Conformations and structures of desflurane and isoflurane

Journal of Fluorine Chemistry 101 (2000) 223±231

Conformations and structures of des¯urane and iso¯urane Angelika Hermann, Hans-Georg Mack, Heinz Oberhammer*

Institut fuÈr Physikalische und Theoretische Chemie, UniversitaÈt TuÈbingen, 72076 TuÈbingen, Germany Received 9 May 1999; accepted 14 June 1999

Abstract The geometric structure and conformational properties of the two inhalation anesthetics des¯urane (2-di¯uoromethoxy-1,1,1,2tetra¯uoroethane, CF3±CHF±O±CHF2) and iso¯urane (2-chloro-2-(di¯uoromethoxy)-1,1,1-tri¯uoroethane, CF3±CHCl±O±CHF2) were studied by gas electron diffraction (GED) and quantumchemical calculations (HF/3-21G*, B3PW91/6-311G(2d) and MP2/6-311G(2d)). Both compounds exist in the gas phase as mixtures of two conformers. The predominant form (80(8)% in des¯urane and 83(11)% in iso¯urane) possesses near trans con®guration of the C±C±O±C skeleton ((C±C±O±C) ˆ ÿ146(4)8 in des¯urane and ÿ136(5)8 in iso¯urane) and trans orientation of the CHF2 group (C±H bond trans to O±C bond). In the minor conformer, the CHF2 group is oriented gauche. These conformational properties are discussed in terms of anomeric effects. According to the theoretical calculations four or ®ve stable conformers exist and the types and relative energies depend on the computational method. However, the two structures which are predicted by all three methods to be lowest in energy correspond to the predominant and minor conformer observed in the GED experiments. The gas phase structures of the predominant form are in very close agreement with the crystal structures which have been reported previously. # 2000 Elsevier Science S.A. All rights reserved. Keywords: Des¯urane; Iso¯urane; Gas electron diffraction; Quantumchemical calculations; Conformational properties

1. Introduction More than 150 years ago Long [1] and Morton [2] demonstrated that diethyl ether can be used to put patients reversibly to sleep before surgery. Halogenation of ethers improved the properties of inhalation anesthetics by increasing the potency and decreasing the toxicity of these gases. At present, the halogenated ethyl methyl ethers en¯urane (2chloro-1-(di¯uoromethoxy)-1,1,2-tri¯uoroethane, CHFCl± CF2±O±CHF2), des¯urane (2-di¯uoromethoxy-1,1,1,2-tetra¯uoroethane, CF3±CHF±O±CHF2) and iso¯urane (2chloro-2-(di¯uoromethoxy)-1,1,1-tri¯uoroethane, CF3± CHCl±O±CHF2) are among the most frequently used human inhalation anesthetics. Des¯urane has been released as a new narcotic gas only recently. Each of these three compounds contains one chiral carbon atom. The gases are synthesized and used for clinical purposes as racemic mixtures of the R- and S-enantiomers. Although the physiological effects of these substances have been studied extensively, there is a little agreement about how and where general anesthetics act in the central *

Corresponding author. Tel.: ‡49-7071-2976907; fax: ‡49-7071295490. E-mail address: [email protected] (H. Oberhammer)

nervous system. For about one hundred years the ``lipid hypothesis'' was generally accepted [3]. This idea is based on work by Meyer [4] and Overton [5] who demonstrated that the potency of anesthetics parallels their fat solubility. The compounds were assumed to act non-speci®cally by dissolving in the fatty membranes of nerve cells, thereby affecting the ion channels. Recent studies, however, have shown that many anesthetics act more speci®cally and operate on certain membrane proteins [6]. The strongest evidence for this ``protein hypothesis'', i.e. a receptor-based mechanism, comes from the observation of stereoselectivity [7]. The (‡)-isomer of iso¯urane was found to be about 50% more potent than the (ÿ)-isomer [8]. These experiments became possible after enantiomerically pure samples could be obtained by gas chromatography [8±13]. If, indeed, inhalation anesthetics act to some extent directly on proteins rather than on lipids, a detailed understanding of this speci®c interaction on the molecular level requires the knowledge of the structural and conformational properties of these compounds. The absolute con®gurations of the enantiomers of en¯urane, R(ÿ) and S(‡), are known from the synthesis [14] and the geometric parameters and conformational properties have been reported recently [15]. The absolute con®gurations of the des¯urane and iso¯urane enantiomers were investigated by circular dichroism in the

