Dissecting Interactions in Solution Scott L. Cockroft UKQSAR Autumn - PowerPoint PPT Presentation

Dissecting Interactions in Solution Scott L. Cockroft UKQSAR Autumn meeting, 29 th September 2017

Understanding & exploiting conformational change Unfolded Folded equilibrium K fold + measurement I. K. Mati & S. L. Cockroft. Chem. Soc. Rev. 39, 4195-05 (2010)

Dissecting interactions D G = – RT ln K observable behaviour Interaction Energy, D G = D H – T D S rotational electrostatic translational induction vibrational repulsion dispersion configurational states van der Waals desolvation interactions

Dissecting interactions D G = – RT ln K observable behaviour Interaction Energy, D G = D H – T D S rotational electrostatic translational induction vibrational repulsion dispersion configurational states van der Waals desolvation interactions

Molecular Balances – geometric control Linear binding - polarisability of H-bond chain? -30 D G complex / kJ mol – 1 -20 -10 0 OR bifurcated binding? CDCl 3 CD 3 CN

Molecular torsion balances BALANCE K fold Δ G fold = – RT ln K fold Unfolded Folded equilibrium K fold + measurement I. K. Mati & S. L. Cockroft. Chem. Soc. Rev. 39, 4195-05 (2010)

Molecular torsion balances K fold Δ G fold = – RT ln K fold 1.00 1.69 Unfolded Folded equilibrium K fold + measurement I. K. Mati & S. L. Cockroft. Chem. Soc. Rev. 39, 4195-05 (2010)

Computational vs. exp. conformational energies -10 R 2 = 0.99 -8 D G balance / kJ mol – 1 -6 -4 -2 0 B3LYP/6-311G* 2 4 10 0 -10 -20 -30 D E balance / kJ mol – 1 N. D. Whiteley, J. J. Brown, S. L. Cockroft, Angew. Chem. Int. Ed., 56, 7658-62 (2017)

Computations of longer chains B3LYP/6-311G* to cc-pVDZ D E balance D E complex -55 -25 -20 -50 -15 -45 -10 -40 -5 0 -35 / kJ mol – 1 / kJ mol – 1 N. D. Whiteley, J. J. Brown, S. L. Cockroft, Angew. Chem. Int. Ed., 56, 7658-62 (2017)

B3LYP/6-311G* to cc-pVDZ -25 k l j m i e g h ∆ E / kJ mol – 1 f -20 -15 a b c d -10 -5 H-Bonds in 0 chain 3 × 4 × 2 × 4 × 1 × 2 × 3 × a b e c External phenol at f h end of chain = ideal H-bond g d i j geometry

Computations of longer chains B3LYP/6-311G* Methanol chain to cc-pVDZ Methanol Chain Amide Chain -50 -80 Interaction E / kJ mol – 1 Interaction E / kJ mol – 1 -40 -60 -30 -40 -20 -20 -10 0 0 N. D. Whiteley, J. J. Brown, S. L. Cockroft, Angew. Chem. Int. Ed., 56, 7658-62 (2017)

H-bond chains Conclusion -Doubling of interaction energy on going from one to two H-bonds (i.e. inductive polarisation is significant) -Short range effect (2 to 3 H-bonds = little additional change) -Limited range = through-space field effects plus inductive polarisation being rapidly maximised at the end of a chain.

Dissecting interactions D G = – RT ln K observable behaviour Interaction Energy, D G = D H – T D S rotational electrostatic translational induction vibrational repulsion dispersion configurational states van der Waals desolvation interactions

s -hole interactions? methanol d+ d- hydrogen bonding iodine d+ d- halogen bonding electrostatic? d+ d- perfluoro- dispersion? selenophene orbital chalcogen bonding delocalisation? group 16 elements e.g. O → S, O → Se, S → Se, O → Te etc – 200 kJ mol – 1 0 kJ mol – 1

Dissecting interactions D G = – RT ln K observable behaviour Interaction Energy, D G = D H – T D S rotational electrostatic translational induction vibrational orbital repulsion delocalisation? dispersion configurational states van der Waals desolvation interactions

The origin of chalcogen bonding interactions O → S Interaction O → Se S → S e - Electrostatics? van der Waals dispersion? Orbital delocalisation?

