Flaminia Rondino CNR – IMIP Università “La

Sapienza"

Molecular recognition in complexes of chiral aromatic molecules with water, amines and alchools: a mass resolved R2PI spectroscopic study.

- Betul Yurdumakan et al. Chem Comm., 2005, 3799- Pavel Hobza et al., Phys. Chem. Chem. Phys., 2007, 9, 5291

1st Italian Workshop on UltraViolet Techniques and Applications.

WUTA08

Non covalent interactions.

The nature has been forced to create weaker bonds to represent the basic machinery for the very existence of life. Several molecules involved in the processes of living systems are linked through non covalent interactions. The molecular aggregates are much more flexible than chemically bonded systems, because non covalent interactions are weaker than covalent ones.

Non-Covalent InteractionsNon-Covalent InteractionsNon-Covalent InteractionsNon-Covalent Interactions

Van der Waals Van der Waals interactionsinteractions

Electrostatic Electrostatic interactionsinteractions

Hydrogen Hydrogen bondbond

Steric Steric repulsionrepulsion

Non covalent interactions in living systems

Non-Covalent InteractionsNon-Covalent InteractionsNon-Covalent InteractionsNon-Covalent Interactions

Molecular recognition in cells:enzime - receptor interaction drug - receptor interaction …

Base pairing in nucleic acidsSecondary structure of the proteins

-sheet

-helix

S-PenicillammineS-PenicillammineAntiartriticAntiartritic

S-PenicillammineS-PenicillammineAntiartriticAntiartritic

R-PenicillammineR-PenicillammineToxicToxic

R-PenicillammineR-PenicillammineToxicToxic

Chiral recognition, or the ability of a chiral probe to differentiate between the two enantiomers of a chiral molecule, is very important in biochemistry and organic synthesis. Most of the processes related to the interaction of a chiral ligand, such as a drug, with enzymes or protein receptors are characterized by marked enantioselectivity.

Chiral Recognition

Molecular and chiral recognition in gas phase

Isolated complexes in gas phase

• Ideal system to investigate at a microscopic level the specific interactions which drive the molecular recognition processes

• the results are directly comparable with advanced theoretical calculations.

• connection between the microscopic processes in molecular clusters and the architecture and function of biomolecules in living matter

DIASTEREOMERIC CLUSTERSDIASTEREOMERIC CLUSTERS

PARTNER MOLECULEPARTNER MOLECULE

R and S CONFIGURATIONR and S CONFIGURATION

CHROMOPHORE MOLECULECHROMOPHORE MOLECULE

FIXED CONFIGURATIONFIXED CONFIGURATION

REMPI – Experimental Apparatus

REMPI/TOF:Resonant Enhanced Multi-Photon Ionization

in supersonic beam coupled with time of flight mass spectrometer (TOF/MS ).

Chromophore Partne

r

REMPI – 1c e 2cR2PI

m/e

(cm-1)

C = chromophore

(cm-

1)

MASS SPECTRUM

IONIZATION THRESHOLDABSORPTION SPECTRUM

1

REMPI – 1c and 2cR2PI

C = chromophore

L = guest molecule

D0" = AE (C+) - IP (C)

D0+ = AE (C+) - IP (C.L)

D0' = D0" -

Resonant Enhanced Multi-Photon Ionization laser spectroscopy, coupled with Time of Flight Mass Spectrometry (MS-TOF), of neutral clusters produced in supersonic beam.

Vibronic spectra Binding energies Photo-fragmentation thresholds

REMPI – The chromophores

ionization potentials ~ 10 eVintense * electronic transitions ~ 5 eV Chiral aromatic molecules

(R)-1-phenylethanol

OH

(R)-1- indanol

(R)- 1-tetralol

H

CF3

HO

OH

(R)-1-phenyl-1-propanol

(1S,2S)-methyl pseudoephedrine

p,m,o-fluoro-secbutyl-benzene

H

C2H5

HOHO

CH3

H

(R)-1-phenyl-2,2,2-trifluoroethanol

FERPR

Chiral partners in the cluster with FER.

