Dissecting Interactions in Solution - UK-QSAR Groupukqsar.org/wp-content/uploads/2017/10/Scott-Cockroft... · 2017. 10. 17. · Scott L. Cockroft UKQSAR Autumn meeting, 29th September

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


electrostatic

induction

dispersion

repulsion


interactions

translational

rotational

vibrational


configurational

states


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


Kfold


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*


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


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)


electrostatic

induction

dispersion

repulsion


interactions

translational

rotational

vibrational


configurational

states


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-


electrostatic

induction

dispersion

repulsion


interactions

translational

rotational

vibrational


configurational

states


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


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


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


Also, measured DG values were very similar in

CS2 = high bulk polarizability

MeOH = low bulk polarizability

DG

chlo

rofo

rm/

kJ m

ol–

1




e-

Bond lengthening seenB3LYP/6-311G*

O lone pair (n)

σ* (C–S)

n→σ* orbital delocalization / interactions

Natural Bond Orbital (NBO)analysis


-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


-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





electrostatic

induction

dispersion

repulsion


interactions

translational

rotational

vibrational


configurational

states


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)



Reference

K′inter

D E

Kinter

CA

B


Kobs = Kinter/(1 + Kintra)


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

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

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



-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…

http://royalsociety.org/

Documents

Dissecting Interactions in Solution - UK-QSAR Groupukqsar.org/wp-content/uploads/2017/10/Scott-Cockroft... · 2017. 10. 17. · Scott L. Cockroft UKQSAR Autumn meeting, 29th September