GB2554430A

GB2554430A - Apparatus and method for detecting molecular chirality

Info

Publication number: GB2554430A
Application number: GB1616382.6A
Authority: GB
Inventors: Greenwood Jason
Original assignee: Queens University of Belfast
Current assignee: Queens University of Belfast
Priority date: 2016-09-27
Filing date: 2016-09-27
Publication date: 2018-04-04
Also published as: WO2018060120A1; GB201616382D0

Abstract

Apparatus 20 for detecting chirality of molecules in a sample comprises an evacuated interaction zone 22 for containing at least one molecule, a radiation source 24 for generating circularly polarised ionising radiation 112 in a forward direction along a propagation axis P that extends through the interaction zone, a magnetic field generator for generating a magnetic field in said interaction zone, directed parallel with the propagation axis, a forward particle detector 40 to detect forward travelling photoelectrons 114F generated by the ionising radiation, and a backward particle detector 42 to detect backward travelling photoelectrons 114B generated by the ionising radiation. The magnetic field confines photoelectrons in the device volume. Deflector electrodes 44, 46 deflect electrons to the detectors. Ion extraction means 56 may direct ions to a particle detector 60. The apparatus can detect both molecular chirality from the forward and backward detector outputs, and chemical identity of a molecule from the particle detector.

Description

(71) Applicant(s):

The Queen's University of Belfast (Incorporated in the United Kingdom) University Road, BELFAST, Northern Ireland, BT7 1NN, United Kingdom (72) Inventor(s):

Jason Greenwood (74) Agent and/or Address for Service:

FRKelly

Mount Charles, BELFAST, Northern Ireland, BT7 1NZ, United Kingdom (51) INT CL:

G01N 21/19 (2006.01) G01N 21/21 (2006.01)

H01J 47/02 (2006.01) H01J 49/16 (2006.01) (56) Documents Cited:

WO 2010/031387 A1

BEAULIEU, S.; Universality of photoelectron circular dichroism in the photoionization of chiral molecules; New Journal of Physics, 2016,18,102002.

NAHON, L.; Determination of accurate electron chiral asymmetries in fenchone and camphor in the VUV range: sensitivity to isomerism and enantiomeric purity; Phys. Chem. Chem. Phys., 2016,18,12696 (58) Field of Search:

INT CL G01N, H01J

Other: WPI, EPODOC, INSPEC (54) Title of the Invention: Apparatus and method for detecting molecular chirality Abstract Title: Detecting molecular chirality (57) Apparatus 20 for detecting chirality of molecules in a sample comprises an evacuated interaction zone 22 for containing at least one molecule, a radiation source 24 for generating circularly polarised ionising radiation 112 in a forward direction along a propagation axis P that extends through the interaction zone, a magnetic field generator for generating a magnetic field in said interaction zone, directed parallel with the propagation axis, a forward particle detector 40 to detect forward travelling photoelectrons 114F generated by the ionising radiation, and a backward particle detector 42 to detect backward travelling photoelectrons 114B generated by the ionising radiation. The magnetic field confines photoelectrons in the device volume. Deflector electrodes 44, 46 deflect electrons to the detectors. Ion extraction means 56 may direct ions to a particle detector 60. The apparatus can detect both molecular chirality from the forward and backward detector outputs, and chemical identity of a molecule from the particle detector.

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Apparatus and Method for Detecting Molecular Chirality

Field of the Invention

The present invention relates to the detection of molecular chirality by discrimination of chiral enantiomers. The invention relates particularly to determining the chirality of chiral molecules using photoelectron circular dichroism (PECD).

Background to the Invention

A molecule that is geometrically distinguishable from its mirror image, i.e. cannot be superposed on its mirror image by rotation alone, is said to be chiral. The molecule and its mirror image are called enantiomers (or optical isomers) and may be designated as the “right-handed” or “left-handed” enantiomer.

Many pharmaceutical compounds comprise chiral molecules and, since molecular binding to biological structures can be dependent on chirality, the response of an organism to a molecule may depend on the chirality of the molecule. The building blocks of life, e.g. sugars and amino acids, are inherently chiral in that they comprise predominantly left-handed or right-handed enantiomers.

