Structure Determination of Two Stereoisomers of Sevoflurane Dimer by CP-FTMW Spectroscopy Nathan A. Seifert, Cristobal Perez, Daniel P. Zaleski, Justin L. Neill, Brooks H. Pate University of Virginia Alberto Lesarri, Montserrat Vallejo-López Universidad de Valladolid Emilio J. Cocincero, Fernando Castaño Universidad del País Vasco

Introduction Suhm and coworkers observed bands blue-shifted from their monomer peaks and tentatively assigned them to larger sevoflurane oligomers (dimers, ++) Sevoflurane homodimers have a number of potential stabilizing factors: Acceptor Donor Two strong deactivating groups (-CF 3 ) Mild donating group (-OCH 2 F)  C-H is a good Lewis acid - O CH 2 F a solid Lewis base C-H/F hydrogen bonding? Diastereomeric pair observed in CP-FTMW scan: In 2011… (SS) [pictured] (SR) [pictured]

Some facts about the new sevoflurane spectrum… 9.1 million averages Dynamic range: 31000:1 Average FWHM: 60 kHz 9,600 lines over 4:1 SNR (1.6 MHz -1 ) 0.2% sevoflurane in Ne, 1 atm backing pressure Spectrometer setup identical to sevoflurane-benzene (previous talk) Experimental

ParameterMP2B3LYPM06-2X A (% Err vs Exp) (0.59%) (1.7%) (1.5%) B (% Err)183.87(4.7%) (8.3%) (7.3%) C (% Err) (4.5%) (7.1%) (6.1%) μ a, μ b, μ c 2.0, 1.4, , 1.8, , 1.4, 0.13 ΔE binding (cm -1 ) ΔE binding CP (cm -1 ) (!) Heterochiral Dimer ParameterFit Value A (MHz) (39) B (MHz) (18) C (MHz) (18) Δ J (kHz) (24) Δ JK (kHz) (62) Δ K (kHz) (13) N lines 725 σ rms (kHz)7.25 Theory Experiment Observed all 8 13 C isotopologues in natural abundance Avg. 130 transitions per isotopologue, for a total of 1720 assigned heterochiral transitions

ParameterMP2B3LYPM06-2X A (% Err vs Exp) (0.15%) (0.18%) (2.0%) B (% Err) (3.1%) (0.68%) (4.5%) C (% Err) (1.4%) (0.00%) (4.6%) μ a, μ b, μ c 1.8, 0.5, , 1.2, , 1.1, 3.1 ΔE binding (cm -1 ) ΔE binding CP (cm -1 ) ΔΔE b CP (cm -1 ) Homochiral Dimer ParameterFit Value A (MHz) (39) B (MHz) (23) C (MHz) (23) Δ J (kHz) (29) Δ JK (kHz) (43) Δ K (kHz) (67) N lines 1051 σ rms (kHz)8.19 Theory Experiment Observed all 8 13 C and both 18 O isotopologues in natural abundance A total of 1770 assigned homochiral transitions

Fix monomer geometry to ab initio (excellent agreement with monomer FTMW results) Vary three intermolecular parameters (…in theory) In STRFIT, better results using dummy atom coordinate system and fitting these parameters effectively Intermolecular r 0 structure fit Homochiral Nearly exact procedure also used for fitting heterochiral dimer (no oxygen isotopologues, so purely carbon-containing parameters were fit) Schema:

Structural Results R0R0 RsRs Significant issues with imaginary coordinates Pictured: MP2/ g(d,p) ab initio structure with r 0 /r s coordinates as small blue spheres σ fit = amu Å 2 σ fit = amu Å 2 No issues with imaginary coordinates Heterochiral Homochiral

Structural Comparison Evaluating the C-H ⋯ F interactions 1 : Typical interactions are around 2.6 Å (average) <[C-H ⋯ F] ≈ 135° for a good average C-H ⋯ F bond (sevo) 2 <[C-H ⋯ F] ≈ ° 1. H.-J. Schneider, Chem. Sci., 3 (2012), 1381, and references therein. HomochiralHeterochiral

Conclusions The (RR) and (RS) dimers, though spectrally dense, only represent ~40% of the lines > 4:1 SNR (sevo) 1 (w/ isotopes) + (sevo) 2 represents somewhere around ~60% of the transitions Therefore, an open question: what else is being formed in the jet? (sevo)(H 2 O) is a possibility, but (H 2 O) 2 is weak in this acquisition [a typical indicator of “wetness”] Higher order (sevo) n clusters?Other isomers? Discovery bottlenecked mostly by the speed/efficiency of computational methods What else can we learn from this spectrum? Structural determination of two diastereomers of (sevoflurane) 2 24 heavy atoms per cluster! Issues with imaginary coordinates easily overcome by use of a simple intermolecular r 0 fit

Acknowledgements Thanks to the NSF for funding: MRI-R2, Award CHE Pate Group Brooks Pate Cristobal Perez Simon Lobsiger Luca Evangelisti Brent Harris Amanda Steber Nathan Seifert Daniel Zaleski Newcastle University Brightspec Justin Neill Universidad de Valladolid Alberto Lesarri Montserrat Vallejo-López Thanks for your time! UPV-EHV Emilio J. Cocincero Fernando Castaño

Heterochiral Dimer Structure Results Alternation of short/long C-F ⋯ H bonds with respect to homochiral isomer Fit ParameterR 0 valueR s valueMP2/6-311+g(d,p) R(C ⋯ C) / Å 4.286(9)4.23(4)4.124 Θ(C donor ⋯ C acc -CH 2 F) / ° 71.5(2)72.2(12)73.2 Φ(C a -C ⋯ C-C a ) / ° 61.6(4) (pictured) 62(1)65.6 Lack of imaginary coordinates saves the day for the Kraitchman determination!

Homochiral Dimer Structure Results C-F ⋯ H interactions quite important, unlike in sevoflurane ⋯ benzene Fit Parameter R 0 value R s value MP2/ g(d,p) R(C ⋯ C) / Å 4.328(5) 4.33(5) Θ(C ⋯ C-O) / ° 41.5(1) 48(2) 41.4 Φ(O-C ⋯ C-O) / ° 66.8(7) (pictured) 45(4) 66.3 Evaluating the C-H ⋯ F interactions 1 : Typical interactions are around 2.6 Å (average) <[C-H ⋯ F] ≈ 135° for a good average C-H ⋯ F bond (sevo) 2 <[C-H ⋯ F] ≈ ° 1. H.-J. Schneider, Chem. Sci., 3 (2012), 1381, and references therein.