0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved. PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 1 6 3 - 3

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A. Hermann et al. / Journal of Fluorine Chemistry 101 (2000) 223±231

Fig. 1. Molecular models of the (T, t) and (T, gÿ) conformers of desflurane (X ˆ F) and isoflurane (X ˆ Cl) with atom numbering.

vibrational transitions (VCD) [16,17]. In these studies (‡)des¯urane is assigned to the (R)-con®guration and (‡)iso¯urane to the (S)-con®guration. However, according to single crystal analyses of the pure (‡)-enantiomers, these possess the (S)-con®guration in both cases [18,19]. After publication of the crystal structures, the result derived by the VCD method for des¯urane has been corrected [20]. In the present study we report the geometric structures and conformational properties of des¯urane and iso¯urane as derived from gas electron diffraction (GED) and quantumchemical calculations. Rotation around the C2±O and O±C3 bonds (see Fig. 1 for atom numbering) can in principle lead to nine different conformers. These can be characterized qualitatively by the torsional orientations around these two bonds, using the symbols t, g‡ and gÿ. Capital letters will be used for the rotation around the central C2±O bond, small letters for rotation around the O±C3bond. For a quantitative description of a certain conformation the dihedral angles 1(C1±C2±O±C3) and 2(C2±O± C3±H2) are given. According to HF/6-31G* ab initio calculations which were performed in connection with the VCD investigation, the two lowest energy conformations of both ¯uranes are (T, t) and (T, gÿ) [16,17]. The latter forms are calculated to be about 1 kcal molÿ1 higher in energy, but the interpretation of the VCD spectra resulted in 50 : 50 mixtures of these two conformations. The microwave spectra for des¯urane [21] give no indication about the presence of more than one conformer. 2. Quantumchemical calculations Geometry optimizations for the nine conformers of both compounds were performed with the HF/3-21G* and B3PW91/6-311G(2d) methods [22]. The hybrid method was chosen, because it is less expensive than the MP2 approximation and it was shown by SchaÈfer and co-workers [23] that the B3LYP method which is very similar to the

B3PW91 method, gives slightly better results for compounds which contain ®rst-row atoms. For conformers with trans orientation of the molecular skeleton or the CHF2 group, dihedral angles 1 and 2 smaller and larger than 1808 were used as starting parameters. For all converged structures, frequencies were calculated in order to ensure that this conformation corresponds to a minimum on the energy hypersurface. According to both computational methods, three of the nine possible conformations, i.e. (G‡, gÿ), (Gÿ, t) and (Gÿ, gÿ), do not correspond to stable structures neither in des¯urane nor in iso¯urane. The types and relative energies of the stable conformations depend on the computational method. Additional optimizations were performed with the MP2/6-311G(2d) method for those three conformers, which are predicted by the B3PW91 calculations to be lowest in energy. The cartesian force constants, which were derived with the B3PW91 method were transformed to a symmetry force ®eld, and vibrational amplitudes were calculated with the program ASYM40 [24]. 2.1. Desflurane The stable conformations, their dihedral angles and relative energies derived with the various computational methods, are listed in Table 1. Four stable structures exist according to the HF approximation and ®ve according to the B3PW91 method. In both cases, the lowest energy form possesses a (T, t) structure, i.e. trans orientation of the C±C± O±C skeleton and of the CHF2 group (H2 trans to C2±O bond, see Fig. 1). The conformer which is next in energy according to both methods is (T, gÿ) with the CHF2 group rotated such that H2 eclipses the ¯uorine atom F and F5 eclipses H1. The B3PW91 and MP2 methods predict also a stable (T, g‡) form, in which the two hydrogens H1 and H2 and the two ¯uorines F and F4 eclipse each other. This conformer is calculated to be 2.16 or 2.85 kcal molÿ1 above the ground state structure. The HF approximation does not predict a minimum for this form. Both, HF and B3PW91

