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Direct Determination of Absolute Molecular Stereochemistry in Gas Phase by Coulomb Explosion Imaging

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Science  06 Sep 2013:
Vol. 341, Issue 6150, pp. 1096-1100
DOI: 10.1126/science.1240362

Absolute Images

Molecules are held together by a balance of charge between negative electrons and positive nuclei. When multiple electrons are expelled by laser irradiation, the remaining, mutually repulsive nuclei fly apart in a Coulomb explosion. Instead of traditional x-ray diffraction methods that require crystalline samples, Pitzer et al. (p. 1096) show that by tracking the fragment trajectories from laser-induced Coulomb explosions of relatively simple gas phase molecules, they can determine the absolute stereochemical configuration of enantiomers (mirror-image isomers).

Abstract

Bijvoet’s method, which makes use of anomalous x-ray diffraction or dispersion, is the standard means of directly determining the absolute (stereochemical) configuration of molecules, but it requires crystalline samples and often proves challenging in structures exclusively comprising light atoms. Herein, we demonstrate a mass spectrometry approach that directly images the absolute configuration of individual molecules in the gas phase by cold target recoil ion momentum spectroscopy after laser ionization–induced Coulomb explosion. This technique is applied to the prototypical chiral molecule bromochlorofluoromethane and the isotopically chiral methane derivative bromodichloromethane.

A molecule that cannot be superposed with its mirror image by pure translation and rotation is termed chiral, with the nonidentical mirror images called enantiomers. If it were not for the predicted tiny contributions due to parity-violating weak interactions (1), which are currently searched for in high-precision molecular physics experiments on chiral molecules (2, 3), the energy levels of both enantiomers would be equal. The enantiomers can be distinguished by their interaction with other chiral objects; for instance, left- or right-handed molecules and left- or right-handed circularly polarized photons. The interaction with polarized light led Louis Pasteur, more than one and a half centuries ago, to the discovery of molecular chirality by observing optical rotation in aqueous solutions of manually separated enantiomorphic crystals from double salts of tartaric acid (4). van’t Hoff (5) and Le Bel (6) independently ascribed Pasteur’s observation to an underlying three-dimensional (3D) structure of molecules, which can result in two nonidentical mirror image structures.

Enantiomers can be distinguished comparatively easily by their chiroptical signals, such as optical rotation, that are of (nearly, due to parity violation) equal magnitude but opposite sign. This is manifested by the frequently used phenomenological (+/−) terminology. The microscopic structure, on the other hand, is classified with the systematic R/S or P/M stereodescriptors (7). However, assigning the absolute (stereochemical) configuration—that is, establishing which of the two possible mirror image spatial structural models gives rise to optical rotation with positive or negative sign—still poses a challenge.

The standard approach to directly determining absolute configuration is Bijvoet’s method (8) of 1951, but in 2001 the technique of Coulomb explosion imaging (CEI) (9) was shown to be a potential means to determine the handedness of chiral molecules (10). Before 1951, chemical or biochemical conversions were used that relate compounds of unknown configuration to others with known configuration, a method that is still applied today. For this purpose, Fischer (11) had arbitrarily assigned a given 3D structural model (denoted as the d form) of saccharic acid to the compound that is weakly (+) rotating in aqueous solution and its mirror image (l form) to the (−) rotating counterpart. Subsequently [see also (12) for the historical development], catalogs of the d and l series were established, the components of which were chemically related, either directly to d- or l-saccharic acid or to other chiral molecules already filed in the catalog. Bijvoet finally confirmed (8) Fischer’s arbitrary choice by studying the sodium rubidium double salt of tartaric acid with anomalous x-ray diffraction. Heavy elemental scatterers induce a pronounced phase and intensity shift when irradiated with x-rays near their absorption edge, which allows the determination of absolute configuration. Although typically quite conclusive, Bijvoet’s method is limited by requiring crystalline samples. A promising new approach using x-ray diffraction has recently been presented by Inokuma et al. (13). They diffused a dissolved chiral compound into a crystalline host framework containing heavy atoms. As a result of the interaction, the framework’s symmetry changed to a chiral space group, thus allowing the application of anomalous x-ray diffraction. Nonetheless, conventional crystallographic challenges and flaws—such as misassigned atoms, symmetry problems, and guest disorder—persist and, hence, require support from mass spectrometry or nuclear magnetic resonance (NMR) (13).

