Macrocycles hydrogen bonding effects

Such modifications can be produced either in the kinetic aspects (proton transfer) or in the equilibrium constant. Both effects are mediated by intramolecular hydrogen bonds. For instance, Navarro et al. (93MI69) showed that the rate of proton transfer between the two nitrogen atoms of pyrazole (annular tautomerism) is considerably reduced in macrocycles containing oxygen or nitrogen atoms in the macroring. 

Dicarbonyl functions have been built into macrocyclic structures, and pKa values for the resulting macrocycles [60] have been determined (Alberts and Cram, 1979). When the open-chain model [62] is compared with the macrocycles [60], identical first pK values were found (pKa = 8.6). Thus for the diketones [60], no macrocyclic effect is noticeable. But for the dissociation of a second proton from the mono-aniorts of [60] much higher pKa values are found. To a certain extent. Coulomb repulsions (see Section 2) are probably the reason for this behaviour, but the large difference in the pKa values (ApKa = 2.9, see Table 26) argues for a special stabilization of the mono-anion. Again hydrogen bonds are not unreasonable. 

Also in macrocyclizations the conformation of the starting diene has an influence on the RCM/ADMET ratio. Substituents on the diene which form hydrogen bonds between each other or with the intermediate carbene complex, or external Lewis acids can have an important effect on the course of the reaction. Such effects, often subtle, might explain the variable results sometimes obtained in macrocyclizations [842], but make synthesis-planning and the formulation of general guidelines difficult. 

SCHEME 8 A STEPWISE ROUTE TO UNSYMMETRICAL MACROCYCLES. WITH 2,6-PYRIDINE DICARBOXYLIC ACID DICHLORIDE BUILDING BLOCK 17 IS FORMED WHICH IS PREORGANIZED FOR MACROCYCLIZATION AND THUS GIVES HIGHER YIELDS OF MACROCYCLE 18 AS COMPARED TO 13. THE INSET SHOWS THE HYDROGEN BONDING PATTERN IN THE PYRIDINE BUILDING BLOCKS AND THE EFFECTS IT HAS ON CONFORMATIONAL EQUILIBRIA AND... 

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