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Table 1 Conformational properties of desflurane (dihedral anglesa in degree and relative energies in kcal molÿ1) from theoretical calculations Conformer

(T, t) (T, gÿ) (T, g‡) (G‡, g‡) (G‡, t) (Gÿ, g‡)

HF/3-21G*

B3PW91/6-311G(2d)

MP2/6-311G(2d)

(1, 2)


E

(1, 2)


E

(1, 2)


E

(ÿ150, ÿ179) (178, ÿ86) ± (74, 12) ± (ÿ96, 90)

0.00 1.56 ± 1.95 ± 4.05

(ÿ146, ÿ177) (ÿ168, ÿ55) (ÿ158, 39) (66, 21) (55, 166) ±

0.00 1.11 2.16 2.61 4.44 ±

(ÿ147, ÿ175) (ÿ171, ÿ56) (ÿ160, 44) Not calculated Not calculated Not calculated

0.00 1.48 2.85 Not calculated Not calculated Not calculated

a

1(C1±C2±O±C3), 2(C2±O±C3±H2).

methods, lead to a stable (G‡, g‡) conformation. G‡ implies that the CHF2 group points to the same side of the C1±C2±O plane than the ¯uorine atom F. The (G‡, t) form which is obtained by the B3PW91 method does not correspond to a stable structure according to the HF approximation and vice versa, the (Gÿ, g‡) conformer obtained by the HF approximation does not correspond to a stable structure according to the B3PW91 method. The dihedral angles and relative energies for the three lowest energy forms derived with the B3PW91 and MP2 methods are in close agreement. A similarly good agreement has been observed previously in the case of en¯urane [15]. 2.2. Isoflurane The conformational properties derived by quantumchemical methods are summarized in Table 2. HF and B3PW91 methods predict ®ve stable conformers for this compound, but not all of them are equivalent. The (T, g‡) form is stable only according to the B3PW91 method and the (Gÿ, g‡) form only according to the HF approximation. Again, the two low energy conformers possess (T, t) and (T, gÿ) structures, with the latter one higher in energy by 2.15 kcal molÿ1 (HF) or 0.62 kcal molÿ1 (B3PW91), respectively. The MP2 calculations for the three lowest energy forms lead to dihedral angles and to relative energies which are similar to those derived with the B3PW91 method, except for the dihedral angles of the (T, g‡) conformer.

3. Gas electron diffraction analyses The experimental radial distribution functions (RDF) were calculated by Fourier transformation of the molecular intensities which were multiplied with an arti®cial damping Ê 2. In the GED experiment function exp(ÿgs2), g ˆ 0.0019 A which determines interatomic distances, the (‡)- and (ÿ)enantiomers cannot be distinguished. Preliminary conformational compositions and geometric parameters, which were derived from these RDFs, were re®ned by least squares ®tting of the molecular intensities. The intensities were modi®ed with a diagonal weight matrix. A complete description of the geometries of these compounds requires 30 parameters. Such a large number of geometric parameters, some of which are very similar, such as C±F or C±O bond distances, cannot be derived from GED data. Therefore, several constraints had to be made and the MP2 results were used as quantitative values: (1) The CF3 group in both compounds was constrained to C3v symmetry and the tilt angle between the C3-axis and the C1±O bond direction was set to the calculated value. (2) Cs symmetry was assumed for the CHF2 group and the calculated F±C±F angle was used. (3) Differences between the C±F bond lengths at the various carbon atoms (C1±F, C2±F and C3±F in des¯urane and C1± F and C3±F in iso¯urane) and the difference between the two O±C bond distances (O±C2 and O±C3) were constrained to the theoretical values. (4) The C±H bond lengths were not re®ned and the calculated results were used for all angles involving hydrogen atoms (O±C±H, C±C±H and

Table 2 Conformational properties of isoflurane (dihedral anglesa in degree and relative energies in kcal molÿ1) from theoretical calculations Conformer

(T, t) (T, gÿ) (T, g‡) (G‡, g‡) (G‡, t) (Gÿ, g‡) a

HF/3-21G*

B3PW91/6-311G(2d)