Some drugs may be provided as a racemic mixture (having equal numbers of left and right handed enantiomers of a chiral molecule) but others may be provided as enantiopure (i.e. comprising only the left or right handed enantiomer of the molecule). Chiral drugs often have dramatically different pharmacological effects depending on their handedness (for instance thalidomide), meaning that it can be critical for the enantiomeric purity of such drugs to be verified. Determining the chirality of molecules is therefore an important aspect of chemical analysis.

Discriminating between chiral enantiomers is very difficult as they have almost identical physical properties. Conventional techniques make use of small differences in their optical polarisation properties or their physical separation via chromatography, diffusion or electrophoresis, in order to assess the purity of samples. As these techniques usually require substantial sample quantities, prior chemical purification or long time periods for analysis, they are slow and lack sensitivity.

It has recently been discovered that if a chiral module is irradiated with a pulse of circularly polarised light that has a sufficiently short wavelength and/or is sufficiently intense to ionize the molecule, then the emitted photoelectron is more likely to be emitted in a forward direction or a backward direction depending on the chirality of the molecule. Detecting this difference, or asymmetry, in photoelectron distribution is an indication that the molecule is chiral (there is no asymmetry for an achiral molecule). Moreover, since the asymmetry reverses when the opposite circular polarisation is used (i.e. from left-to-right circular polarisation to right-to-left circular polarisation or vice versa) or the opposite enantiomer is irradiated, measurement of the asymmetry in principle allows the proportion of the, or each, enantiomer in a sample to be determined. The asymmetry in the angular distribution of photoelectrons emitted from photoionization of enantiomers is known as photoelectron circular dichroism (PECD).

PECD has been studied using a device called a velocity map imager (VMI). In a VMI an electric field is used to project the photoelectrons onto a position sensitive detector. The resulting data can be processed to determine the angular and energy distribution of the emitted photoelectrons. A VMI provides very detailed information in relation to PECD but is relatively complex and expensive.

It would be desirable to provide an apparatus for discriminating chiral enantiomers that mitigates the problems outlined above.

Summary of the Invention

A first aspect of the invention provides an apparatus for detecting molecular chirality, the apparatus comprising: an evacuated interaction zone for containing at least one molecule of a target sample; a electromagnetic radiation source configured to generate circularly polarised ionizing radiation in a forward direction along a propagation axis that extends though said interaction zone; a forward particle detector having a receiving part located forwardly of said interaction zone; a backward particle detector having a receiving part located backwardly of said interaction zone; and a magnetic field generator configured to generate a magnetic field in said interaction zone, said magnetic field extending substantially parallel with said propagation axis.

The interaction zone typically has a forward particle exit and a backward particle exit, said receiving part of said forward particle detector being positioned to receive electrons that emerge in use from said forward particle exit, and said receiving part of said backward particle detector being positioned to receive electrons that emerge in use from said backward particle exit.

The apparatus may include focusing means for focusing said ionizing radiation on an ionizing location in said interaction zone.

Preferably, said interaction zone has a forward particle exit, the apparatus further including a forward electron deflection device located between said interaction zone and said forward particle detector, said forward electron deflection device being operable to deflect electrons that emerge in use from said forward particle exit away from said propagation axis.

Preferably, said interaction zone has a forward particle exit, the apparatus further including a forward electron deflection device located between said interaction zone and said forward particle detector, and wherein said forward electron deflection device is operable to deflect electrons that emerge in use from said forward particle exit to said receiving part of said forward particle detector.

Said forward deflection device typically comprises at least two electrodes, each electrode preferably comprising a plate, that are spaced apart in a direction perpendicular to said propagation axis and positioned such that, in use, said electrons from said forward particle exit, and typically also said ionizing radiation, pass between said at least two electrodes.

In typical embodiments said interaction zone has a backward particle exit, the apparatus further including a backward electron deflection device located between said interaction zone and said backward particle detector, said backward electron deflection device being operable to deflect electrons that emerge in use from said backward particle exit away from said propagation axis.

