1. Javix Thomas, Wolfgang Jäger, Yunjie Xu Department of Chemistry, University of Alberta Edmonton, Alberta, Canada ISMS, Medical Sciences Building 274, TE11, 11:30 am, Tuesday, June 17, 2014 A PEPTIDE CO SOLVENT IN A CHIRALITY INDUCTION MODEL SYSTEM: BROADBAND ROTATIONAL SPECTROSCOPY OF THE 2,2,2-TRIFLUOROETHANOL··PROPYL ENE OXIDE ADDUCT J. Thomas

2. Motivation Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/ 2 Xu, Fraser, Lovas, Suenram, Gillies, Warner, Gillies, J.Chem. Phys. 1995, 103, 9541. interconvert rapidly on the time scale of 170 ps. 2,2,2-trifluoroethanol (TFE) is widely used as a peptide co-solvent. TFE is known to promote chirality induction and amplification processes. Permanent chirality (reactants/catalysts)  new chirality in activated complex/intermediate with prochiral or transiently chiral species  one or more new permanent stereogenic centers or helicity of the product. H-bonding and other non-covalent interactions between chiral units and TFE are responsible for the observed chirality induction.

3. Chirality synchronization in trifluoroethanol (TFE) dimer Gas phase chiral clusters http://www.chem.ualberta.ca/~xu / 3 Scharge, Cézard, Zielke, Schütz, Emmeluth, Suhm, Phys. Chem. Chem. Phys. 2007, 9, 4472; Scharge, Wassermann, Suhm, Z. Phys. Chem. 2008, 222, 1407. “Among the possible dimer conformations, only an all-gauche, homoconfigurational, compact, OH–F connected structure is observed in an extreme case of chiral discrimination. Quantum tunneling assisted pathways for this surprising helicity synchronization are postulated. ROTATIONAL SPECTRA OF THE TRIFLUOROETHANOL (TFE)- WATER CLUSTERS AND THE TFE DIMERS. Thomas, Xu J. Chem. Phys. 2014 140, in press; J. Phys. Chem. Lett. 2014, 5, 1850. Strong chirality preference compared to ethanol dimers and 2-fluoroethanol (FE) dimers.

4. Chirality induction in the TFE··propylene oxide adduct Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/ 4 trans conf. Ethanol Extra binding site FE gauche conf. The ethanol··propylene oxide adduct and FE··propylene oxide adduct were investigated before. Borho, Xu, Angew. Chem. Int. Ed. 2007, 46, 2276; Borho, Xu, J. Am. Chem. Soc. 2008, 130, 5916. + TFE gauche conf.

5. Experimental details Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/ 5 Initial searches were carried out using a chirp pulsed FTMW spectrometer. Final measurements were done with a cavity based FTMW spectrometer. 0.3%~0.5% TFE or propylene oxide (PO) or both in Neon or Helium backing gas (2~8 atm). Transitions due to (PO) n, (TFE) n, (PO) n (RG) m, or (TFE) n (RG) m (with RG = He or Ne; n, m = 1, 2…) were removed.

6. Brown, Dian, Douglass, Geyer, Shipman, Pate, Rev. Sci. Inst. 2008, 79, 053103; Dempster, Sukhorukov, Lei, Jäger, J. Chem. Phys. 2012, 137, 174303. Thomas, Yiu, Rebling, Jäger, Xu, J. Phys. Chem. A. 2013, 117, 13249. Rotational spectroscopy with a cavity based and a chirped pulse FTMW spectrometer microwave cavity nozzle Balle, Flygare, Rev. Sci. Instrum. 1981, 52, 33; Xu, Jäger, J. Chem. Phys. 1997, 106, 7968. 6 Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/

7. 7 Most stable TFE··propylene oxide (PO) conformers Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/ D 0 (I) = 27.70 kJ/mol Thomas, Jäger, Xu, Angew. Chem. Int. Ed. 2014, DOI:10.1002/anie.201403838.  D 0 (kJ/mol) = -0.29 -0.69 -0.94 -3.76  D 0 (kJ/mol) = 0 -0.49 -0.91 -1.12 MP2/6-311++G(2d,p)

8. 8 Broadband experimental spectra of TFE··PO Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/ 1 2 3 4