MP2/6-311G(2d)

(1, 2)


E

(1, 2)


E

(1, 2)


E

(ÿ143, 176) (ÿ168, ÿ78) ± (62, 28) (52, 168) (ÿ90, 89)

0.00 2.15 ± 3.41 3.28 2.85

(ÿ138, ÿ179) (ÿ165, ÿ60) (ÿ155, 28) (64, 26) (77, ÿ163) ±

0.00 0.62 2.27 2.45 5.22 ±

(ÿ136, ÿ177) (ÿ167, ÿ61) (ÿ141, 54) Not calculated Not calculated Not calculated

0.00 1.11 3.07 Not calculated Not calculated Not calculated

1(C1±C2±O±C3), 2(C2±O±C3±H2).

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Table 3 Experimental and calculated geometric parameters for the (T, t) conformer of desflurane (angles involving hydrogen atoms are not given) GEDa OÿC2 OÿC3 C1ÿC2 C1ÿF C2ÿF C3ÿF (CÿH)mean C1ÿC2ÿO C2ÿOÿC3 FÿC1ÿF Tilt (CF3) C1ÿC2ÿF OÿC2ÿF OÿC3ÿF FÿC3ÿF 1(C1ÿC2ÿOÿC3) 2(C2ÿOÿC3ÿH2) 3(F1ÿC1ÿC2ÿO) % (T, t)
G0/
E (kcal molÿ1)k

1.375 (9) 1.354d 1.528 (10) 1.336 (3) 1.363e 1.354f 1.100g 105.8 (19) 119.7 (24) 107.4 (5) 1.1g,h 108.3 (7) 110.9i 111.4j 106.3g ÿ146 (4) 176 (11) ÿ177.6g 80 (8) 0.8 (3)

p1 p2 p3

p4 p5 p6 p7

p8 p9

X-rayb,c

MP2/6-311G(2d)c

B3PW91/6-311G(2d)c

HF/3-21G*c

1.387 1.372 1.524 1.327 1.368 1.341 0.942 106.9 116.3 108.4 0.1 107.3 109.4 110.2 106.2 ÿ142.7 ÿ170.0 ÿ169.9 100

1.391 1.370 1.516 1.333 1.360 1.351 1.087 107.0 114.7 108.7 1.1 107.8 110.4 110.9 106.5 ÿ147.2 ÿ175.1 ÿ177.6 92l 1.48

1.390 1.370 1.529 1.334 1.359 1.350 1.090 107.6 116.0 108.6 1.3 108.1 110.3 111.1 106.5 ÿ145.9 ÿ176.6 ÿ177.4 86l 1.11

1.402 1.379 1.499 1.343 1.371 1.360 1.069 105.8 119.2 108.6 1.9 108.4 111.1 109.6 106.3 ÿ150.2 ÿ178.6 180.0 93l 1.56

Ê and degree, error limits are 3 values. For atom numbering see Fig. 1. ra values in A Refs. [18,19]; the geometric parameters are not included in this publication. The cartesian coordinates without standard deviations have been provided by the authors. c Mean values are given for parameters which are not unique. d Ê. (OÿC2)ÿ(OÿC3) ˆ 0.021 A e Ê. (C2ÿF)ÿ(C1ÿF) ˆ 0.027 A f (C3ÿF)ÿ(C1ÿF) ˆ 0.018. g Not refined. h Tilt angle between C3-axis and C1ÿC2 bond, away from F. i (OÿC2ÿF)ÿ(C1ÿC2ÿF) ˆ 2.68. j (OÿC3ÿF)ÿ(C1ÿC2ÿF) ˆ 3.18. k
G0 ˆ G0 (T, gÿ)ÿG0(T, t). l Estimated from
E values. a