Typically, said interaction zone has a backward particle exit, the apparatus further including a backward electron deflection device located between said interaction zone and said backward particle detector, and wherein said backward electron deflection device is operable to deflect electrons that emerge in use from said backward particle exit to said receiving part of said backward particle detector.

Preferably, said backward deflection device comprises at least two electrodes, each electrode preferably comprising a plate, that are spaced apart in a direction perpendicular to said propagation axis and positioned such that, in use, said electrons from said backward particle exit, and typically also said ionizing radiation, pass between said at least two electrodes.

Preferably, the respective receiving part of at least one of and preferably each of said forward and backward particle detector are spaced apart from said propagation axis.

Preferred embodiments include forward electron accelerating device located between said interaction zone and said forward particle detector, preferably at said forward particle exit, and wherein said forward electron acceleration device is operable to accelerate electrons that emerge in use from said forward particle exit towards said receiving part of said forward particle detector.

Preferred embodiments include a backward electron accelerating device located between said interaction zone and said backward particle detector, preferably at said backward particle exit, and wherein said backward electron acceleration device is operable to accelerate electrons that emerge in use from said backward particle exit towards said receiving part of said backward particle detector.

Optionally, the apparatus includes an ion extraction device operable to extract ions from said interaction zone. The ion extraction device may comprise first and second spaced apart extraction electrodes, typically in the form of plates, operable to create an electric field for accelerating ions away from the interaction zone. The extraction electrodes may be configured to accelerated said ions in a direction that is substantially perpendicular to, or oblique to, said propagation axis.

The extraction electrodes may be located at opposite sides of the interaction zone, spaced apart in a direction perpendicular with the light propagation axis, preferably being disposed substantially parallel with the light propagation axis. Typically at least one of said extraction electrodes includes an aperture providing an outlet for extracted ions. Preferred embodiments include a particle detector for receiving extracted ions. Said ion extraction device may be configured to accelerate ions from said interaction zone to said particle detector. The particle detector (for the ions) may comprise a microchannel plate detector (MCP) and/or a mass spectrometer.

In preferred embodiments, the radiation source is a light source, preferably a laser, typically a short pulse laser. In any event the preferred configuration is such that the radiation source emits said circularly polarised ionizing radiation along said propagation axis in pulses.

In use, said radiation source and said forward and backward particle detectors may be operated to implement a succession of ionization and electron detection cycles during which a plurality of molecules of said target sample are ionized and the resulting photoelectrons are detected by said forward or backward particle detector, said apparatus being further configured to make a determination on the chirality of said molecules depending on the relative number of photoelectrons detected by said forward and backward particle detectors.

Optionally said radiation source, said forward and backward particle detectors and said extracted ion particle detector are operated in a succession of ionization and detection cycles wherein, in each cycle, a single molecule is ionized and the resulting photoelectron and corresponding ion are detected. Said extracted ion particle detector may be configured to identify a chemical species for the respective molecule ionized in each cycle, and wherein said apparatus is configured to make a determination on the chirality of the or each molecule of the or each identified chemical species depending on the relative number of photoelectrons detected by said forward and backward particle detectors in respect of each identified chemical species.

Preferably said magnetic field generator configured to generate said magnetic field such that it extends at least from said receiving part of said backward particle detector to said receiving part of said forward particle detector.

Said magnetic field generator may comprise one or more electromagnets and/or one or more permanent magnets.

Typically the apparatus includes means for introducing said target sample into said interaction zone in a gaseous form. The introducing means includes an inlet, optionally comprising a capillary, formed in a structure bounding said interaction zone. Said introducing means may include an injector for injecting said target sample into said interaction zone in a gaseous form. Said introducing means may include an energy source configured to vaporise said target sample.

Optionally, the configuration is such that in each cycle the apparatus causes ionization by a single pulse of said electromagnetic radiation.

Optionally, the configuration is such that in each cycle the apparatus causes ionization series of two or more time-spaced pulses of said electromagnetic radiation.

