June 21 st , 2017 University of Virginia - PowerPoint Presentation

Slide1

June 21st, 2017University of VirginiaDepartment of ChemistryInternational Symposium on Molecular SpectroscopyDavid Pratt, University of VermontLuca Evangelisti University of BolognaTaylor Smart, Martin Holdren, Kevin Mayer, Channing West and Brooks Pate, University of Virginia

A Chiral Tag Study of the Absolute Configuration of CamphorSlide2

Chiral Analysis: The Search For a Universal Tool

Image Credit: http://doktori.bme.hu/bme_palyazat/2013/honlap/Bagi_Peter_en.htm

Enantiomers: Mirror images of each other that are not superimposable and have opposite configurations at their stereocenters

Diastereomers: Distinct compounds that have different configurations at one or more, but not all of the stereocenters

For “N” chiral centers

2

N

isomers

2

N-1

unique diastereomers

2 enantiomers per diastereomer

Need for

universally applicable

chiral analysis methods

Quantitative ratios of

all stereoisomers

Complex

mixture

analysis

Rapid

monitoring

Molecules with multiple chiral centers pose an issue for current techniquesSlide3

Rotational Spectroscopy for Chiral Analysis: DiastereomersChirped-Pulse FTMW SpectroscopyExtreme sensitivity

to changes in mass distribution

Agreement with Theory:

“Library-Free” Diastereomer Identification

Low Frequency (2-8 GHz):

Peak Transition Intensity of Large Molecules

High Resolution + Broadband Coverage:

Mixture Analysis

C. Perez, S.

Lobsiger

, N. A. Seifert, D. P.

Zaleski

, B.

Temelso

, G.C. Shields, Z.

Kisiel

, B. H. Pate, Chem. Phys. Lett.

571

, 1 (2013).Slide4

The sign of the product of dipole vector components are opposite for enantiomersRotational Spectroscopy for Chiral Analysis: Three Wave Mixing for Enantiomers

D. Patterson, M. Schnell, and J.M Doyle, Nature

497

, 475- 478 (2013).

D. Patterson and J.M. Doyle, Phys. Rev.

Lett

.

111

, 023008 (2013).

J.U.

Grabow

,

Angew

. Chem. 52, 11698 (2013).

V.A Shubert, D. Schmitz, D. Patterson, J.M Doyle, and M. Schnell,

Angew

. Chem. 52, (2013).

m

b

Simon Lobsiger, Cristobal Perez, Luca Evangelisti, Kevin K. Lehmann, Brooks H. Pate, “Molecular Structure and Chirality Detection by Fourier Transform Microwave Spectroscopy”, J. Phys. Chem. Lett. 6, 196-200 (2015).

m

a

m

b

m

c

(-)

m

a

m

b

m

c

(+)Slide5

Challenges of Three Wave MixingAbsolute Configuration (AC):Enantiomeric Excess (EE

):

Since AC is determined by the phase of the chiral signal,

t

0

must be known

Phase Calibration is currently unsolved

Needs a reference sample with known EE due to

single detection window

for enantiomers

Potential for errors in

high EE limitSlide6

Advantages

Enantiomers now have distinct spectra

“Tag” can provide dipole moment

Reference-free EE determination

High enantiopurity limit

Disadvantages

Spectral complexity from complexes

Fraction of molecules complexed can be low (<10%) limiting sensitivity

Accuracy of quantum chemistry for complexes needs to be determined

Rotational Spectroscopy: The Classical Approach of Chiral Tagging

S-

Butynol

S-3MCH

R-

Butynol

S-3MCH

Enantiomers DiastereomersSlide7

Dipole Moment Directionality and Three Wave Mixing Rotational SpectroscopyCamphorB3LYP D3BJ 6-311++G**

Experiment Theory (S-camphor)

A = 1446.968977(72) MHz

m

a

= 2.9934(23) D (76.2

o

) A = 1445.94 MHz (0.07%)

m

a

= 3.19 D (75.8

o

)

B = 1183.367110(47) MHz

m

b

= 0.7298(6) D (13.7

o

) B = 1180.60 MHz (0.23%)

mb = -0.80 D (14.1o

)C = 1097.101031(33) MHz mc = 0.0804(7) D (1.49o

) C = 1094.23 MHz (0.26%) mc = 0.10 D (1.94o) mtot

= 3.0821(22) D

m

tot

= 3.29 D (-6.7%)

Small angle shift (1.5

o

) changes sign of dipole moment component on c-axis (Z)