- Ethero alcohols

Chiral Partners

- Alcohols

- Amines

- Ethers

OH

(R/S) 2-butanol

NH2

(R/S) 2- butylamine

O

tetrahydrofuran

(R/S) 3-Hydroxy-Tetrahydrofuran

O

OH

1cR2PI spectrum of PR

H

C2H5

HO

(R)-1-phenyl-1-propanol (PR)

B3LYP/6-31G**-calculated structures

Erel=0.0 KJmol-1

Erel=2.5 KJmol-1

B

A

C

A

B

CA

B

Erel=1,7 KJmol-1

C

000(A)= 37577 cm-1

000(B)= 37618 cm-1

000(C)= 37624 cm-1

Electronic shift of the S1 S0 transition

When a chromophore C interacts with a molecule L, a decrease or an increase for the S1 S0 transition energy can be observed.

< 0Red Shift

> 0Blue Shift

C*

C

(CL)*

(CL)

(CL’)*

(CL’)

S0

S1

intra and intermolecular hydrogen bond interaction

OH --- interaction

dispersion interaction

Red Shift In the interaction of C with L, the excited state is more stabilized than the ground state

Blue Shift In the interaction of C with L, the excited state is less stabilized than the ground state

Cluster of PR with water

ground state

B3LYP/6-31G**-calculated structure

1cR2PI spectrum of a mixture of PR

and water

Cluster of PR with 2-butanol (BR/S)

THE DIFFERENT SPECTRAL SHIFTS LET TO DISCRIMINATE THE HOMOCHIRAL AND HETEROCHIRAL CLUSTER

OH

(R/S)-2-butanol

1cR2PI spectra of a mixture of PR and BR or BS HOMOCHIRAL CLUSTER

the chromophore P and the partner B have the same chiral configuration

HETEROCHIRAL CLUSTER

the chromophore P and the partner B have different chiral configuration

Photodissociation and photoreaction

L ∙∙∙∙∙

+•

HHO

C2H5

[PR]+ + Lh

[PR · L]

[PR-C2H5 · L]+ + C2H5

•

[PR-C2H5]+ + C2H5

• + L

[PR · L]h

[PR · L]+

D0”

D0+

ionization thresholdof [PR · BS]

Dissociative ionization threshold of [PR · BS]

ionization thresholdof bare PR

Chem. Eur. J. 2000, 6, No. 6

D0" = AE (C+) - IP (C)

D0+ = AE (C+) - IP (C.L)

D0' = D0" -

OH

(R/S)-2-butanol

Cluster of PR with 2-butanol (BR/S)

Binding energies of neutral, excited and ionized clusters

(R)-2-pentanolPR

6,0 ± 0.4(S)-2-pentanolPR

(R)-2-butanolPR

4,7 ± 0.4(S)-2-butanolPR

D0”Experimental binding

energy differenceKJ/mol

Solvent moleculeChromophore

We measured the binding energies for benzyl alcohol

derivatives clustered with chiral alcohols and amines, and

found that the homochiral clusters are more stable than the

heterochiral ones in the ground, excited and ionic state.

Photodissociation and photoreaction

L ∙∙∙∙∙

+•

HHO

C2H5

[PR]+ + Lh

[PR·L]

[PR-C2H5 · L]+ + C2H5

•

[PR-C2H5]+ + C2H5

• + L

[PR·L]h

[PR · L]+

Photofragmentation of PR ion

[PR] [PR]*h

+•

HHO

C2H5

[PR ]+•h

[PR-C2H5 ]+ + C2H5•

PR+ [PR

-C2H5]+

7500 cm-1

Phys.Chem.Chem.Phys 2004Angew. Chem. 43 1868 2004

Photofragmentation of PR ion

[PR] [PR]*h

+•

HHO

C2H5

[PR ]+•h

[PR-C2H5 ]+ + C2H5•

Fragmentation in clusters

4255 ± 50[PR · ThS() ]

4129 ± 50[PR · ThS () ]

4436 ± 50[PR · ThS () ]

4178 ± 50[PR · ThR () ]

4058 ± 50[PR · ThR () ]

4515 ± 50[PR · ThR () ]

740 ± 50[PR · Bdss]

1140 ± 50[PR · BdRR]

3500 ± 50[PR · H2O]

7500 ± 50PR

Eexp/th (cm-1)

The solvation of PR causes a decrease of the fragmentation barrier for the ethyl loss, due to the stabilization of the positive charge on the chiral C of the PR

Fragmentation in clusters.