b

X±C±H). (5) Differences between similar angles were ®xed to calculated values (see Tables 3 and 5). (6) The torsional angle for the CF3 group, 3(F1±C1±C2±O), was constrained to the theoretical result. (7) Vibrational amplitudes which either caused high correlations or which were poorly determined by the GED experiment were set to the calculated values. (8) The geometric parameters of the minor conformer ((T, gÿ) in both cases) were coupled to those of the main conformer using the respective theoretical differences. Calculated vibrational amplitudes were used for the minor conformer. Most of these constraints are evident from Tables 3 and 5. 3.1. Desflurane Comparison of the experimental RDF (Fig. 2) with calculated curves shows, that the (T, t) conformer is the predominant form. The ®t of the experimental intensities improves slightly, if about 20% of the (T, gÿ) conformer are added. Contributions of the (T, g‡) form were not considered, since this structure does either not correspond to a minimum on the energy surface (HF) or possesses a considerably higher energy according to B3PW91 and MP2

calculations (see Table 1). Structures with gauche conformation of the C±C±O±C skeleton (G‡ or Gÿ) can be excluded, since their RDFs differ strongly from the experimental curve. With the above constraints nine geometric parameters (p) and four vibrational amplitudes (l) were re®ned simultaneously. The following correlation coef®cients had values larger than j0.7j: p1/p2 ˆ ÿ0.89; p1/ p6 ˆ 0.86; p2/p6 ˆ ÿ0.80; p2/p7 ˆ ÿ0.77; p6/p7 ˆ 0.71. Least squares re®nements were performed with different conformational compositions and the quality of the ®t was judged by the agreement factor R. The best ®t was obtained for 80(8)% (T, t) and 20(8)% (T, gÿ) conformers. The experimental uncertainty was derived by Hamilton's test [25] at the 1% signi®cance level. The ®nal results are summarized in Table 3 (geometric parameters) and Table 4 (vibrational amplitudes). 3.2. Isoflurane The comparison between experimental and calculated RDFs (Fig. 3) demonstrates that, again, the (T, t) form is predominant. The least squares analyses for the compound were performed analogous to those for des¯urane. Ten

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227

Fig. 2. Calculated and experimental radial distribution functions for desflurane and difference curve for the mixture. Important interatomic distances for the predominant conformer (T, t) are given by vertical bars. Table 4 Interatomic distances and vibrational amplitudes for desflurane without non-bonded distances involving hydrogensa

C±H C±F C±O C±C F

Xd C

Ye F

Ye F

F5 F

C3 F1

O F

F2 C1

C3 F

Zf C

F F

Zf F

F

Distance

Amplitudes GED

Amplitudes B3PW91/6-311G(2d)b

1.09 1.34±1.36 1.35±1.38 1.53 2.15±2.24 2.26±2.39 2.71±2.84 3.07 3.13 3.50 3.52 3.53 3.65±3.81 4.06±4.29 4.63±4.76 4.81±5.19

0.076c 0.045c 0.047c 0.050c 0.057c 0.060c 0.111(13) 0.154(44) 0.154(44) 0.066(10) 0.066(10) 0.095c 0.247(56) 0.134c 0.192c 0.163c

0.076 0.045 0.047 0.050 0.057 0.060 0.135 0.245 0.136 0.064 0.062 0.095 0.250 0.134 0.192 0.163

l1 l2 l2 l3 l3 l4

Ê ; error limits are 3 values. For atom numbering see Fig. 1. Values in A Mean values are given for amplitudes which are not unique. c Not refined. d X ˆ F or O. e Y ˆ F, O or C. f Z ˆ F or C. a

b

geometric parameters and seven vibrational amplitudes were re®ned simultaneously and the following correlation coef®cients had values larger than j0.7j: p1/p2 ˆ ÿ0.87; p1/ p7 ˆ 0.88; p1/l1 ˆ 0.76; p2/p3 ˆ 0.70; p2/p6 ˆ ÿ0.83; p2/ p7 ˆ ÿ0.86; p2/l1 ˆ ÿ0.88; p3/p7 ˆ ÿ0.75; p6/p7 ˆ 0.70;

p6/l1 ˆ 0.73; p7/l1 ˆ 0.76. The best ®t of the experimental intensities was obtained for 83(11)% (T, t) and 17(11)% (T, gÿ) conformers. The ®nal results are collected in Table 5 (geometric parameters) and Table 6 (vibrational amplitudes).

