] + leading to the formation of the ionic species [ II + H] + .…”

Investigating the Ritter Type Reaction of α‐Methylene‐β‐hydroxy Esters in Acidic Medium: Evidence for the Intermediacy of an Allylic Cation

“…The chemistry of allylic derivatives and the propensity of their nucleophilic substitution reactions to result in rearranged products have been the subject of intensive study for over a century 1–3. However, the exact structures of the possible products formed, as well as their relative distribution, are often rather unpredictable because they are dependent on the allylic substrate and on a range of reaction variables.…”

Stereoselectivity in the collision-activated reactions of gas phase salt complexes

“…These differences can be exploited (i.e., by comparison to data for known standards) and used to determine the enantiomeric purity of a sample. Cooks [3][4][5][6][7][8][9][10][11][12][13][14][15][16], Dearden , Lebrilla [21][22][23][24][25][26], Speranza [27][28][29][30][31][32][33][34][35], and others have provided useful examples of this approach to stereochemical analysis.…”

“…In general, these processes have been probed in the condensed phase, but there is no reason why mass spectrometry could not also be used to screen gas phase reactions for stereoselectivity [35,36]. An advantage of this approach is that in the solvent-free environment of the gas phase, it is possible to gain a clear understanding of the molecular interactions that lead to stereoselectivity in a chemical transformation.…”