4255 ± 50[PR · ThS() ]

4129 ± 50[PR · ThS () ]

4436 ± 50[PR · ThS () ]

4178 ± 50[PR · ThR () ]

4058 ± 50[PR · ThR () ]

4515 ± 50[PR · ThR () ]

740 ± 50[PR · Bdss]

1140 ± 50[PR · BdRR]

3500 ± 50[PR · H2O]

7500 ± 50PR

Eexp/th (cm-1)

Monosolvation of the [Pr]+• radical cation strongly reduces the activation

barrier of its C-Cbond cleavage and markedly depend on the specific

configuration and conformation of the chiral solvent molecule.

(R)-1-phenylethanol

H

CF3

HO

p,m,o-fluoro-secbutil-benzene

HO

CH3

H

p,m,o-fluoro- (R)-1-phenylethanol

FER

ionization potentials ~ 10 eV

intense * electronic transitions ~ 5 eV Chiral aromatic molecules

The fluorinated chromophores

The insertion of fluorine into organic molecules causes important changes of their physico-chemical properties, chemical reactivity and biological activity in comparison to the non- fluorinated analogues.

Furthermore, fluorinated compounds, in which fluorine replaces hydrogen, have great impact on our daily life, as they are drugs, inhibitors and substrates of enzymatic reactions...

(R)-1-phenyl-2,2,2-trifluoroethanol

Clusters of FER with the two enantiomers of 3-hydroxy-tetrahydrofuran.

3 mains bands are present in each cluster spectrum

R S

Heterochiral cluster

Homochiral cluster

R S

Heterochiral cluster - HF

Homochiral cluster - HF

Clusters of FER with the two enantiomers of 3-hydroxy-tetrahydrofuran.

HF loss reaction in the cluster

h1

[FER-HF · ThR/S]

++ HF

[FER · ThR/S]•+h1

[FER · ThR/S]*FER + L

FF

F

HHO

HF loss

OR’

R+•

HF loss reaction in the cluster

h1

[FER-HF · ThR/S]

++ HF

[FER · ThR/S]•+h1

[FER · ThR/S]*FER + ThR/S

[FERThR/S] mass=264 [FER(ThR/S-HF)] mass=244

Eterochiral cluster

Homochiral cluster

This results indicates that the HF elimination

reaction is strongly affected by the selective

interaction with the chiral solvent.

Intracluster reactions with different solvents

HF elimination

HF elimination

HF elimination

-H2O

REACTIONSOLVENT

O

OH

O

OH

Intracluster reactions with different solvents

HF elimination199

206

HF elimination196

HF elimination195

-165H2O

REACTIONPA

(Kcal/mol)SOLVENT

O

OH

O

OH

Intracluster reactions with different solvents

8.9dissociative

electron transfer215CH3NH2

dissociative electron transfer

HF elimination

HF elimination

HF elimination

-

REACTION

8.5222

9.8199

206

9.4196

9.9195

12.6165H2O

IP (eV)PA

(Kcal/mol)SOLVENT

O

OH

O

OH

NH2

IP(FER)EXP = 9.2 eV

J. Phys. Chem. A 2007, 111, 12559-12563

The REMPI-TOF technique is a powerful tool to enantiodiscriminate molecules through their complexation with a suitable chiral selector ( absorption spectrum, binding energies in the ground, excited and ionic state).

The gas phase reactivity of a chiral species can be deeply affected by asymmetric microsolvation (photo fragmentation, effect on the HF elimination, barrier aromatic substitution).

Conclusions

These observations open the way to a understanding of the role of non covalent interactions in reactive processes and transfer mechanism in the living system.

Prof. Anna Giardini Dr. Lorenzo Avaldi

Prof. Maurizio Speranza Dr. Susanna Piccirillo

Dr. Alessandra Paladini Dr. Daniele Catone

Dr. Mauro Satta Dr. G. Cattenacci

Acknowledgments

(R)-1-phenyl-2,2,2-trifluoroethanol (FER)

Ab initio B3LYP/6-31G** theoretical calculations

Cluster of FER with water

Ab initio B3LYP/6-31G** theoretical calculations

Potential Energy Surface PM3

C-C bond distance

energy

OH

C2H5•+

H

•••solv

OH

H+

•C2H5

••• solv

OH

H• •C2H5

•+••• solv

solv=none

solv=W

solv=BdRR

solv=H2O (proton affinity=165 kcal mol-1)

solv=2,3-butanediols (proton affinity=206 kcal mol-1)