A simple macrocyclic amine is alkylated by methylene chloride to give a quaternary ammonium chloride salt. When methylene chloride is the solvent, the reaction exhibits pseudo-first-order kinetics, and the reaction half-life at 25.0 degrees C is 2.0 min. The reaction half-life for a structurally related, acyclic amine is approximately 50 000 times longer. Detailed calculations favor a mechanism where the methylene chloride associates with the macrocycle to form an activated prereaction complex. The macrocyclic nitrogen subsequently attacks the methylene chloride with a classic SN2 trajectory, and although the carbon-chlorine bond breaks, the chloride leaving group does not separate from the newly formed cationic macrocycle, such that the product is a tightly associated ion-pair. X-ray crystal structures of the starting amine and the product salt, as well as kinetic data, support this mechanism.

Compared to structurally related linear trialkylamines, a simple macrocyclic amine with an anion-binding cavity exhibits very large rate enhancements (>10(5)) for stoichiometric N-alkylation with primary alkyl, allyl, and benzyl halides in the weakly polar solvent CDCl3. There is also a major distortion of the halide leaving-group order. For example, with benzyl halides the relative leaving-group order with a control amine is Cl (1) < Br (71) < I (160), whereas the leaving-group order with the macrocyclic amine is I (0.4) < Cl (1) < Br (8.5). Reaction with the macrocyclic amine is inhibited by the addition of DMSO, which is unusual because the Menschutkin reaction is normally enhanced by the presence of a polar aprotic solvent. Competitive inhibition studies indicate that the reaction proceeds through a prereaction complex. Effective molarities for the subsequent unimolecular N-alkylation step with 4-t-butylbenzyl halides are 4-t-BuBnCl (62,000 M) > 4-t-BuBnBr (2200 M) > 4-t-BuBnI (35 M); thus, the free energy of activation is selectively decreased for organohalides having smaller and more charge dense leaving groups. Likely reasons for this selective enhancement effect are: (a) increased transition-state stabilization due to hydrogen bonding in the macrocyclic pocket and (b) reduced entropic penalty in the transition state due to an increased fraction of prereaction complexes that are oriented in a near attack conformation. The study suggests that it should be possible to develop highly reactive macrocyclic amines that selectively sense or scavenge carcinogenic haloalkanes from the atmosphere.

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