Dissecting Interactions in Solution - UK-QSAR...

Dissecting Interactions in Solution

Scott L. CockroftUKQSAR Autumn meeting, 29th September 2017

Folded

+

Unfolded

Kfold

measurement

equilibrium

Understanding & exploiting conformational change

I. K. Mati & S. L. Cockroft. Chem. Soc. Rev. 39, 4195-05 (2010)

Interaction Energy, DG = DH – TDS

electrostatic

induction

dispersion

repulsion

desolvationvan der Waals

interactions

translational

rotational

vibrational

Dissecting interactions

configurational

states

DG = –RT lnK observable

behaviour

Interaction Energy, DG = DH – TDS

electrostatic

induction

dispersion

repulsion

desolvationvan der Waals

interactions

translational

rotational

vibrational

Dissecting interactions

configurational

states

DG = –RT lnK observable

behaviour

-30

-20

-10

0 OR bifurcated binding?CD3CNCDCl3

Linear binding - polarisability of H-bond chain?

DG

com

ple

x/ k

J m

ol–

1Molecular Balances – geometric control

Folded

+

Unfolded

Kfold

ΔGfold= – RT lnKfold

measurement

BALANCE

equilibrium

Molecular torsion balances

I. K. Mati & S. L. Cockroft. Chem. Soc. Rev. 39, 4195-05 (2010)

Kfold

I. K. Mati & S. L. Cockroft. Chem. Soc. Rev. 39, 4195-05 (2010)

1.00 1.69

ΔGfold= – RT lnKfold

+

Unfolded

Kfold

Folded

measurement

equilibrium

Molecular torsion balances

Kfold

-10

-8

-6

-4

-2

0

2

4

-30-20-10010

DG

ba

lan

ce

/ k

J m

ol–

1

DEbalance / kJ mol–1

R2 = 0.99

Computational vs. exp. conformational energies

B3LYP/6-311G*

N. D. Whiteley, J. J. Brown, S. L. Cockroft, Angew. Chem. Int. Ed., 56, 7658-62 (2017)

Computations of longer chains

DEcomplexDEbalance

-25

-20

-15

-10

-5

0

-55

-50

-45

-40

-35/ kJ mol–1 / kJ mol–1

B3LYP/6-311G*

N. D. Whiteley, J. J. Brown, S. L. Cockroft, Angew. Chem. Int. Ed., 56, 7658-62 (2017)

to cc-pVDZ

-25

-20

-15

-10

-5

04 ×

a

b

c

d

e

f h

ig

j

a bc d

ef

ig

jh

1 × 2 × 3 × 4 ×2 × 3 ×

k l m

H-Bonds in chain

∆E

/ kJ m

ol–

1

External phenol at end of chain

= ideal H-bond geometry

B3LYP/6-311G*

to cc-pVDZ

Methanol chain

-80

-60

-40

-20

0Inte

raction E

/ k

J m

ol–

1

Computations of longer chains

Amide Chain

-50

-40

-30

-20

-10

0Inte

raction E

/ k

J m

ol–

1

Methanol Chain

N. D. Whiteley, J. J. Brown, S. L. Cockroft, Angew. Chem. Int. Ed., 56, 7658-62 (2017)

B3LYP/6-311G*

to cc-pVDZ

H-bond chains Conclusion

-Doubling of interaction energy on going from one to two

H-bonds (i.e. inductive polarisation is significant)

-Limited range = through-space field effects plus

inductive polarisation being rapidly maximised at the

end of a chain.

-Short range effect (2 to 3 H-bonds = little additional

change)

Interaction Energy, DG = DH – TDS

electrostatic

induction

dispersion

repulsion

desolvationvan der Waals

interactions

translational

rotational

vibrational

Dissecting interactions

configurational

states

DG = –RT lnK observable

behaviour

methanol

iodine

0 kJ mol–1–200 kJ mol–1

s-hole interactions?

perfluoro-selenophene

halogen bonding

chalcogen bonding

e.g. O→S, O→Se, S→Se, O→Te etc

electrostatic?

dispersion?

orbital

delocalisation?

group 16 elements

hydrogen bonding

d+ d-

d+ d-

d+ d-

Interaction Energy, DG = DH – TDS

electrostatic

induction

dispersion

repulsion

desolvationvan der Waals

interactions

translational

rotational

vibrational

Dissecting interactions

configurational

states

DG = –RT lnK observable

behaviour

orbital

delocalisation?

Electrostatics? van der Waals dispersion? Orbital delocalisation?

