Propylene Oxide and 3Butyn2ol Luca Evangelisti Dipartimento di Chimica G Ciamician Universit à di Bologna Channing West Ellie Coles Brooks Pate Department of Chemistry University of Virginia ID: 632949
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Slide1
Complexes of Small Chiral Molecules:Propylene Oxide and 3-Butyn-2-ol
Luca EvangelistiDipartimento di Chimica G. CiamicianUniversità di BolognaChanning West, Ellie Coles, Brooks PateDepartment of ChemistryUniversity of VirginiaSlide2
For “N” chiral centers
2N stereoisomers2(N-1) unique geometries2 enantiomers per diastereomer
Need for
universally applicable enantiomeric excess
methods
Quantitative ratios of
all stereoisomersComplex mixture analysisRapid monitoringEnantiomers – mirror images but not superimposableDiastereomers – molecules with multiple chiral centers that are not mirror images (distinct geometries)
Chiral Analysis
Image Credit: http://doktori.bme.hu/bme_palyazat/2013/honlap/Bagi_Peter_en.htm
Carlos
Kleber
Z. Andrade*,
Otilie
E.
Vercillo
, Juliana P. Rodrigues and Denise P.
Silveira
,
J. Braz. Chem. Soc
.,
15
,
813-817, 2004. Slide3
The sign of the product of dipole vector components are opposite for enantiomers
Three Wave Mixing: Enantiomer AnalysisD. 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
mc
(+)Slide4
Challenges of Three Wave Mixing: Enantiomeric Excess
Enantiomeric Excess (EE):Needs a reference sample with known EE due to single detection window for enantiomersPotential for errors in high EE limitAbsolute Configuration (AC):
Phase dependence
Small dipole component can produce erroneous resultsSlide5
S-3MCH
Enantiomers Diastereomers
Rotational Spectroscopy: Chiral Tagging
S-
Butynol
S-3MCH
R-ButynolBy complexing with a separate chiral moleculeAdvantagesEnantiomers now have distinct spectra“Tag” can provide dipole moment
Reference-free EE determinationHigh enantiopurity limitSlide6
Rotational Spectroscopy for Chiral Analysis: Diastereomers
Chirped-Pulse FTMW SpectroscopyLow Frequency (2-8 GHz):Peak Transition Intensity of Large MoleculesHigh Resolution + Broadband Coverage: Mixture AnalysisExtreme sensitivity to mass distributionAgreement with Theory: “Library-Free” Diastereomer Identification
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).Slide7
Enantiopure 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 windowsBackground 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
)
(1S)-(-)-verbenone
+
(S)-(-)-3-butyn-2-ol
(1R)-(+)-verbenone
+
(S)-(-)-3-butyn-2-ol
Ideal Case: Enantiopure Chiral TagSlide8
Calibration and Analysis for Enantiomer Excess Determination
53.6% EESlide9
Actual Measurement Conditions: Effects Due to the Enantiomeric Excess of the Chiral Tag
Chiral Tag Has High Enantiopurity: Alfa Aesar Sample(S)-(-)-butynol: 99.3%(R)-(+)-butynol: 0.7%EE: 98.6%
Homochiral Species:
Tag(-) + Analyte(-): (1-
) (1-f
+
)Tag(+) + Analyte(+): f
+
Heterochiral Species:
Tag(-) + Analyte(+): (1-
) f
+
Tag(+) + Analyte(-):
(1- f
+
)
Sample mole fractions:
Chiral Tag: (-): 1-
Analyte: (-): (1-f
+
)
(+): (<<1) (+): f+
ee
= (1-2)
ee
= (1-2f
+
)
Note:
EE =
ee
x 100
Linear Assumption: Number Density of Complex Proportional to the
Product of Number Densities for the EnantiomersSlide10
Linear Assumption: Signal Level for an Individual Rotational Transition
SignalHOMO = CHOMO * ( [Tag(-)][Analyte(-)] + [Tag(+)][Analyte(+)] )SignalHETERO
= C
HETERO
* ( [Tag(-)][Analyte(+)] + [Tag(+)][Analyte(-)] )
Signal Normalization:
For a racemic tag sample ( = 0.5):
Signal
HOMO = C
HOMO * 0.5
Signal
HETERO
= CHETERO
* 0.5
N =
(SignalHOMO
