Kevin Mayer , Martin Holdren - PowerPoint Presentation

Slide1

Kevin Mayer, Martin Holdren, Taylor Smart, Channing West, Brooks H. Pate, Department of Chemistry, University of Virginia; Frank E Marshall and G. S. Grubbs II Department of Chemistry, Missouri University of Science and Technology, Rolla, MO, USA; Galen Sedo, Department of Natural Sciences, University of Virginia’s College at Wise, Wise, VA, USA; June 21

CHIRAL TAGGING OF VERBENONE WITH 3-BUTYN-2-OL FOR ESTABLISHING ABSOLUTE CONFIGURATION AND DETERMINING ENANTIOMERIC EXCESSSlide2

Chiral Analysis: The Search For a Universal Tool

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

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

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 techniques

For “N” chiral centers

2

N

isomers

2

N-1

unique diastereomers

2 enantiomers per diastereomerSlide3

Rotational Spectroscopy for Chiral Analysis: DiastereomersChirped-Pulse FTMW Spectroscopy

Extreme 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

AdvantagesEnantiomers now have distinct spectra“Tag” can provide dipole momentReference-free EE determinationHigh 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

Chiral Tag Rotational Spectroscopy

S-

Butynol

S-3MCH

R-

Butynol

S-3MCH

Enantiomers DiastereomersSlide7

Determination of Enantiomeric Excess using Chiral TagEnantiopure Chiral Tag ((S)-3-butyn-2-ol)

Heterochiral Spectrum

Homochiral Spectrum

Enantiomer populations converted to different

diastereomers with distinct spectra

Analogy to Chromatography

Different enantiomers gives signals in distinct detection windows

Background free detection permits determination of high EE when peaks are highly resolved

Rotational spectroscopy can be used to identify which enantiomer gives each signal

Rotational spectroscopy has the potential for significant decreases in analysis time

(Chiral GC Example:

30 min

) Slide8

Calibration and Analysis for Enantiomer Excess DeterminationA racemic sample of the chiral tag is used to normalize the signals for homochiral and heterochiral diastereomer complexesIf signals are linear in both tag and molecule concentration (number density), then the racemic tag produces equal concentrations of homochiral and heterochiral complexes.Linear Assumption:EE Analysis using Ratios of Individual Transitions in the Spectra: (Enantiopure Tag: WG09)

For racemic chiral tag (butynol):

For enantiopure tag (butynol):

EE Determination:

 Slide9

Verbenone EnantiomericExcess Determination

Analysis was done on the verbenone monomer and

butynol

complex

Measurement with Racemic Tag was preformed to

Calibrate Spectral Intensities

Recondition Sample to drive out racemic tag

Use neon flow to purge

Replace sample and sample linesSlide10

Verbenone EnantiomericExcess DeterminationMeasurement with “Enantiopure” Tag Assumed Butynol Enantiopure

Identified strongest transitions of

homochiral

and heterochiral complexes

About 50 of each across 2-8GHz

Calculated all transitions ratios and converted to EE

About 2500 transitions

Compared to COA from Sigma-AldrichSlide11

Enantiomeric Excess Determination from a Single Pair of Transitions

Heterochiral

complex

Homochiral

complex Slide12

EE Results for Deep Average and Neon PurgeSlide13

EE Results with Sample ReplacementSlide14

EE Results with Lower S/N ratio: Single nozzle, Fewer Averages

S-

butyno

l

R/S-

butynol

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).Slide15

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:Luca EvangelistiDave Patterson, Yunjie Xu, Walther Caminati, Javix Thomas, Smitty Grubbs, Galen SedoMark Marshall, Helen Leung, Kevin Lehmann, Justin Neill, David PrattFrank Marshall, Marty Holdren, Taylor Smart, Reilly Sonstrom, Channing WestEllie Coles, Elizabeth Franck, John Gordon, Julia Kuno, Pierce Eggan, Victoria Kim, Ethan Wood, Megan Yu Slide16

ConclusionsChiral Tag method gives quantitative EE in this case – no reference requiredMeasurement precision is good, but affected by S/N ratio/sample handlingPotential for high speed EE monitoring using cavity enhancement (Balle-Flygare)Linearity and detection limits (high EE) need to be assessed

Limits posed by spectrum congestion of added tag (especially in mixtures) need to be evaluated