Enhanced Chelate Cooperativity in Polar Solvents

High-throughput UV-vis titrations in combination with chemical double-mutant cycles (DMCs) have been used to study the competition of a polar solvent for formation of intramolecular H-bonds. Twenty-four different zinc porphyrin-pyridine complexes were investigated in mixtures of toluene and phenol. DMCs were used to determine effective molarities (EM) for the formation of intramolecular phenol-amide H-bonds as a function of solvent composition. The values of EM increase by an order of magnitude with increasing concentrations of the more polar solvent, phenol. Phenol solvates the amide groups on the ligands strongly, increasing the steric bulk and destabilizing the complexes. These adverse steric interactions are removed when intramolecular H-bonds are formed and therefore provide an increased driving force for formation of cooperative interactions. The result is that the effects of competitive interactions with polar solvents that reduce binding affinity are attenuated to a significant extent by a corresponding increase in EM in multivalent complexes.Engineering and Physical Sciences Research Council (EP/K025627/2), German Research Foundation (DFG) (Postdoctoral Research Fellowship

Highly efficient catalysis of the Kemp elimination in the cavity of a cubic coordination cage.

The hollow cavities of coordination cages can provide an environment for enzyme-like catalytic reactions of small-molecule guests. Here, we report a new example (catalysis of the Kemp elimination reaction of benzisoxazole with hydroxide to form 2-cyanophenolate) in the cavity of a water-soluble M8L12 coordination cage, with two features of particular interest. First, the rate enhancement is among the largest observed to date: at pD 8.5, the value of kcat/kuncat is 2 × 10(5), due to the accumulation of a high concentration of partially desolvated hydroxide ions around the bound guest arising from ion-pairing with the 16+ cage. Second, the catalysis is based on two orthogonal interactions: (1) hydrophobic binding of benzisoxazole in the cavity and (2) polar binding of hydroxide ions to sites on the cage surface, both of which were established by competition experiments

Solvent effects on chelate cooperativity

High-throughput UV/Vis absorption titrations have been used to characterise the properties of 120 different zinc porphyrin–pyridine complexes that contain between zero and four additional intramolecular H-bond interactions. Chemical double mutant cycles were used to measure the free energy contribution of each H-bond in each complex and hence determine the effective molarities (EM) for the intramolecular interactions. The experiments have been carried out in 1,1,2,2-tetrachloroethane (TCE) and previously in toluene. For an ester-phenol H-bond, the strength of the intermolecular H-bond does not change with solvent, and the values of EM for formation of intramolecular interactions are also solvent-independent. Intermolecular phosphonate diester–phenol H-bonds are one order of magnitude stronger than ester–phenol H-bonds in TCE and two orders of magnitude stronger in toluene. However, the differences in intermolecular interaction strength are not fully expressed in the intramolecular interactions. Thus the values of EM measured in TCE are up an order of magnitude larger than the values measured for the same complexes in toluene. This suggests that there may be some internal compensation in cooperative recognition interfaces, where stronger interactions lead to more organised structures reducing the value of EM. There is also evidence of structure specific effects due to differences in the details of the solvation shells of the complexes

Influence of H-bond strength on chelate cooperativity

Intermolecular complexes formed between metalloporphyrins and pyridine ligands equipped with multiple H-bond donors and acceptors have been used to measure the free energy contributions due to intramolecular ether–phenol H-bonding in the 24 different supramolecular architectures using chemical double mutant cycles in toluene. The ether–phenol interactions are relatively weak, and there are significant populations of partially bound states where between zero and four intramolecular H-bonds are made in addition to the porphyrin–ligand coordination interaction. The complexes were analyzed as ensembles of partially bound states to determine the effective molarities for the intramolecular interactions by comparison with the corresponding intermolecular ether–phenol H-bonds. The properties of the ether–phenol interactions were compared with phosphonate diester–phenol interactions in a closely related ligand system, which has more powerful H-bond acceptor oxygens positioned at the same location on the ligand framework. This provides a comparison of the properties of weak and strong H-bonds embedded in the same 24 supramolecular architectures. When the product of the intermolecular association constant and the effective molarity KEM > 1, there is a linear increase in the free energy contribution due to H-bonding with log EM, because the intramolecular interactions contribute fully to the stability of the complex. When KEM 1 for the phosphonate diester ligands. The values of EM measured for two different types of H-bond acceptor are linearly correlated, which suggests that EM is a property of the supramolecular acrchitecture. However, the absolute value of EM for an intramolecular phosphonate diester H-bond is about 4 times lower than the corresponding value for an intramolecular ether–phenol interaction embedded in the same supramolecular framework, which suggests that there may be some interplay of K and EM

