Reconciling Electrostatic and n→π* Orbital Contributions in Carbonyl Interactions

Abstract

Interactions between carbonyl groups are prevalent in protein structures. Earlier investigations identified dominant electrostatic dipolar interactions, while others implicated lone pair n→π* orbital delocalisation. Here these observations are reconciled. A combined experimental and computational approach confirmed the dominance of electrostatic interactions in a new series of synthetic molecular balances, while also highlighting the distance‐dependent observation of inductive polarisation manifested by n→π* orbital delocalisation. Computational fiSAPT energy decomposition and natural bonding orbital analyses correlated with experimental data to reveal the contexts in which short‐range inductive polarisation augment electrostatic dipolar interactions. Thus, we provide a framework for reconciling the context dependency of the dominance of electrostatic interactions and the occurrence of n→π* orbital delocalisation in C=O⋅⋅⋅C=O interactions.

Quantifying Interactions and Solvent Effects Using Molecular Balances and Model Complexes

“…64 A third series of molecular balance variants based on formyl balances were synthesized (Figure 11A, pink) and a unified analysis of the experimental data performed. 65 The experimentally determined conformational energies of all three systems were similar, but the geometries of the C=O … C=O interactions differed. However, NBO calculations…”

Solvation stabilizes intercarbonyl n→π* interactions and polyproline II helix

“…This similar interaction strength in water and vacuum also suggests only a modest role for either unfavorable or favorable dipole-dipole interactions on complex stability. 14,55,56 Natural bond orbital (NBO) analysis 33,34 confirmed the predominantly stereoelectronic component to the n-p* interaction, with a second-order perturbation energy of 2.7 kcal mol À1 due to electron delocalization via orbital overlap of the s-like and p-like oxygen lone pairs with the p* molecular orbital of the acceptor carbonyl (O s /p* 0.6 kcal mol À1 , O p /p* 2.1 kcal mol À1 ) (Fig. 2a).…”

“…n-p* interactions are also important in other diverse contexts, including the structure of organic molecules and stabilizing transition states in catalysis. [9][10][11][12][13][14][15][16] The n-p* interaction has been implicated as a significant factor in the disordered states of proteins. 4,6,7,17 n-p* interactions stabilize the a-helix conformation locally (as an i/i + 1 interaction), without 7 a need for hydrogen bonding (which involves i/i + 3 or i/i + 4 interactions for 3 10 helices or a-helices, respectively).…”

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

“…The effect occurs indirectly due to the impact onto the side-chain envelope conformation: the C 4 -exo conformation creates a favorable relative arrangement of the mainchain groups. This energetic favorability is typically attributed to the n→π* donative interaction between the carbonyl groups, although the exact nature of this interaction (orbital or dipolar) is debatable [82]. Result of this effect though, is that the transfluoroproline shifts the equilibrium towards a higher abundance of the trans-amide, while cis-fluoroproline promotes the cis-amide (Figure 8).…”