A second aspect of the invention provides a method of detecting molecular chirality of the molecules of at least one chemical species of a target sample in an evacuated interaction zone, the method comprising: generating a magnetic field in said interaction zone, said magnetic field being directed substantially parallel with a propagation axis that extends through said interaction zone; ionizing said molecules using an electromagnetic radiation source configured to generate circularly polarised ionizing radiation in a forward direction along said propagation axis; detecting, at a location forward of said interaction zone, each forwardly travelling photoelectron generated by said ionizing radiation; detecting, at a location backward of said interaction zone, each backwardly travelling photoelectron generated by said ionizing radiation; and determining the chirality of said molecules depending on the relative number of photoelectrons detected respectively at said forward and backward locations.

Preferably, the method includes deflecting said forwardly travelling photoelectrons away from said propagation axis. Preferably the method includes deflecting said backwardly travelling photoelectrons away from said propagation axis.

The preferred method involves causing substantially no electric field to be present in said interaction zone during said ionization and fora period of time after said ionization. The preferred method includes applying an electric field to said interaction zone after said period of time has elapsed, said electric field being configured to direct ions in said interaction zone out of said interaction zone. The preferred method includes detecting and/or analysing said ions directed out of said interaction zone.

Typically the method includes implementing a plurality of ionization and electron detection cycles during which a plurality of said molecules are ionized and the resulting forward and backwardly travelling photoelectrons are detected.

Optionally the method includes implementing a plurality of ionization and detection cycles wherein, in each cycle, a single one of said molecules is ionized and the resulting photoelectron and corresponding ion are detected. The method may further include identifying a chemical species for the respective molecule ionized in each cycle, and making a determination on the chirality of the or each molecule of the or each identified chemical species depending on the relative number of detected forwardly travelling and backwardly travelling photoelectrons in respect of each identified chemical species.

Advantageously, apparatus and methods embodying the invention make use of the physical phenomenon PECD which produces much greater differences in the measured quantities (e.g. an asymmetry parameter of between 1% and 20%) compared to conventional optical techniques (less than < 0.1% asymmetry). The asymmetry parameter can be measured in a mass spectrometer using a very efficient laser ionization source, thereby allowing the chiral purity of very small quantities (e.g. femtomoles) to be measured almost in real time. This compares favourably to current analysis techniques such as chiral chromatography which have a detection limit of nanomoles.

Preferred embodiments of the invention employ a chiral analysis method that may include mass spectrometry technology, which is the fastest and most sensitive chemical analysis technique currently available. Advantageously mass analysis is performed in conjunction with stereo detection of the emitted photoelectrons so that chiral (as well as chemical) analysis can be performed on a sample. This allows chiral enantiomers to be distinguished with orders of magnitude increases in sensitivity and speed.

Further advantageous aspects of the invention will be apparent to those ordinarily skilled in the art upon review of the following description of a specific example and with reference to the accompanying drawings.

Brief Description of the Drawings

An embodiment of the invention is now described by way of example with reference to the accompanying drawings in which like numerals are used to denote like parts and in which:

Figure 1 is a schematic illustration of photoelectron circular dichroism (PECD);

Figure 2 is a schematic view of an apparatus for detecting chiral enantiomers embodying one aspect of the invention;

Figure 2A is a schematic illustration of a sample vaporising arrangement suitable for use with the apparatus of Figure 2; and

Figure 3 is a graph plotting an asymmetry parameter G against enantiomer proportions in a sample of camphor.

Detailed Description of the Drawings

Figure 1 shows chiral molecules 10 being irradiated by circularly polarised electromagnetic radiation, typically light 12, of suitable wavelength and/or intensity to ionize the molecules 10 resulting in photoelectrons 14 being emitted from the molecules 10. The light may comprise laser light from a laser (not shown) and is typically pulsed but may alternatively be non-pulsed. Alternatively, other circularly polarised light may be used, for example circularly polarised vacuum ultraviolet light, and may be continuous or pulsed. The radiation 12 may be such that it produces single photon ionization (SPI) or multi-photon ionization (MPI). Typically, the wavelength of the radiation 12 determines whether SPI or MPI is produced. In typical embodiments a short pulse laser (not shown) is used as the source of radiation to provide the light 12 in pulses to cause multi-photon ionization. In alternative embodiments the light 12 may be vacuum ultraviolet light (VUV) from a synchrotron light source (not shown) or other suitable radiation source. With VUV light it does not matter whether the light is pulsed or not to produce SPI. For longer wavelengths, e.g. in UV, visible or infrared for which the ionization is MPI, pulsed radiation is used in order to achieve sufficient intensity.