Interaction

The origin of chalcogen bonding interactions

e-

O→S

O→Se

S→S

-10

-8

-6

-4

-2

0

Chloroform-d

DG

(kJ

/mo

l)

EDG → EWG

-6

-4

-2

0

2

4

DG

(kJ

/mo

l)

Chloroform-d

X =

Me

X =

H

X =

Cl

X =

CO

OM

e

X =

CO

Me

X =

CO

H

X =

Me

X =

H

X =

CO

H

X =

H

X =

Me

X =

H

X =

Cl

The origin of chalcogen bonding interactions

Chloroform-dChloroform-d

DG

EX

P/

kJ m

ol–

1

DG

EX

P/

kJ m

ol–

1

The origin of chalcogen bonding interactionsD

GE

XP

/ k

J m

ol–

1D

GE

XP

/ k

J m

ol–

1

EDG → EWG

D. J. Pascoe, K. B. Ling, S. L. Cockroft, J. Am. Chem. Soc., accepted, (2017)

Electrostatics van der Waals dispersion? Orbital delocalisation

The origin of chalcogen bonding interactions

e-

R² = 0.94

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

-10 -5 0 5

ΔG

EXP(C

DC

l 3)/

kJm

ol–

1

ΔECALC/kJ mol–1

R² = 0.88

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

-10 -5 0 5

ΔG

EXP(C

DC

l 3)/

kJm

ol–

1

ΔECALC/kJ mol–1

NO DISPERSIONB3LYP/6-311G*

DISPERSION “CORRECTED”M06-2X/6-311G*

DG

chlo

rofo

rm/

kJ m

ol–

1

The origin of chalcogen bonding interactions

Also, measured DG values were very similar in

CS2 = high bulk polarizability

MeOH = low bulk polarizability

DG

chlo

rofo

rm/

kJ m

ol–

1

D. J. Pascoe, K. B. Ling, S. L. Cockroft, J. Am. Chem. Soc., accepted, (2017)

Electrostatics van der Waals dispersion? Orbital delocalisation

The origin of chalcogen bonding interactions

e-

Bond lengthening seenB3LYP/6-311G*

O lone pair (n)

σ* (C–S)

n→σ* orbital delocalization / interactions

Natural Bond Orbital (NBO)analysis

D. J. Pascoe, K. B. Ling, S. L. Cockroft, J. Am. Chem. Soc., accepted, (2017)

-11

-10

-9

-8

-7

-6

-5

-11 -10 -9 -8 -7 -6

Orb

ital

en

ergy

-cl

ose

d c

on

f. /

eV

Orbital energy - open conf. / eV

The origin of chalcogen bonding interactions

-8

-6

-4

-2

0

2

-8.2 -8.0 -7.8 -7.6 -7.4 -7.2

Energy of n→σ* orbital / eV

X

Y

-8

-6

-4

-2

0

2

-11.4 -11.2 -11.0 -10.8 -10.6 -10.4

Energy of res.-delocalised orbital / eV

•X

Y

R² = 0.99

n→σ*S-C

n→σ*H-C

and orbitals Resonance-delocalised orbitals

n→σ* orbital delocalization / interactions

DG

chlo

rofo

rm/

kJ m

ol–

1

DG

chlo

rofo

rm/

kJ m

ol–

1

D. J. Pascoe, K. B. Ling, S. L. Cockroft, J. Am. Chem. Soc., accepted, (2017)

Electrostatics van der Waals dispersion? Orbital delocalisation

The origin of chalcogen bonding interactions

Interaction Energy, DG = DH – TDS

electrostatic

induction

dispersion

repulsion

desolvationvan der Waals

interactions

translational

rotational

vibrational

Dissecting interactions

configurational

states

DG = –RT lnK observable

behaviour

What about entropic effects on H-bonding?

orbital

delocalisation

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)

Reference

K′inter

D E

Kinter

CA

B

The limit of intramolecular H-bonding

Kobs = Kinter/(1 + Kintra)

T. A. Hubbard, S. L. Cockroft, J. Am. Chem. Soc., 138, 15114-7 (2016)

C. A. Hunter, H. L. Anderson, Angew. Chem.

Int. Ed. 48, 7488-99 (2009)

-Entropic penalty of 5-6 kJ mol-1 per rotor!

The limit of intramolecular H-bonding

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.

Whiteley John

BrazierJames

BrownCath

Adam Lina

Mati Lixu

Yang

Tom

Hubbard

Dominic

Pascoe

And… finally…