The Conversion of Styrene Oxide Enantiomers into Spectroscopically

The Conversion of Styrene Oxide Enantiomers into Spectroscopically Distinguishable Diastereomers through Complexation with 3, 3, 3 -Trifluoro-1, 2 -Epoxypropane Mark D. Marshall, Helen O. Leung Department of Chemistry Amherst College Melanie Schnell, Sergio R. Domingos, Anna Krin FS-SMP, Deutsches Elektronen-Synchrotron (DESY) Supported by the National Science Foundation

Chiral analysis • Determine the absolute stereochemistry for an enantiopure analyte • Measure enantiomeric excess for a sample of mixed chirality (R)-Analyte + chiral tag Tag---R (S)-Analyte + chiral tag Tag---S Same rotational spectrum Diastereomers Different rotational spectra

Requirements for chiral tag • • • Easily available in enantiopure form Small, chiral molecule Easy to introduce into free-jet expansion Functionalized for noncovalent interactions Simple rotational spectrum § Minimal isotopic dilution (13 C, § No hyperfine § No internal rotation • Spectroscopically characterized • Structure determined 18 O helpful) 2 -(trifluoromethyl)-oxirane (TFO)

• Experimental methods Three chirped pulse Fourier transform microwave spectrometers in three countries and two continents • 6. 1 – 18. 1 GHz, 20 W (Amherst) • 2. 0 – 6. 0 GHz, 400 W (Alberta) • 2. 0 – 8. 0 GHz, 400 W (DESY) • • 0. 1% – 1% TFO in argon (Amherst), neon (Alberta), or helium (Alberta, DESY) is expanded through one (two at Amherst) pulsed valves with 0. 8 mm nozzle Multiple FIDs per gas pulse • 10 μs Amherst • 20 μs Alberta • 40 μs DESY Photo courtesy of Jessica Mueller, Amherst College • Long averaging • 50/100/200 k. Hz FWHM • • Some initial assignments and analysis using PGOPHER Final analysis using Kisiel’s AABS package in conjunction with Pickett’s SPFIT/SPCAT

Amherst Balle-Flygare FTMW Spectrometer • Used to observe (TFO)2 RR/SS 5 • 0. 5 % TFO in Argon (weak) • 0. 5 % TFO in Neon (better) • • • 6 – 22 GHz Cavity-enhanced sensitivity 1 MHz bandwidth Double heterodyne detection at 2. 5 MHz 10 MS/s digitization 1 k – 2 k data points Zero filled to 2 k – 4 k pts 1 – 5 k. Hz resolution 5 – 10 k. Hz linewidth Doppler doublets

(TFO)2 RR/SS 1 Ka = 5 – 4 b-type Q branch • • Lowest energy conformer First assigned at DESY, 2 – 8 GHz Also found in Amherst 6 – 18 GHz broadband spectrum (argon) and Alberta 2 – 6 GHz spectrum. Measurement uncertainty • • • 20. 0 k. Hz (Amherst) ~10 k. Hz (Alberta) ~6 k. Hz (DESY) 391 lines, 6 k. Hz rms Uncertainties adjusted with PIFORM B 3 LYP-GD 3 BJ//def 2 tzvp Exp. Theory A / MHz 1305. 78580(11) 1290 B / MHz 267. 047006(44) 266 C / MHz 246. 774863(49) 245

(TFO)2 RR/SS 5 • • J = 7 – 6 a-type • • Higher energy conformer First observed & assigned in Alberta, 2 – 6 GHz Not seen in Amherst broadband spectrum (argon) Extended to 20 GHz at Amherst (narrow band) Additional lines, 5 – 8 GHz, at DESY Measurement uncertainty • • • 1. 68 k. Hz (Amherst) 8. 87 k. Hz (Alberta) 6. 00 k. Hz (DESY) 254 lines, 5 k. Hz rms Χ 2 = 1. 00 B 3 LYP-GB 3 BJ//def 2 tzvp Exp. Theory A / MHz 1352. 20278(17) 1375 B / MHz 290. 382045(63) 282 C / MHz 276. 378429(66) 269