The lack of versatile direct approaches has led to the active exploration of indirect physicochemical approaches based on optical rotation and circular dichroism. Indirect methods rely on quantum chemical calculations or empirical rules to interpret the experimental data. Alternatively, liquid chromatography with an enantioselective stationary phase is a widespread method for chiral discrimination. Its drawback for assignment lies in the need for a suitable analog with known stereochemical configuration. Recent activities focus on NMR spectroscopy, either by seeking to turn NMR directly into a chiroptical method (14) or by exploring possibilities to use residual dipolar couplings in chiral nonracemic alignment media (15). Also, photoelectron circular dichroism has received renewed interest (16), and promising three-wave mixing strategies to obtain chiroptical signals in microwave spectroscopy have been reported recently (17).

Herein, we focus on direct determination of absolute configuration in the gas phase by a molecular imaging technique that displays the 3D structure of individual chiral molecules on a detector and thereby permits assignment of absolute configuration on a single-molecule basis. As an alternative to displaying the full structure, one can also 3D-align the molecule and image decisive fragments (18). Kitamura et al. used a similar approach to ours, but with highly charged argon atoms from an ion source as ionizing agents, to detect dynamical chirality in perdeuterated methane (10) and pointed out the possibility of detecting molecular handedness. In 2008, Gagnon et al. employed a related variant to study the structure of achiral dichloromethane (CH2Cl2) (19) by CEI. For the direct assignment of the absolute configuration, high count rates for fourfold or higher fragmentation coincidence events are required. The laser systems commercially available in 2008 were unable to produce such rates. To overcome these technical limitations for stereochemical assignments, we combine the latest high-power femtosecond lasers [with repetition rates that are 10 to 100 times higher (100 kHz)] with improved fast hexanode delay-line detectors to surmount otherwise prohibitively long data acquisition time. In addition, we employ high-performance data recording techniques, together with an offline analysis protocol, to cope with the increasing complexity emerging for polyatomic molecules (20). These improvements enable the use of CEI to determine the absolute configuration of the prototypical chiral compound bromochlorofluoromethane (CHBrClF) and isotopically chiral methane derivatives in natural abundance such as CHBr37Cl35Cl.

CHBrCl2 is commercially available and was used without further purification, as impurities are easily discarded in the analysis step of coincidence experiments. Racemic CHBrClF was synthesized as described in (21) by reacting CHBr2Cl with HgF2. The spectrometer system employed was described in detail in (22). For the present study, the setup was augmented by an assembly of cold traps to recycle the volatile sample compounds.

The approach for direct determination of absolute configuration employs the well-established cold target recoil ion momentum spectroscopy (COLTRIMS), as depicted in fig. S1 in the supplementary materials. A supersonic gas jet of chiral molecules (y axis in the laboratory system) crosses a high-power femtosecond laser (laboratory x axis) to induce multiple ionization and the resulting Coulomb explosion. Charged fragments are projected by a static electric field along the laboratory z axis onto a position- and time-sensitive multichannel plate detector (MCP) with hexagonal delay-line readout (23), where all fragments are detected in coincidence (fig. S2). From the impact position on the detector (x, y) and the known distance between the ionization zone and MCP, as well as the measured time-of-flight, the velocities of all cations (formed in coincidence) can be derived. By assigning masses and charges to the various fragments, corresponding linear momenta of all detected particles can be obtained. In molecular multiple ionization and fragmentation, the momenta of photons and electrons are usually negligible compared with the momenta of the Coulomb exploding ionic fragments. Hence, in a cold molecular beam, the sum of the ion momentum vectors must be close to zero because of momentum conservation. The mass assignment can, therefore, be confirmed by checking this computed total momentum of all ions. Assignment of absolute configuration is, in principle, already possible, once four charged fragments (e.g., Br+, Cl+, F+, and CH+ for CHBrClF) are detected in coincidence. Signatures of those breakups could be found in the data and used for assignment (results not reported here). Herein, however, we focus on the complete fragmentation into five singly charged ions, because analysis and interpretation are more straightforward. Additionally, the background can be suppressed quite efficiently. Mass resolution in COLTRIMS is sufficient to distinguish various isotopes of bromine and chlorine in natural abundance, thereby even allowing stereochemical characterization of isotopically chiral molecules. Further details of the measurement method can be found in the supplementary materials (24).