/Signal
HETERO )
The ratio of the transition intensities using racemic
tag
Effect: For any PAIR of heterochiral
and homochiral
transitions in the spectrum
Normalization
Transitions have unequal intensity due to intrinsic transition strength, isomer populations, and instrument intensity calibration
Enantiomeric Excess MeasurementsSlide11
Linear Assumption: Signal Level for an Individual Rotational Transition
SignalHOMO = CHOMO * ( [Tag(-)][Analyte(-)] + [Tag(+)][Analyte(+)] )SignalHETERO
= C
HETERO
* ( [Tag(-)][Analyte(+)] + [Tag(+)][Analyte(-)] )
EE Determination:
Using the high enantiopurity tag ( << 1):
Signal
HOMO = C
HOMO * [(1-
) (1-f+
) +
f
+]
Signal
HETERO
= C
HETERO * [(1-
) f
+ + (1- f
+) ]
Calculate the Normalized Signal Ratio (R):
R = N * (SignalHETERO/
Signal
HOMO
)
Effect: For any PAIR of
heterochiral
and
homochiral
transitions in the spectrum
Normalized Signal
With Racemic Tag
Intensity Changes with use of High Enantiopurity Tag
Normalized Signal
Ratio (R)
Result:
Enantiomeric Excess MeasurementsSlide12
Butynol:
AUTOTAG (Walther Caminati)Measure the spectrum of racemic butynol and high enantiopurity butynol and use the rotational transitions of the homochiral and heterochiral dimer spectra
EE calibration does not require assignment of the dimer spectra
(for the high enantiopurity sample, homochiral complexes approximately double in intensity and heterochiral complexes nearly disappear when compared to the intensities in the racemic spectrum)
Calibration of
Butynol and Propylene Oxide Chiral TagsSample Composition:(S)-butynol: 99.05(15)%(R)-butynol: 0.95(15)%Certificate of Analysis:(S)-butynol: 99.3%
(R)-butynol: 0.7%Slide13
Calibration of
Butynol and Propylene Oxide Chiral TagsPropylene Oxide: Calibration with ButynolThe lowest energy isomer of the propylene oxide dimer has a small dipole moment limiting the measurement sensitivity.The transition intensities for the propylene oxide – butynol complex are a factor of 10 higher than the strongest transitions observed for the propylene oxide dimer (RR2).The homochiral and heterochiral complexes of propylene oxide – butynol have been assigned and verified by Kraitchman substitution structures and can be used for chiral tagging
Homochiral
HeterochiralSlide14
Butynol Dimer Present in this Measurement: Can Calibrate both Butynol and Propylene Oxide
Calibration of Butynol and Propylene Oxide Chiral TagsSlide15
Using Auto Tag Calibration of Butynol:
EE = 98.1(3)The verbenone EE determinations are:Four Nozzle: EE = 53.0(5.9)Single Nozzle: EE = 52.7(4.8)Certificate of Analysis: EE = 53.6%Enantiomeric Excess of Verbenone RevisitedSlide16
Acknowledgements
This 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, David Pratt, Smitty Grubbs, Galen SedoMark Marshall, Helen Leung, Kevin Lehmann, Justin NeillFrank Marshall, Marty Holdren, Kevin Mayer, Taylor Smart, Reilly Sonstrom, Ellie Coles, Elizabeth Franck, John Gordon, Julia Kuno, Pierce
Eggan, Victoria Kim, Ethan Wood, Megan Yu
Slide17
Conclusion
Rotational spectroscopy has the potential to be a powerful analytical tool for determining enantiomeric excess in the high EE limitCorrection for tag enantiopurity is necessary for accurate analytical work Results are reproducible and narrowly distributed in the high EE limitSlide18
Effect of Intensity Fluctuations Between Racemic and Enantiopure MeasurementsModeling of EE Determination using 5% intensity fluctuation on transitions
Distribution width is linear in (100-EE) – amount of enantio impurityDistribution width is linear in the intensity fluctuation