Complexes of Small Chiral Molecules: Propylene Oxide and 3-Butyn-2-ol

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Presentation transcript:

Complexes of Small Chiral Molecules: Propylene Oxide and 3-Butyn-2-ol Luca Evangelisti Dipartimento di Chimica G. Ciamician Università di Bologna Channing West, Ellie Coles, Brooks Pate Department of Chemistry University of Virginia

Chiral Analysis For “N” chiral centers 2N stereoisomers 2(N-1) unique geometries 2 enantiomers per diastereomer Image Credit: http://doktori.bme.hu/bme_palyazat/2013/honlap/Bagi_Peter_en.htm Need for universally applicable enantiomeric excess methods Quantitative ratios of all stereoisomers Complex mixture analysis Rapid monitoring Enantiomers – mirror images but not superimposable Diastereomers – molecules with multiple chiral centers that are not mirror images (distinct geometries) Carlos Kleber Z. Andrade*, Otilie E. Vercillo, Juliana P. Rodrigues and Denise P. Silveira, J. Braz. Chem. Soc., 15, 813-817, 2004.

Three Wave Mixing: Enantiomer Analysis The sign of the product of dipole vector components are opposite 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). mambmc(-) mambmc(+) 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). mb 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).

Challenges of Three Wave Mixing: Enantiomeric Excess Absolute Configuration (AC): Phase dependence Small dipole component can produce erroneous results Enantiomeric Excess (EE): Needs a reference sample with known EE due to single detection window for enantiomers Potential for errors in high EE limit

Rotational Spectroscopy: Chiral Tagging By complexing with a separate chiral molecule Enantiomers Diastereomers S-Butynol R-Butynol Advantages Enantiomers now have distinct spectra “Tag” can provide dipole moment Reference-free EE determination High enantiopurity limit S-3MCH S-3MCH The basic idea, since rot spec yields different spectra for distinct geometries/mass distributions, let’s turn enantiomers into diastereomers by ‘tagging’ the molecule with a small molecule like Butynol that interacts via a hydrogen bond and van der Waals attractions in the pulsed jet. Structures are clearly different when looking at the mirror image of the butynol and then attaching the 3MCH below Show difference In two structures. Include spectra to show difference? Advantages No reference sample needed for EE measurement Preferred for high EE measurements Good chemical selectivity Can find absolute configuration from theoretical spectra Dipole moment can be provided by tag Disadvantages Need for accurate quantum mechanical structures Fraction of molecule complexed may be low (<10%) Spectral complexity through isomers of complexes

Rotational Spectroscopy for Chiral Analysis: Diastereomers Chirped-Pulse FTMW Spectroscopy Low Frequency (2-8 GHz): Peak Transition Intensity of Large Molecules High Resolution + Broadband Coverage: Mixture Analysis Extreme sensitivity to mass distribution Agreement 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).

Ideal Case: Enantiopure Chiral Tag Enantiopure Chiral Tag ((S)-(-)-3-butyn-2-ol) Analogy to Chromatography Heterochiral Spectrum (+/-) Homochiral Spectrum (-/-) 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) (1R)-(+)-verbenone + (S)-(-)-3-butyn-2-ol (1S)-(-)-verbenone + (S)-(-)-3-butyn-2-ol Enantiomer populations converted to different diastereomers with distinct spectra

Calibration and Analysis for Enantiomer Excess Determination 53.6% EE Include Kevin’s histogram and previous value for EE  Chiral tagging works Chiral tagging as analytical technique (pharma  4 decimal places) What do we need to know? High tag enantiopurity

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% 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 Enantiomers More general nomenclature Based on optical rotational properties When delta = 0 -> simple When delta=/= 0 -> apparently not simple Homochiral Species: Tag(-) + Analyte(-): (1-) (1-f+) Tag(+) + Analyte(+):  f+ Heterochiral Species: Tag(-) + Analyte(+): (1-) f+ Tag(+) + Analyte(-):  (1- f+)

Enantiomeric Excess Measurements Linear Assumption: Signal Level for an Individual Rotational Transition SignalHOMO = CHOMO * ( [Tag(-)][Analyte(-)] + [Tag(+)][Analyte(+)] ) SignalHETERO = CHETERO * ( [Tag(-)][Analyte(+)] + [Tag(+)][Analyte(-)] ) Signal Normalization: For a racemic tag sample ( = 0.5): SignalHOMO = CHOMO * 0.5 SignalHETERO = CHETERO * 0.5 Effect: For any PAIR of heterochiral and homochiral transitions in the spectrum Normalization What do you do when you don’t know the enantiopurity of the tag? Measure racemic -> normalization Transitions have unequal intensity due to intrinsic transition strength, isomer populations, and instrument intensity calibration N = (SignalHOMO/SignalHETERO ) The ratio of the transition intensities using racemic tag

Enantiomeric Excess Measurements Linear Assumption: Signal Level for an Individual Rotational Transition SignalHOMO = CHOMO * ( [Tag(-)][Analyte(-)] + [Tag(+)][Analyte(+)] ) SignalHETERO = CHETERO * ( [Tag(-)][Analyte(+)] + [Tag(+)][Analyte(-)] ) EE Determination: Using the high enantiopurity tag ( << 1): SignalHOMO = CHOMO * [(1-) (1-f+) +  f+] SignalHETERO = CHETERO * [(1-) f+ +  (1- f+) ] Effect: For any PAIR of heterochiral and homochiral transitions in the spectrum Intensity Changes with use of High Enantiopurity Tag Highe enant purity tag Product of the tag ee and analyte ee How do we get tag ee Calculate the Normalized Signal Ratio (R): Normalized Signal With Racemic Tag Normalized Signal Ratio (R) R = N * (SignalHETERO/SignalHOMO ) Result:

Calibration of Butynol and Propylene Oxide Chiral Tags 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) Sample Composition: (S)-butynol: 99.05(15)% (R)-butynol: 0.95(15)% Certificate of Analysis: (S)-butynol: 99.3% (R)-butynol: 0.7%

Calibration of Butynol and Propylene Oxide Chiral Tags Propylene Oxide: Calibration with Butynol The 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 Heterochiral

Calibration of Butynol and Propylene Oxide Chiral Tags Butynol Dimer Present in this Measurement: Can Calibrate both Butynol and Propylene Oxide

Enantiomeric Excess of Verbenone Revisited 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%

Acknowledgements This work supported by the National Science Foundation (CHE 1531913) and The Virginia Biosciences Health Research Corporation Special thanks for work on chiral tag rotational spectroscopy: Luca Evangelisti Dave Patterson, Yunjie Xu, Walther Caminati, Javix Thomas, David Pratt, Smitty Grubbs, Galen Sedo Mark Marshall, Helen Leung, Kevin Lehmann, Justin Neill Frank 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

Conclusion Rotational spectroscopy has the potential to be a powerful analytical tool for determining enantiomeric excess in the high EE limit Correction for tag enantiopurity is necessary for accurate analytical work Results are reproducible and narrowly distributed in the high EE limit

Effect of Intensity Fluctuations Between Racemic and Enantiopure Measurements Modeling of EE Determination using 5% intensity fluctuation on transitions Distribution width is linear in (100-EE) – amount of enantio impurity Distribution width is linear in the intensity fluctuation