Figure 1 shows the sum of all ion momenta in the case where five fragments of CHBrClF are measured in coincidence. The peak at zero total momentum shows events with the correct mass assignment: 79Br+, 35Cl+, 19F+, 12C+, and 1H+. These events were used for the determination of the absolute configuration. The peaks at lower momentum in the z direction are contributions from other isotopologues.

Fig. 1 Sum of linear momentum (p) components in fivefold ionization of CHBrClF, demonstrating the excellent resolution achieved in this experiment.

Those events detected with px and pz close to zero correspond to a fragment assignment to 79Br+, 35Cl+, 19F+, 12C+, and 1H+ (denoted in bold). Fragments of other isotopologues can also be identified but are not used in the present analysis. The atomic unit for momentum is defined as ħa0−1 ≈ 1.992 ·10−24 kg m s−1 (ħ, Planck’s constant h divided by 2π; a0, Bohr radius).

Figure 2 demonstrates the capability to distinguish enantiomers in our racemic sample. For this purpose, an angle θ is defined, indicating if the momenta of bromine, chlorine, and fluorine form a right- or left-handed coordinate system. As distinct peaks are obtained in the histogram, almost all events can be assigned clearly to one enantiomer or the other. This shows the robustness of our method against the laser pulse length: Being ~40-fs long, our pulses are not short enough to consider the hydrogen frozen during multiple ionization. The clear separation of enantiomers in the histogram indicates, however, that the motion of hydrogen during the laser pulse does not alter bond angles to an extent that would prevent identification of enantiomers. These results also show that reconstruction of the exact geometric structure is not necessary for the determination of absolute configuration. Classical molecular dynamics simulations confirm that the enantiomers are mapped unambiguously onto their momentum space analogs that are presented here.

Fig. 2 Chiral discrimination for CHBrClF.

The histogram for the cosine of the chirality angle θ shows the clear separation between enantiomers in our racemic sample of CHBrClF. As is illustrated in the insets, the angle is defined via Embedded Image. The peak at negative values of cos(θ) corresponds to the S enantiomer, whereas the one at positive values corresponds to the R enantiomer.

Figure 3 overlays measured linear momenta on a rigid structural model of neutral CHBrClF, with the linear momentum of carbon fixed along the x axis, the momentum sum of chlorine and bromine defining the xy plane, and all other linear momenta being oriented relative to these. For better visibility, momenta are normalized with respect to the carbon momentum. The momentum of hydrogen, being very small due to the low mass, is expanded by a factor of 2 in this figure. It is evident that the configuration of the two enantiomers is directly imaged on the detector. As a racemic mixture of CHBrClF was employed, an equal ratio for the S and R configurations was obtained within the statistical uncertainty [329 and 302 events for S and R, respectively, with |cos(θ)| > 0.6 in each case]. At first sight, one might be surprised that the carbon ion is detected in the same direction as the proton. This is due to the fact that the position of the center of mass is conserved; thus, H+ and C+, as the lightest two ions of the system, are repelled from the slowly moving heavier ions, as has been confirmed with the help of molecular dynamics simulations.

Fig. 3 Linear momenta in fivefold fragmentation of CHBrClF enantiomers.