The origin of chalcogen bonding interactions EDG → EWG X = Me X = H X = Cl X = COH X = Me X = H X = COH X = H X =Me X = H X = Cl X = COOMe X = COMe -10 -6 -4 -8 D G EXP / kJ mol – 1 D G EXP / kJ mol – 1 D G (kJ/mol) D G (kJ/mol) -2 -6 0 -4 2 -2 4 0 Chloroform- d Chloroform- d Chloroform-d Chloroform-d

The origin of chalcogen bonding interactions EDG → EWG D G EXP / kJ mol – 1 D G EXP / kJ mol – 1 D. J. Pascoe, K. B. Ling, S. L. Cockroft, J. Am. Chem. Soc. , accepted, ( 2017)

The origin of chalcogen bonding interactions e - Electrostatics van der Waals dispersion? Orbital delocalisation

The origin of chalcogen bonding interactions DISPERSION “CORRECTED” NO DISPERSION M06-2X/6-311G* 2 B3LYP/6-311G* 2 1 1 0 D G chloroform / kJ mol – 1 D G chloroform / kJ mol – 1 0 Δ G EXP (CDCl 3 )/ kJmol – 1 Δ G EXP (CDCl 3 )/ kJmol – 1 -1 -1 -2 -2 -3 -3 R² = 0.94 -4 -4 R² = 0.88 -5 -5 -6 -6 -7 -7 -8 -8 -10 -5 0 5 -10 -5 0 5 Δ E CALC /kJ mol – 1 Δ E CALC /kJ mol – 1 Also, measured D G values were very similar in CS 2 = high bulk polarizability MeOH = low bulk polarizability D. J. Pascoe, K. B. Ling, S. L. Cockroft, J. Am. Chem. Soc. , accepted, ( 2017)

The origin of chalcogen bonding interactions e - Electrostatics van der Waals dispersion? Orbital delocalisation

n→σ * orbital delocalization / interactions O lone pair (n) σ * (C – S) Natural Bond Orbital (NBO) Bond lengthening seen analysis B3LYP/6-311G* D. J. Pascoe, K. B. Ling, S. L. Cockroft, J. Am. Chem. Soc. , accepted, ( 2017)

The origin of chalcogen bonding interactions -5 Orbital energy - closed conf. / eV -6 -7 -8 -9 -10 -11 -11 -10 -9 -8 -7 -6 Orbital energy - open conf. / eV

n→σ * orbital delocalization / interactions n→σ * n→σ * and orbitals Resonance-delocalised orbitals S-C H-C 2 2 R² = 0.99 D G chloroform / kJ mol – 1 D G chloroform / kJ mol – 1 0 0 -2 -2 -4 -4 -6 -6 -8 -8 -11.4 -11.2 -11.0 -10.8 -10.6 -10.4 -8.2 -8.0 -7.8 -7.6 -7.4 -7.2 Energy of n → σ * orbital / eV Energy of res.-delocalised orbital / eV • X X Y Y D. J. Pascoe, K. B. Ling, S. L. Cockroft, J. Am. Chem. Soc. , accepted, ( 2017)

The origin of chalcogen bonding interactions Electrostatics van der Waals dispersion? Orbital delocalisation

Dissecting interactions D G = – RT ln K observable behaviour Interaction Energy, D G = D H – T D S rotational electrostatic translational induction vibrational orbital repulsion delocalisation dispersion configurational states van der Waals desolvation interactions What about entropic effects on H-bonding?

The limit of intramolecular H-bonding T. A. Hubbard, S. L. Cockroft, J. Am. Chem. Soc., 138, 15114-7 (2016)

The limit of intramolecular H-bonding T. A. Hubbard, S. L. Cockroft, J. Am. Chem. Soc., 138, 15114-7 (2016)

The limit of intramolecular H-bonding B A C K inter K obs = K inter /(1 + K intra ) D Reference E K ′ inter C. A. Hunter, H. L. Anderson, Angew. Chem. Int. Ed. 48, 7488-99 (2009) T. A. Hubbard, S. L. Cockroft, J. Am. Chem. Soc., 138, 15114-7 (2016)

The limit of intramolecular H-bonding -Entropic penalty of 5-6 kJ mol - 1 per rotor!

The limit of intramolecular H-bonding -Surprising, almost binary behaviour. -Large penalty of 5-6 kJ mol - 1 per rotor! Overall summary -Folding molecules/atropisomers are excellent tools for dissecting non-covalent interactions and solvent effects OR solvent effects great for understanding conformational preferences!

Nick D. Dominic Tom John James Whiteley Brown Cath Hubbard Pascoe Brazier Adam Lina Lixu Mati Yang And… finally…