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Fig. 3. Calculated and experimental radial distribution functions for isoflurane and difference curve for the mixture. Important interatomic distances for the predominant conformer (T, t) are given by vertical bars. Table 5 Experimental and calculated geometric parameters for the (T, t) conformer of isoflurane (angles involving hydrogen atoms are not given) GEDa OÿC2 OÿC3 C1ÿC2 C1ÿF C3ÿF C2ÿCl (CÿH)mean C1ÿC2ÿO C2ÿOÿC3 FÿC1ÿF Tilt (CF3) C1ÿC2ÿCl OÿC2ÿCl OÿC3ÿF FÿC3ÿF 1(C1ÿC2ÿOÿC3) 2(C2ÿOÿC3ÿH2) 3(F1ÿC1ÿC2ÿO) % (T, t)
G0/
E (kcal molÿ1)j

1.401 (15) 1.372d 1.536 (11) 1.332 (3) 1.350e 1.773 (8) 1.100f 108.5 (19) 113.4 (28) 107.6 (7) 1.6f,g 109.9 (7) 111.4h 111.8i 106.4f ÿ136 (5) 170 (9) ÿ177.2f 83 (11) 1.0 (4)

p1 p2 p3 p4 p5 p6 p7 p8

p9 p10

X-rayb,c

MP2/6-311G(2d)c

B3PW91/6-311G(2d)c

HF/3-21G*c

1.402 1.372 1.519 1.334 1.350 1.772 0.988 106.0 116.2 108.0 1.5 109.7 110.3 110.2 106.0 ÿ133.5 179.9 ÿ174.9 100

1.399 1.370 1.518 1.333 1.351 1.778 1.086 106.7 114.4 108.5 1.6 110.0 111.5 110.9 106.4 ÿ135.5 ÿ177.0 179.9 86k 1.10

1.393 1.370 1.531 1.333 1.349 1.787 1.088 107.4 116.1 108.4 1.6 109.8 111.7 111.2 106.5 ÿ137.8 ÿ178.5 179.7 74k 0.62

1.419 1.377 1.507 1.343 1.360 1.766 1.069 104.8 118.7 108.5 1.2 110.8 111.0 110.0 106.2 ÿ143.2 175.9 179.0 97k 2.15

Ê and degree, error limits are 3 values. For atom numbering see Fig. 1. ra values in A Refs. [18,19]; the geometric parameters are not included in this publication. The cartesian coordinates without standard deviations have been provided by the authors. c Mean values are given for parameters which are not unique. d Ê. (OÿC2)ÿ(OÿC3) ˆ 0.029 A e Ê. (C3ÿF)ÿ(C1ÿF) ˆ 0.018 A f Not refined. g Tilt angle between C3-axis and C1ÿC2 bond, away from chlorine atom. h (OÿC2ÿC1)ÿ(C1ÿC2ÿC1) ˆ 1.58. i (OÿC3ÿF)ÿ(C2ÿC1ÿF)mean ˆ 0.58; (C2±C1±F)mean ˆ 111.3(7)8 (derived from the F±C1±F angle). j
G0 ˆ G0 (T, gÿ)ÿG0(T, t). k Estimated values from
E values. a

b

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229

Table 6 Interatomic distances and vibrational amplitudes for isoflurane without non-bonded distances involving hydrogensa

C±H C±F C±O C±C C±Cl F

Xd C

Ye O

Cl C1

Cl F

Zf F

Cl F5

Cl C1

C3 F

F C

F C3

Cl O

F1 Cl

F2 Cl

F4 C

F C3

F1 F

F F

F

Distance

Amplitude GED

Amplitude B3PW91/6-311G(2d)b

1.10 1.33±1.35 1.37±1.40 1.54 1.77 2.14±2.25 2.32±2.39 2.63 2.71 2.65±2.83 2.96±3.09 3.31 3.51 3.41 3.63 3.45 3.55 3.91 4.07 4.11±4.29 4.57 4.52±4.69 4.91±5.15

0.075c 0.049(4) l1 0.048c 0.050c 0.057(9) l2 0.051(5) l3 0.065c 0.073(12) l4 0.073(12) l4 0.128c 0.110(18) l5 0.232c 0.099c 0.349c 0.202c 0.126c 0.082(14) l6 0.082(14) l6 0.189c 0.140c 0.221(41) l7 0.221(41) l7 0.158c