Typically, one photoelectron 14 is emitted for each molecule 10 that is ionized although it is possible to produce more than one photoelectron 14 from the ionization of a single molecule 10 (e.g. depending on the intensity of the light 12, or if the wavelength is sufficiently short (e.g. in extreme UV or x-ray region)).

The photoelectrons 14 may be emitted in a forward direction or a backward direction with respect to the direction of propagation P of the light 12. The forward direction may comprise the direction of propagation P and any direction disposed at less than 90° from the direction of propagation P, while the backward direction may comprise any direction disposed at more than 90°, e.g. between 90° and 180°, from the direction of propagation P. In Figure 1, the forwardly emitted photoelectrons 14 are those that are emitted forwardly of a notional plane 16 that is perpendicular to the direction of propagation P, while the backwardly emitted photoelectrons 14 are those that are emitted rearwardly of the plane 16.

Because the molecule 10 is a chiral molecule, the angular distribution of the photoelectrons 14 with respect to the direction of propagation P is asymmetric, i.e. proportion of photoelectrons 14 emitted in one of the forward or rearward directions (forward in the illustrated example) is greater than the proportion emitted in the other direction (backward in the illustrated example). Which of the forward and backward directions has the greater proportion depends on the chirality of the molecule 10 (i.e. whether it is a left or right handed enantiomer) and on how the light 12 is polarised (i.e. whether the light 12 is Left Circularly Polarised Light (LCP) or Right Circularly Polarised Light (RCP)). The degree of asymmetry can be relatively large (typically 1% to 20%), which facilitates its detection.

In arriving at the present invention it is observed that the asymmetry in the photoelectron emission is predominantly encoded in the simple ratio of forward to backward photoelectron emission. This ratio may be calculated by providing means for channelling the forward and backward photoelectrons into separate respective single particle detectors. Any conventional electron detection device may be used for this purpose, for example an electron multiplier, preferably a channel electron multiplier (CEM). In preferred embodiments, a magnetic field is applied parallel to the direction of propagation Pto confine the forward and backward emitted photoelectrons in directions perpendicular to the direction P but allowing the photoelectrons to travel in the forward and backward directions under their own momentum (at least initially). This is described in more detail with reference to the specific embodiment of Figure 2.

Figure 2 shows, generally indicated as 20, an apparatus for detecting molecular chirality, and in particular for distinguishing between chiral enantiomers. The preferred apparatus 20 analyses a target substance comprising chiral molecule(s) and determines the chirality of the molecule(s), which may involve determining which chiral enantiomer(s) are present (left handed and/or right handed) and optionally in what proportion the chiral enantiomer(s) are present.

The apparatus 20 includes an interaction zone 22 in which ionization of molecules occurs. The interaction zone 22 may be provided within any convenient structure, for example a chamber, enclosure or between any other suitable components of the apparatus 20, e.g. electrode plates. The interaction zone 22 is evacuated, i.e. under vacuum, preferably at 1 e-3 mbar or less. To this end apparatus 20 typically includes a vacuum chamber (not illustrated) in which the interaction zone 22 is located, typically along with any one or more of the other components of the apparatus 20 as is convenient.

The apparatus 20 includes, or is connectable to, an electromagnetic radiation source 24 configured to produce circularly polarised electromagnetic radiation 112. In typical embodiments the radiation source is a light source that circularly polarised light 112. In preferred embodiments the light source 24 comprises a laser for producing circularly polarised laser light. It is particularly preferred that the light source 24 produces pulses of light and to this end preferably comprises a short pulse laser. In alternative embodiments, the light source may be of a type that produces other types of light, e.g. a synchrotron light source producing vacuum ultraviolet light. In any event the light, or other radiation, is provided at an intensity high enough to ionize chiral molecules and may therefore be referred to as ionizing radiation or ionizing light.