9. 9 Spectroscopic constants of the TFE··PO conformers Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/ MP2/6-311++G(2d,p) Para. IIIIIIIVVVIVIIVIII ∆D e 0-0.85-1.45-1.25-1.56-0.83-1.82-3.05 ∆D 0 0-0.29-0.49-0.69-0.91-0.94-1.12-3.76 A 21612471295421802360232623062078 B 684609530646593659599666 C 594570505640572615560617 |μ a | 2.762.982.912.622.383.192.983.44 |μ b | 0.030.390.101.411.630.21.782.38 |μ c | 0.010.09 0.381.120.060.570.52 Para1234 A 2170.106(11)2426.6781(19)2920.124(71)2336.440(30) B 652.14861(29)594.67934(12)516.98121(23)632.57360(30) C 569.66525(28)560.17041(12)491.67870(22)589.52799(23) Experimental results: all a-type transitions except very weak b-type for 2.

10. 10 Conformational distribution Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/ Exp. rel. abund. of I : II : III : VI = 1 : 0.75 : 0.35 : 0.40 Open Closed Cal. rel. abund. of I to VIII = 1.00:0.56:0.37:0.25:0.16:0.15:0.11:0.00

11. 11 Conformational conversion Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/ Exp. rel. abundance of I : II : III : VI = 1 : 0.75 : 0.35 : 0.40 Open Closed Cal. rel. abundance of I : II : III : VI = 1 : 0.73 : 0.48 : 0.14 Cal. rel. abund. of I to VIII = 1.00:0.56:0.37:0.25:0.16:0.15:0.11:0.00

12. 12 Comparison to the 2-FE··PO adduct Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/ Open Closed 2-FE··PO prefers Closed structures. Borho, Xu, J. Am. Chem. Soc. 2008, 130, 5916.

13. Relative stability of TFE··PO vs. 2-FE··PO Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/ ConfE dist PO E dist TFE E int BSSEZPE I-0.42-1.2843.62-9.56-4.66 II-0.43-1.3842.87-8.94-4.72 III-0.43-1.3442.24-8.65-4.61 IV-0.43-1.6642.76-9.08-4.58 V-0.38-1.6042.34-8.97-4.60 VI-0.4742.56-9.55-4.79 VII-0.36-1.7442.20-8.99-4.53 VIII-0.32-1.8240.07-8.85-4.44 Max. 0.15 0.82 3.550.910.35 2-FE··PO E monomer E int Open (open gauche FE) -11.0~+4 Closed (compact gauche FE) 0.0 Factors contributed to the relative stability of TFE··PO Main factors contributed to the relative stability of 2-FE··PO In both cases, E int is maximized in the open structures. Thomas, Jäger, Xu, Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201403838. 13 Borho, Xu, J. Am. Chem. Soc. 2008, 130, 5916. kJ/mol

14. The effects of fluorination on binding energy Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/ 14 1.For the TFE··PO adduct, the binding energy increases by ~70% over its ethanol counterpart. 2. The effect of fluorination on dissociation energy switches on more gradually in the complexes with PO than with water. 3. Ethanol··PO subtly favors syn diastereofacial interactions, while both FE··PO and TFE··PO favor anti arrangements. Binary alcohol··PO adducts 1  D 0 (kJ/mol) Binary alcohol··H 2 O adducts 2  D 0 (kJ/mol) ethanol16ethanol19 2-FE182-FE26 TFE27TFE28 Borho, Xu, Angew. Chem. Int. Ed. 2007, 46, 2276; Borho, Xu, J. Am. Chem. Soc. 2008, 130, 5916. Heger, Scharge, Suhm, Phys. Chem. Chem. Phys. 2013, 15, 16065.

15. Conclusion and future work 15 1. A preference for the g+ TFE··S-PO diastereomers versus g- TFE··S-PO was observed. This is to a much lesser degree compared to the TFE dimer, yet much more compared to the FE··PO system. 2. Fluorination has great effects on the overall binding strength of the binary adducts and on the corresponding conformational distribution. 3. We are working on rotational spectroscopic studies of TFE with permanently chiral molecules which are more flexible than PO. Gas phase chiral clusters http://www.chem.ualberta.ca/~xu/

16. 16Acknowledgements Funding $$$: Dr. Barbara Mez-Starck Foundation. Thank you for your attention!