Measured linear momenta in the fivefold fragmentation of (left) (S)-CHBrClF [cos(θ) < −0.6] and (right) (R)-CHBrClF [cos(θ) > 0.6] are indicated by the following color codes: C, gray arrow; H, white; F, green; Cl, yellow; Br, red. Momenta are rotated to the molecular frame of reference, defined by the momentum of the carbon ion and the momentum sum of the bromine and chlorine ions. All momenta are normalized with respect to the carbon momentum. For better visibility, hydrogen momenta are expanded by a factor of 2. Whereas the substituents are expelled during the Coulomb explosion into the directions expected from the classical structural model, the central atom C is also accelerated away from the center of mass and ejected in a similar direction as hydrogen. An animated version of the figure can be found in the supplementary materials (movies S1 and S2).

For CHBrClF, the direct assignment of absolute configuration works unequivocally in the majority of fivefold coincidence events because of the comparatively large mass difference between the ions. The situation is considerably more challenging for the case of isotopically chiral systems. In the case of CHBrCl2 (Fig. 4), not all fivefold fragmentation events allow an unambiguous assignment of the isotope masses to each fragment; hence, no determination of absolute configuration is possible for such events. However, a subset of events that permit a conclusive assignment can be selected by a procedure detailed in the supplementary materials (figs. S3 and S4 and supplementary text). Again, as a racemic sample was used, an almost 50:50 ratio of S:R is detected [282:273 events (not corrected for outliers) with |cos(θ)| > 0.6] (see fig. S5).

Fig. 4 Measured linear momenta in the fivefold fragmentation of (S)-CH79Br37Cl35Cl (left) and (R)-CH79Br37Cl35Cl (right).

The color codes used correspond to: C, gray arrow; H, white; 35Cl, green; 37Cl, yellow; Br, red. Momenta are rotated to the molecular frame of reference, defined by the momentum of the carbon ion and the momentum sum of 79Br and 35Cl, and normalized with respect to the momentum of the carbon ion. Again, the hydrogen momentum is scaled by a factor of 2. A histogram and an animated version of the figure can be found in the supplementary materials (fig. S5 and movies S3 and S4). For a wider angle of vision, see fig. S7, where a few outlier signals also become clearly visible.

The technique still has several limitations: Volatile molecules and a large amount of substance are required due to the molecular beam source. Comparatively simple, rigid structures were studied. In the case of more complicated molecules, the kinematic properties of the fragments may not directly illustrate the geometric structure, making the identification of the absolute configuration less straightforward. In this case, geometrical reconstruction or comparison with simple molecular dynamics simulations might become necessary, especially when several stereogenic elements are present. On a technical level, the probability of multifragment detection decreases dramatically with the increasing amount of fragments, as both the fragmentation yield and the detection efficiency diminish exponentially with the increasing number of fragments.

Stepwise fragmentation is a limitation as well. Additionally, when multiple ionization is slow compared with vibrational time scales, assignment can be hampered or even completely prohibited. For this purpose, faster ionization schemes with shorter laser pulses and higher laser intensity are required.

The present imaging approach allows for determination of absolute configuration of gas phase molecules on a per-molecule basis. Apart from a rigid structural model, it does not require theoretical input. Besides structure determination, as demonstrated herein, the coincidence technique creates opportunities to study chirality in single molecules.

Supplementary Materials

www.sciencemag.org/cgi/content/full/341/6150/1096/DC1

Supplementary Text

Figs. S1 to S7

Reference (25)

Movies S1 to S5

Databases S1 and S2

References and Notes

  1. Further details on the measurement principle, with six additional figures and four movies, are available in the supplementary materials on Science Online.
  2. Acknowledgments: This paper is dedicated to Helmut Schwarz on the occasion of his 70th birthday. We thank D. Avnir, T. Isaev, and F. Lichtenthaler for discussion; M. Meckel for help with some figures; and A. Czasch for support concerning data analysis. This work was supported by the State Initiative for the Development of Scientific and Economic Excellence (LOEWE) in the LOEWE-Focus ELCH. The momentum data used to draw the figures are provided in the supplementary materials. Raw data are archived at the University of Frankfurt and are available upon request.

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