The configuration is such that, in use, the light 112 passes through the interaction zone 22 in along a propagation axis in a direction P (which may also be said to be the forward direction). The apparatus 20 may be provided within any convenient conventional light channel for this purpose. Typically, the light 112 travels through the apparatus 20 along the propagation axis from an inlet 26 to an outlet 28 via the interaction zone 22. To this end, the light channel may comprises one or more conventional light guiding elements, apertures and/or light focusing elements (not shown) as may be required. Alternatively one or more focusing element may be provided in the light source 24.

By way of specific example only, the light 112 may comprise laser pulses with a wavelength of 395 nm, pulse length of 250 fs, and repetition rate of 200 kHz. The light may be focussed to a diameter of approximately 40 microns giving an intensity of 4e10 W/cm2.

More generally, in typical embodiments any laser wavelength can be used provided the intensity is sufficiently high to ionize by multi-photon or tunnelling ionization, typically greater than 1e10W/cm2 but may be lower if the laser wavelength is resonant with intermediate excited state(s) of the molecule. The laser wavelength can be chosen to maximise the PECD asymmetry and/or the ionization efficiency. Wavelengths which correspond to photon energies greater than the ionization energy of the molecule ionize by single photon absorption and require considerably lower intensities. The diameter of the light beam 112 in the interaction zone 22 is focussed and/or otherwise configured to meet the intensity requirements. Pulse duration is typically less than one picosecond to provide a sufficiently intense pulse for ionization, but pulses greater than one nanosecond duration may provide sufficient ionization probability if a resonant wavelength is chosen.

The repetition rate is typically at least 1 kHz but higher rates may be used and improve the counting statistics and increase the speed of analysis.

In use the interaction zone 22 contains at least one molecule of a target substance 30 that is to be analysed. The target substance 30 may be provided in gaseous (including vapour), liquid or solid form, although for ionization the target substance is in gaseous form (including vapour), i.e. such that the molecules are separated from one another, and at least some of its molecules are located, in use, in the path of the light 112 in order for the light 112 to ionize the molecules to produce photoelectrons 114. It is preferred that the light 112 is focused to an ionization location in the interaction zone 22 where it impinges on the molecules of the target substance 30 in use.

The apparatus 20 may include, or be connectable to, a device for supplying the target substance 30 to the interaction zone 22. For example, in the embodiment of Figure 2, the apparatus includes a gas injection device 32 for delivering the target substance as a stream of gas 34 into the interaction zone

22. The arrangement is such that the stream of gas 34 impinges upon the light 112. In preferred embodiments, the arrangement is such that the stream of gas 34 is substantially perpendicular to the propagation direction P. The apparatus 20 includes an inlet 36, for example comprising a capillary, through which gas may be introduced to the interaction zone 22. In alternative embodiments any other conventional input device(s) may be provided for supplying the target substance (in gaseous, liquid or solid form) to the interaction zone 22, for example comprising a syringe, pump or other injection device. Alternatively still, a quantity of the target substance may be introduced into the interaction zone 22 by any other means, e.g. by coupling to a gas chromatograph. It is preferred that the target substance 30 is in gaseous form (i.e. comprises a gas or a vapour) for ionization by the light 112. In cases where the target substance 30 is provided in a non-gaseous form the apparatus 20 preferably includes means for vaporising the target substance 30. The vaporising means typically comprises one or more lasers, and vaporisation may be achieved via any suitable mechanism, for example laser induced acoustic desorption or desorption from a thin foil by laser. For example, with reference to Figure 2A, a solid sample 30S may be located adjacent to or remote from the interaction zone 22 with an energy source 37 used to induce vaporisation of the sample 30S into or within the interaction zone 22. The energy source 37 may for example be an electrical heater and/or one or more lasers which irradiate or otherwise energise the sample 30S directly or indirectly via a substrate on which the sample is deposited. The arrangement may be such that the sample is vapourised by laser induced acoustic desorption or laser induced thermal desorption. In Figure 2A the sample 30S is provided on a metallic foil 39 of micrometer thickness provided on electrode 56B. A pulsed or continuous wave laser 37 irradiates the foil 39 on the opposite side to that on which the sample 30S is deposited. Transport of acoustic or thermal energy through the foil vaporises the sample 30S.The vaporised sample 30V then enters the interaction region 22, e.g. via capillary 32, or other inlet provided in electrode 56B.

