Luigi Mandolini

The Role of Ring Strain on the Ease of Ring Closure of Bifunctional Chain Molecules

The role of ring strain on the ease of ring formation over a wide range of ring sizes is discussed on the basis of a comparison of transition state versus product-ring strain energies. A general procedure is illustrated for the assessment of transition-state strain energies, based on experimental effective molarities (EMs) and an extra-thermodynamic treatment of entropy data for ring closure. It is found that the ring product is a good model of the transition state of cyclisation for all but the shortest chains. Our earlier interpretation of this remarkable lack of correspondence between transition state and product-ring strain energies in intramolecular nucleophilic substitutions of the very short chains, is compared with the results of recent theoretical calculations.

Intramolecular Reactions of Chain Molecules

Publisher Summary This chapter focuses that the field of intramolecular reactions is a mature area in which the merging of concepts from both physical organic chemistry and polymer chemistry leads to a unified treatment of cyclization rates and equilibria in terms of a few simple generalizations and theories. It is concerned with reaction rates, equilibria, and mechanisms of cyclization reactions of chain molecules. It discusses that parallel to the search for synthetic methods to make rings of all sizes, kinetic studies have appeared with the aim of providing insight into physical aspects of ring closure. A significant portion of the evidence available on the kinetics of intramolecular reactions falls in the domain of neighboring group participation. The term is sufficiently wide to encompass “all intramolecular reactions and all reactions that involve nonelectrostatic through-space interactions between groups in the same molecule.” However, the most common types of neighboring group participation involve nucleophilic participation either with or without anchimeric assistance and intramolecular acid and base catalysis. The chapter explores that intramolecular catalysis phenomena have attracted much attention, both from the experimental and theoretical points of view, not only on account of their inherent mechanistic interest, but also because they are believed to model the extraordinary efficiency of enzyme catalysis.

Bridged calix[6]arenes in the cone conformation: New receptors for quaternary ammonium cations

Abstract The synthesis of calix[6]arene crown ethers 3 and 4 has been accomplished for the first time by selective bridging of the parent macrocycles. The alkylation of 3 with α-chloro-N,N-diethyl acetamide produces a compound 6 whose conformational flexibility is strongly reduced and which assumes a cone conformation both in solution and in the solid state. Compound 6 represents a new type of ditopic receptor which binds tetramethylammonium cation in the polar region at the lower rim, showing an association constant Ka=750 M−1 in CDCl3.

“Inherent chirality” and curvature

“Inherent chirality” in molecules like calix[4]arenes, fullerenes, and uranyl-salophen complexes can be related to the presence of curvature. This observation serves as a basis for the introduction of a new chirality descriptor.

Zinc–salophen complexes as selective receptors for tertiary amines

Zinc–salophen compounds 1–3 incorporating in the given order 1,2-diaminobenzene, 2,3-diaminonaphthalene, and 9,10-diaminophenantrene moieties were synthesised. Their binding properties toward a series of tertiary amines were assessed by UV-Vis and fluorescence spectroscopy in chloroform solution. Unprecedented selectivities of quinuclidine vs. triethylamine higher than 105 were recorded, thereby revealing the dramatic influence of steric effects on axial coordination of tertiary amines. X-Ray diffraction analyses showed that in the solid state compound 2 is dimeric, but its 1 : 1 quinuclidine complex is monomeric. Strong indications were obtained that both free receptors and their amine adducts are monomeric in dilute chloroform solution.

Cation-π interactions between neutral calix[5]arene hosts and cationic organic guests

Abstract The binding properties of the 1,3-bridged calix[5]crowns 1–3 towards a number of quaternary ammonium, phosphonium, and iminium ions have been investigated by 1H NMR in CDCl3 solution, where the sole driving force for association is provided by cation-π interactions. We have found that the cavity of a calix[5]arene fixed in a cone-like conformation provides a fairly efficient, but rather unselective, receptor site for quaternary salts. The conformationally mobile p-tert-butylcalix[5]arene (4) is in general a much less efficient binder than the more preorganized calixcrowns, but displays a remarkable selectivity towards N-methylquinuclidinium ion that is believed to arise from a good complementarity between the globe-shaped guest and the highly adaptable host. The adverse effect on complexation of the p-tert-butyl groups at the upper rim has been assessed by comparing the binding properties of 1 vs. its de-tert-butylated analogue 3. Furthermore, some information on the importance of counterion and solvent effects have been obtained.