(TFO)2 heterochiral – not observed experimentally RS/SR 2 0 cm– 1 RS/SR 1 3. 7 cm– 1 A = 1721 MHz B = 228 MHz C = 222 MHz A = 1462 MHz B = 259 MHz C = 244 MHz μb = μa = μc =0 μa > μb >> μc B 3 LYP-GD 3 BJ/def 2 tzvp ZPE corrected Relaxed monomer geometry

Tagging styrene oxide • • • Small, chiral molecule Easy to introduce into free-jet expansion Simple rotational spectrum Spectroscopically characterized Structure determined Styrene oxide (SO)

TFO-SO – ABCluster RS/SR: 0 cm– 1 • • • Developed by Jun Zhang Locates minima via CHARMM force field Then optimize candidates with DFT • B 3 LYP-GD 3 BJ/def 2 tzvp • ZPE corrected • Relaxed monomer geometry RR/SS: 112 cm– 1 Zhang, J. ; Dolg, M. ABCluster: The Artificial Bee Colony Algorithm for Cluster Global Optimization. Phys. Chem. Phys. 2015, 17, 2417324181. Zhang, J. ; Dolg, M. Global Optimization of Rigid Molecular Clusters by the Artificial Bee Colony Algorithm. Phys. Chem. Phys. 2016, 18, 3003 -3010. http: //www. zhjun-sci. com/software-abcluster-download. php

TFO-SO – DFT predictions B 3 LYP-GD 3 BJ/def 2 tzvp ZPE corrected Relaxed monomer geometry RS/SR: 0 cm– 1 RR/SS: 112 cm– 1 A = 755 MHz B = 345 MHz C = 278 MHz A = 799 MHz B = 305 MHz C = 259 MHz μa > μb ≈ μc μa >> μb > μc

TFO-SO RS/SR J = 10 – 9 a-type • • • Normalized Intensity 0 Observed at DESY, 2 – 8 GHz 1% TFO in helium is expanded through one heated pulsed valve with liquid SO reservoir and 0. 8 mm nozzle 6 k. Hz measurement uncertainty Fit with SPFIT/SPCAT 266 lines, 4 k. Hz rms Uncertainties adjusted with PIFORM 20 40 6225 6230 6235 6240 6245 6250 6255 Frequency/MHz 6260 6265 6270 B 3 LYP-GB 3 BJ//def 2 tzvp 6275 Exp. Theory A / MHz 754. 996414(86) 755 B / MHz 343. 389276(55) 345 C / MHz 276. 525971(57) 278

TFO-SO RR/SS J = 10 – 9 a-type • • • Normalized Intensity 0 2 Observed at DESY, 2 – 8 GHz 1% TFO in helium is expanded through one heated pulsed valve with liquid SO reservoir and 0. 8 mm nozzle 6 k. Hz measurement uncertainty Fit with SPFIT/SPCAT 173 lines, 6 k. Hz rms Uncertainties adjusted with PIFORM 4 5650 5655 5660 5665 5670 5675 5680 Frequency/MHz 5685 5690 5695 5700 B 3 LYP-GB 3 BJ//def 2 tzvp Exp. Theory A / MHz 800. 86742(93) 799 B / MHz 305. 40820(12) 305 C / MHz 259. 85494(10) 259

Summary and future work • • • 2 -(trifluoromethyl)-oxirane is used to tag styrene oxide, converting enantiomers into spectroscopically distinguishable diastereomers. ABCluster followed by B 3 LYP/def 2 tzvp with GD 3 BJ empirical dispersion correction identifies suitable conformers and provides excellent estimates of rotational constants. Future work will include use of enantiopure 2 -(trifluoromethyl)-oxirane in determining its ability to successfully determine the enantiomeric excess of known styrene oxide samples.