The apparatus 20 includes a forward particle detector 40 located forwardly of the interaction zone 22 (with respect to the propagation direction P) and a backward particle detector 42 located backwardly of the interaction zone 22. More particularly it is the respective particle inlet 41,43 (or other particle receiving part, depending on the configuration of the detector 40, 42) of the forward and backward particle detectors 40, 42 that are located forwardly and backwardly, respectively, of the interaction zone 22 in order to receive forwardly and backwardly emitted electrons 114F, 114B respectively, although in practice the whole detector is typically forwardly or backwardly located. Each particle detector 40, 42 may comprise any conventional electron detection device, for example an electron multiplier, preferably a channel electron multiplier (CEM) such as the Magnum (trade mark) electron multiplier provided by Photonis Technologies S.A.S of Merignac, France.

In preferred embodiments, a respective electron deflection device 44, 46 is provided between the interaction zone 22 and each of the particle detectors 40, 42 for deflecting the forwardly emitted phototelectrons 114F and backwardly emitted photoelectrons 114B, respectively, away from the propagation axis of the light 112. Each deflection device 44, 46 may comprise spaced apart (typically in a direction perpendicular to the propagation axis) deflection electrodes. The electrodes are spaced apart such that in use the respective forward or backward photoelectrons pass between the electrodes, and as such are located on opposite sides of the propagation axis in preferred embodiments. Typically the electrodes comprise deflection plates 44A, 44B and 46A, 46B, to which a deflection voltage may be applied creating an electric field between the respective electrodes which deflects the respective photoelectrons 114F, 114B away from the light 112 and into the respective particle detector 40, 42. To this end, the respective inlet 41,43 of each particle detector 40, 42 is spaced apart from the propagation axis. Respective pairs of deflection electrodes 44A, 44B and 46A, 46B are typically located on opposite sides of the propagation axis. The respective pairs of deflection plates 44A, 44B and 46A, 46B may be described as trochoidal plates in that they each create a region in which the electric and magnetic fields are perpendicular to each other, causing the motion of electrons to be trochoidal in that region. In any event, preferred embodiments include an arrangement of electrodes between the interaction zone 22 and each particle detector 40, 42 generating an electric field to separate electrons 114F, 114A from the radiation beam 112 and directing them to the inlet of the respective particle detector. In principle a magnetic field configuration could be used to separate the electrons from the radiation beam without the need for an electric field. However, such an arrangement may compromise collection of the electrons as some might be trapped in the interaction zone. Therefore, a combination of electric and magnetic fields is preferably provided to separate and detect the electrons 114F, 114B.

In preferred embodiments, a respective electron accelerator 48, 50 is provided between the interaction zone 22 and each of the particle detectors 40, 42 for accelerating the forwardly emitted phototelectrons 114F and backwardly emitted photoelectrons 114B, respectively, towards the respective particle detector 40, 42. The forward electron accelerator 48 is preferably located at the forward exit 52 of the interaction zone 22. In preferred embodiments the forward electron accelerator 48 is located between the interaction zone 22 and the forward particle detector 40. The backward electron accelerator 50 is preferably located at the backward exit 54 of the interaction zone 22. In preferred embodiments the backward electron accelerator 50 is located between the interaction zone 22 and the backward particle detector 42. Each accelerator device 48, 50 may comprise spaced apart (typically in a direction parallel with the propagation axis) electrodes, typically in the form of plates 48A, 48B and 50A, 50B, to which an accelerating voltage may be applied creating an electric field between the respective electrodes which accelerates the respective photoelectrons 114F, 114B forwards and backwards respectively, i.e. towards respective particle detector 40, 42. In preferred embodiments the accelerator devices 48, 50 are located not only in the path of the emerging photoelectrons but also in the path of the light 112, i.e. intersecting the propagation axis. Accordingly, each of the electrodes 48A, 48B and 50A, 50B has a respective aperture through which the light 112 and respective photoelectrons 114F, 114B pass.

