The Limit of Intramolecular H-Bonding

Abstract

Hydrogen bonds are ubiquitous interactions in molecular recognition. The energetics of such processes are governed by the competing influences of pre-organization and flexibility that are often hard to predict. Here we have measured the strength of intramolecular interactions between H-bond donor and acceptor sites separated by a variable linker. A striking distance-dependent threshold was observed in the intramolecular interaction energies. H-bonds were worth less than -1 kJ mol when the interacting groups were separated by ≥6 rotating bonds, but ranged between -5 and -9 kJ mol for ≤5 rotors. Thus, only very strong external H-bond acceptors were able to compete with the stronger internal H-bonds. In addition, a constant energetic penalty per rotor of ∼5-6 kJ mol was observed in less strained situations where the molecule contained ≥4 rotatable bonds.

Predicting the Limit of Intramolecular Hydrogen Bonding with Classical Molecular Dynamics

“…Chloroform-derived results for compounds 1-10 show an on-trivial dependence between DG intra and the donoracceptor separation ( Figure 3A,b lue plot). This complex dependence predicted by theoretical calculations is in quantitative agreement with the data derived from NMR experiments [26] ( Figure 3A,g ray plot), thus validating the parameters and the theoretical framework used herein. Forv ery small linkers (2-3), strained intramolecular cycles are formed with an H-bond angle around 1008 8 (C=O···H angle;s ee Figure 3B)a nd a DG intra of about À5kJmol À1 .W hen4 rotatable bonds separate donor and acceptors,the cyclization leads to am ore favorable H-bond with a DG intra of about À8kJmol À1 and the C = O···H angle populating values around 1208 8 ( Figure 3B), which is the most abundant acceptor directionality of C=Og roups in structural databases.…”

“…[18][19][20][21][22][23] Unfortunately,t he characterization of intramolecular H-bonds (and their utilization) is still limited, most likely as ac onsequence of the complexities that hamper the interpretation of experimental data obtained for large and flexible entities. [11] Fori nstance,i th as long been known that conformational flexibility poses al imit to the occurrence of intramolecular H-bonds, [24,25] but only recently,H ubbard et al [26] have quantified such al imit using competition experiments in CDCl 3 within acontrolled molecular context. As am atter of fact, these measurements in deuterated chloroform [26] set an unprecedented experimental reference in the field.…”

“…[11] Fori nstance,i th as long been known that conformational flexibility poses al imit to the occurrence of intramolecular H-bonds, [24,25] but only recently,H ubbard et al [26] have quantified such al imit using competition experiments in CDCl 3 within acontrolled molecular context. As am atter of fact, these measurements in deuterated chloroform [26] set an unprecedented experimental reference in the field. Yet, in aqueous environments,the tiny population of H-bonded species still challenges the limit of their experimental quantification and it remains unclear to which extent H-bond measurements performed in non-competitive solvents can be extended to polar solvents,such as water.…”

“…Here,building on recent experimental data, [26] we present ac omputational investigation of the influence of conformational flexibility on H-bonding in as trictly intramolecular context using as eries of model compounds [26] ( Figure 1A) immersed in apolar (water), polar aprotic (tetrahydrofuran), and apolar solvent (chloroform, for which partial experimental data is available for comparison and calibration [26] ). The effect of molecular crowding on H-bonding behavior is also presented.…”

Crystal Structure of 1,8-Bis(4-Fluorobenzoyl)naphthalene-2,7-Diyl Dibenzoate: Role of (Sp2)c–h…f Hydrogen Bonding as Distinctly Strong Interaction Among Non-Classical Hydrogen Bonds Contributing Stability of the Crystal

“…[10][11][12][13] Attempts of formation of tough hydrogen bonds involving CONR2 group and OH group, and COOH group and NH2 group were undertaken both experimentally and theoretically. [14][15][16] These have been successfully employed for the preparation of numerous molecular assemblies. However, to grasp nature of weak hydrogen bonds including "non-classical" hydrogen bonds where C-H group acts as hydrogen donor, for example, has scarcely achieved probably because they are often hidden by strong hydrogen bonds.…”