Comparative analysis of the influence of H-bond strength and solvent on chelate cooperativity in H-bonded supramolecular complexes

Free energy contributions due to intramolecular ether–phenol H-bonds were measured for 24 different complexes in 1,1,2,2-tetrachloroethane solution. High throughput UV/Vis titrations were used in combination with chemical double mutant cycles to dissect out the contributions of different functional group interactions to the stabilities of 120 different zinc porphyrin–pyridine ligand complexes. The effective molarities for intramolecular ether–phenol interactions in TCE range from 70 mM to 400 mM depending on the complementarity of the binding partners. The values are practically identical to the corresponding effective molarities measured for the same ether–phenol interactions in toluene. The ether ligands were compared with analogous ligands, which have a phosphonate diester oxygen H-bond acceptor located at the same site on the ligand framework as the ether oxygen. The effective molarities for the ether–phenol interactions measured in TCE are practically identical to the corresponding values measured for phosphonate diester–phenol H-bonds embedded in the same supramolecular architecture. The experiments contradict the previous results obtained for the phosphonate diester complexes and suggest that effective molarity is a property of the molecular framework and is independent of the solvent

Steric desolvation enhances the effective molarities of intramolecular H-bonding interactions

Free energy contributions due to intramolecular phosphonate diester–phenol H-bonds have been measured for 20 different supramolecular architectures in cyclohexanone solution. High throughput UV/Vis titrations were used in combination with chemical double mutant cycles to dissect out the contributions of different functional group interactions to the stabilities of over 100 different zinc porphyrin–pyridine ligand complexes. These complexes have previously been characterised in toluene and in 1,1,2,2-tetrachloroethane (TCE) solution. Intramolecular ester–phenol H-bonds that were measured in these less polar solvents are too weak to be detected in cyclohexanone, which is a more competitive solvent. The stability of the intermolecular phosphonate diester–phenol H-bond in cyclohexanone is an order of magnitude lower than in TCE and two orders of magnitude lower than in toluene. As a consequence, only seven of the twenty intramolecular phosphonate diester–phenol interactions that were previously measured in toluene and TCE could be detected in cyclohexanone. The effective molarities (EM) for these intramolecular interactions are different in all three solvents. Determination of the EM accounts for solvent effects on the strengths of the individual H-bonding interactions and the zinc porphyrin–pyridine coordination bond, so the variation in EM with solvent implies that differences in the solvation shells make significant contributions to the overall stabilities of the complexes. The results suggest that steric effects lead to desolvation of bulky polar ligands. This increases the EM values measured in TCE, because ligands that fail to replace the strong interactions made with this solvent are unusually weakly bound compared with ligands that make intramolecular H-bonds

Quantification of the effect of conformational restriction on supramolecular effective molarities

The association constants for a family of 96 closely related zinc porphyrin–pyridine ligand complexes have been measured in two different solvents, toluene and 1,1,2,2-tetrachloroethane (TCE). The zinc porphyrin receptors are equipped with phenol side arms, which can form intramolecular H-bonds with ester or amide side arms on the pyridine ligands. These association constants were used to construct 64 chemical double mutant cycles, which measure the free energy contributions of intramolecular H-bonding interactions to the overall stability of the complexes. Measurement of association constants for the corresponding intermolecular H-bonding interactions allowed determination of the effective molarities (EM) for the intramolecular interactions. Comparison of ligands that feature amide H-bond acceptors and ester H-bonds at identical sites on the ligand framework show that the values of EM are practically identical. Similarly, the values of EM are practically identical in toluene and in TCE. However, comparison of two ligand series that differ by one degree of torsional freedom shows that the values of EM for the flexible ligands are an order of magnitude lower than for the corresponding rigid ligands. This observation holds for a range of different supramolecular architectures with different degrees of receptor–ligand complementarity and suggests that in general the cost of freezing a rotor in supramolecular complexes is of the order of 5 kJ/mol

Cooperativity in multiply H-bonded complexes

The free energy of complexation of supramolecular complexes containing phenol–carbamateH-bonds is an additive function of the number of H-bonds, with a constant increment of 6 kJ mol−1 per interaction in carbon tetrachloride