Di-and trinuclear Zn2+ complexes of calyx

The calix[4]arene scaffold, blocked in the cone conformation by proper alkylation of the lower rim hydroxyls, was used as a convenient molecular platform for the design of bi- and trimetallic Zn2+ catalysts. The catalytic activity of the Zn2+ complexes of calix[4]arenes decorated at the 1,2-, 1,3-, and 1,2,3-positions of the upper rim with 2,6-bis[(dimethylamino)methyl]pyridine units were investigated in the cleavage of ester 6 and of the RNA model compound HPNP. High rate enhancements, up to 4 orders of magnitude, were observed in a number of catalyst-substrate combinations. Interestingly the order of catalytic efficiency among regioisomeric dinuclear complexes in the cleavage of ester 6 is 1,2-vicinal >> 1,3-distal, but it is reversed in the reaction of HPNP. The higher efficiency of trinuclear compared to dinuclear complexes provides an indication of the cooperation of three Zn2+ ions in the catalytic mechanism.

Fast transimination in organic solvents in the absence of proton and metal catalysts. A key to imine metathesis catalyzed by primary amines under mild conditions

Amine–imine exchange reactions of sterically unhindered reactants were found to be surprisingly fast at room temperature in a variety of nonaqueous solvents in the absence of proton and metal catalysts. The reaction mechanism suggested by ab initio calculations in the gas phase involves nucleophilic addition to the CN bond in concert with proton transfer from the amine NH bond to the imine nitrogen via a highly imbalanced transition state. These very fast transimination reactions were utilized in the catalysis of imine metathesis. Imine metathesis, usually carried out in organic solvents at high temperature in the presence of metal catalysts, occurs smoothly at room temperature in the presence of primary amines under nonacidic conditions as a result of coupled transimination processes. Kinetic data fully consistent with the proposed reaction mechanism were obtained.

Upper Rim Guanidinocalix[4]arenes as Artificial Phosphodiesterases

Calix[4]arene derivatives, blocked in the cone conformation and functionalized with two to four guanidinium units at the upper rim were synthesized and investigated as catalysts in the cleavage of the RNA model compound 2-hydroxypropyl p-nitrophenyl phosphate. When compared with the behavior of a monofunctional model compound, the catalytic superiority of the calix[4]arene derivatives points to a high level of cooperation between catalytic groups. Combination of acidity measurements with the pH dependence of catalytic rates unequivocally shows that a necessary requisite for effective catalysis is the simultaneous presence, on the same molecular framework, of a neutral guanidine acting as a general base and a protonated guanidine acting as an electrophilic activator. The additional guanidinium (guanidine) group in the diprotonated (monoprotonated) trifunctional calix[4]arene acts as a more or less innocent spectator. This is not the case with the tetrasubstituted calix[4]arene, whose mono-, di-, and triprotonated forms are slightly less effective than the corresponding di- and triguanidinocalix[4]arene derivatives, most likely on account of a steric interference with HPNP caused by overcrowding.

Toward an Artificial Acetylcholinesterase

The methanolysis of choline p-nitrophenylcarbonate in chloroform containing 1 % methanol is catalyzed with turnover by ditopic receptors 1 and 2, consisting of a calix[6]arene connected to a bicyclic guanidinium by means of a short spacer. The calix[6]arene subunit strongly binds to the trimethylammonium head group through cation–π interactions, whereas the guanidinium moiety is deputed to stabilize through hydrogen bonding reinforced by electrostatic attraction the anionic tetrahedral intermediate resulting from methoxide addition to the ester carbonyl. The observed cholinesterase activity had been anticipated on the basis of the ability of the ditopic receptors 1 and 2 to bind strongly to the choline phosphate DOPC, which is a transition state analogue for the BAc2-type cleavage of choline esters.