Analysis Issues for a Small Dipole Moment Component

Potential for quantum chemistry to determine the incorrect sign of the dipole moment product leading to incorrect absolute configuration

Potential to limit measurement sensitivity because pulse durations for optimum signal become too longSlide8

Determination of Absolute Configuration by Chiral Tag Rotational SpectroscopyComplexes of enantiomers with an enantiopure “chiral tag” form diastereomers that have different rotational spectra

Heterochiral Complex

A = 975.3 MHz

m

a

= 3.3 D

B = 320.1 MHz

m

b

= 1.6 D

C = 301.6 MHz mc = 0.9 D

Homochiral ComplexA = 1038.6 MHz m

a = 3.1 D B = 294.6 MHz mb = -1.9 D C = 278.5 MHz

mc = - 0.1 D

Lowest Energy Isomers: B3LYP D3BJ def2TZVPEnantiomers of molecules have identical rotational spectraSlide9

The ProblemGiven an unknown sample of CamphorWhich Camphor is it?

R Camphor

or

S Camphor

?

Add enantiopure tagging molecule

Results in either homo or hetero chiral complexes

Compare values to theoretical values

R,R-Camphor

S,S-CamphorSlide10

Chiral Tag Rotational Spectroscopy and Isomers

Relative Electronic Energy (kcal/mol)

Heterochiral

Complexes

Homochiral

Complexes

0.00

0.05

0.16

0.16

0.92

0.94

Expect a few isomers to be formed in the pulsed jet expansion.

Spectroscopy “match” is to the set of high abundance isomers

Requires accurate structures, thorough isomer searches, and accurate energies from computational chemistry

B3LYP D3BJ def2TZVP

Lowest Energy

Heterochiral

Second Lowest

Energy Heterochiral

Lowest Energy

Homochiral

…

…Slide11

MethodologyMonomer spectra: Cut out monomer signalsEnantiopure samples: Identify the homochiral or heterochiral spectraBased on quantum calculations

S and R Camphor result in different spectraSlide12

Absolute Configuration: Spectral Comparison10% Camphor complexed in the lowest Homochiral conformation3% complexed in the second lowest Homochiral conformationSlide13

Absolute Configuration by Rotational Constant ComparisonCompare experimental rotational constants to the theoreticalExperimental spectra compared to simulated spectra of 2 lowest energy formsFirst Camphor R-Butynol

Complex

Experimental

Theoretical Lowest Energy Homochiral

Theoretical Lowest Energy Heterochiral

1036.63867(23)

1038.6

(-0.21

%)

975.3

291.898140(63)

294.6

(-0.93

%)

320.1

275.812670(65)

278.5 (-0.97%)

301.6

Second Camphor R-Butynol ComplexExperimentalTheoretical Second Lowest Energy Homochiral

Theoretical Second Lowest Energy Heterochiral922.86399(22)923.3 (-0.06%)975.722

307.166560(74)312.1 (-1.61%)290.8291.902210(79)296.19 (-1.47%)274.2

Dipole component values all very similar for the isomers: Can’t be used to confirm analysisSlide14

Determination of Absolute Structure from

Isotopologue Analysis

Enantiomers for the lowest energy homochiral complex from quantum chemistry

Experimental carbon atom positions from isotopologue analysis (Kraitchman)

Measurement uses (R)-butynol as the chiral tag so the absolute structure of the sample is known:

(R)-camphorSlide15

AcknowledgementsThis work supported by the National Science Foundation (CHE 1531913) and The Virginia Biosciences Health Research CorporationSpecial thanks for work on chiral tag rotational spectroscopy:David PrattLuca EvangelistiDave Patterson, Yunjie Xu, Walther Caminati, Javix Thomas, Smitty Grubbs, Galen SedoMark Marshall, Helen Leung, Kevin Lehmann, Justin NeillFrank Marshall, Marty Holdren, Kevin Mayer, Reilly Sonstrom, Channing WestEllie Coles, Elizabeth Franck, John Gordon, Julia Kuno, Pierce Eggan, Victoria Kim, Ethan Wood, Megan Yu Slide16

Conclusion and Final refinements Camphor is a simple starting case with only one effective chiral centerStable molecule with no conformational changesFuture work

More complex chiral molecule with conformational changes

Accuracy of quantum chemistry needs to be explored for larger complexes

Absolute configuration of a chiral molecule can be determined by rotational spectroscopy

Unambiguous result with X-ray quality

However