0.075 0.046 0.048 0.050 0.053 0.057 0.065 0.068 0.071 0.128 0.134 0.232 0.099 0.349 0.202 0.126 0.064 0.066 0.189 0.140 0.106 0.226 0.158

Ê ; error limits are 3 values. For atom numbering see Fig. 1. Values in A Mean values are given for amplitudes which are not unique. c Not refined. d X ˆ F or O. e Y ˆ F, O or C. f Z ˆ F or C. a

b

4. Discussion The GED intensities for both inhalation anesthetics, des¯urane and iso¯urane, are reproduced very well with mixtures of two conformers. Both forms possess a trans con®guration of the C±C±O±C skeleton and differ in the orientation of the CHF2 group. In the predominant (T, t) form, the hydrogen atom of the CHF2 group is oriented trans to the C2±O bond and one C±F bond of this group (C3±F5) eclipses the C2±X bond. In the less stable (T, gÿ) conformer the C±H bond of the CHF2 group eclipses the C2±X bond. Intuitively, one would expect that this latter structure is favored for steric reasons. The experimental result, i.e. higher stability of the (T, t) conformer, can be rationalized by an anomeric effect. Strong hyperconjugative lp(O) !*(C±F) interactions between the rabbit-ear-shaped oxygen lone pairs and the two C3±F bonds, which are trans to the lone pairs, stabilize this orientation of the CHF2 group. This orbital interaction shows up also in the calculated O±C bond lengths. The O±C3 bond is considerably shorter than the O±C2 bond, which is a typical consequence of such interactions [26]. The repulsion between the eclipsing C3± F5 and C2±X bonds leads to torsion around the C2±O bond and the C±C±O±C skeleton deviates from the ideal trans

orientation by 34(4)8 in des¯urane and 44(5)8 in iso¯urane. No such strong torsion of the C±C±O±C skeleton occurs according to the theoretical calculations in the (T, gÿ) conformers (see Tables 1 and 2). In contrast to des¯urane and iso¯urane, all four lowest energy conformers of en¯urane, CHFCl±CF2±O±CHF2, possess gauche orientations (g‡ or gÿ) of the CHF2 group. In this ether the oxygen lone pairs are predominantly engaged in anomeric interactions with the two C2±F bonds and do not stabilize trans orientation of the CHF2 groups [15]. In the solid state only the (T, t) conformer, which is the predominant form in the gas phase, is present and considering systematic differences between gas phase and crystal structures, the geometric parameters in both phases are nearly identical (see Tables 3 and 5). Even the dihedral angles, which are most easily distorted by intermolecular interactions in the crystal are equal within the experimental uncertainties. The strong distortion of the C±C±O±C skeletons from the ideal trans con®guration occurs also in the solid state. The experimental bond lengths and bond angles are reproduced by the MP2 and B3PW91 methods better Ê and  28, and the calculated dihedral angles than  0.02 A agree with the experimental values within their uncertainties.

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Fig. 4. Experimental (dots) and calculated (full line) molecular intensities and differences for desflurane.

5. Experimental Samples of des¯urane and iso¯urane which were puri®ed by gas chromatography were provided by Prof. V. Schurig. Racemic mixtures were used in the GED experiment. The scattering intensities were recorded with a Gasdiffraktograph KD-G2 [27] at 25 and 50 cm nozzle-to-plate distances and with an accelerating voltage of approximately 60 kV. The sample reservoirs were kept at ÿ548C (des¯urane) and ÿ308C (iso¯urane) and the inlet system and nozzle were at room temperature. The photographic plates were analyzed by the usual methods [28]. For des¯urane averaged moleÊ ÿ1 and cular intensities in the scattering ranges s of 2±18 A ÿ1 Ê are presented in Fig. 4. The intensities for iso8±35 A ¯urane are similar and are not shown. Acknowledgements We thank Prof. V. Schurig, Institut fuÈr Organische Chemie, UniversitaÈt TuÈbingen, for highly pure samples of des¯urane and iso¯urane. This work was supported by the Deutsche Forschungsgemeinschaft.

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