The apparatus 20 further includes means for generating a magnetic field (illustrated as arrow B in Figure 2), preferably a uniform magnetic field, in a direction parallel with the propagation axis of the light 112. For example the magnetic field may have a strength of approximately 30-40 Gauss, although other field strengths may be used as suits the application. The magnetic field generating means may comprise any convenient arrangement of permanent magnet(s) and/or electromagnet(s). By way of example one or more electrically energised coils may be used to generate the magnetic field. In the example of Figure 2, first and second spaced apart coils 80A, 80B are provided, the axis of each coil 80A, 80B being substantially parallel with the propagation axis. The coils 80A, 80B, when electrically energised, generate a substantially uniform magnetic field in the interaction zone 22, the deflection devices 44, 46 and the particle detectors 40, 42 (essentially the whole volume shown in Figure 2A). The magnetic field B confines the photoelectrons 114 and so is present throughout the volume of space in which the photoelectrons travel (i.e. from the interaction zone 22 to the inlet of the detectors 40, 42). This magnetic field B can alternatively be generated with permanent magnets. The direction (polarity) of the B field does not matter, except that if it is switched the direction (polarity) of the deflection E field must also be switched.

In preferred embodiments, the apparatus 20 includes an ion extraction device 56 for extracting ions 58 that are produced by ionization of the target sample 30. The ion extraction device 56 may direct the ions 58 to a particle detector 60 which may also be configured to perform analysis as required. The particle detector 60 may for example comprise a microchannel plate detector (MCP) (which may be configured to determine the mass of each ion by measuring time of flight) and/or a mass spectrometer. To provide the functionality of mass spectrometry, the time at which a pulse is generated by the MCP can be recorded and this time can be assigned a mass (this is called a time of flight mass spectrometer). In alternative embodiments, a mass spectrometer may be provided, the ions being directed to the mass spectrometer which may analyse each ion’s mass by a different method or do so in combination with the time taken for the ion to reach the mass spectrometer.

In the example of Figure 2, the apparatus 20 includes a tube electrode 82 (or part of the vacuum chamber) which is grounded to form a drift region where there is no electric field. The MCP 60 has a detecting surface onto which the ions impinge and this surface is typically perpendicular to the direction of ion motion.

The ion extraction device 56 may comprise first and second spaced apart extraction electrodes, typically in the form of extraction plates 56A, 56B, to which an extraction voltage may be applied creating an electric field between the electrodes 56A, 56B which accelerates the ions 58 away from the interaction zone 22 towards the particle detector 60. The preferred arrangement is such that the ions 58 are accelerated in a direction that is substantially perpendicular to the light propagation axis, or at least obliquely with respect to the light propagation axis. The extraction plates 56A, 56B are typically located at opposite sides of the interaction zone 22 spaced apart in a direction perpendicular with the light propagation axis. The plates 56A, 56B may extend from end-to-end of the interaction region between the forward and backward exits 52, 54. The plates 56A, 56B are typically disposed substantially parallel with the light propagation axis. The plate 56A located between the interaction zone 22 and the particle detector 60 includes an aperture 62 through which the ions 58 pass, i.e. an outlet by which ions may leave the interaction zone. The other plate 56B may include the inlet 36. Optionally, one or more additional extraction electrodes 56C may be provided for directing the ions 58 to the particle detector analyser 60.

In use, the focussed circularly polarised light 112 is directed into the interaction zone 22 whereupon it ionizes the chiral molecules of the target substance 30. Depending on the mode of operation of the apparatus 20, a single molecule may be ionized at a time or a plurality of molecules may be ionized at a time. Each molecule when ionized provides at least one (and usually only one) photoelectron 114 and a corresponding ion 58. The mode of operation may be determined by controlling one or more characteristics of the light 112 (e.g. its intensity, wavelength and/or pulse duration) and/or by controlling the rate at which the molecules of the target substance 30 are provided in the path of the light 112. In preferred modes of operation, the light 112 is pulsed, each pulse causing an ionization event within the interaction zone 22 during which one or more molecules are ionized as described above.

During and immediately after the ionization process, the apparatus 20 is configured such that there is no electric field in the interaction zone 22. This may be achieved by connecting any components around the interaction zone 22 to electrical ground. For example in the illustrated embodiment the extraction plates 56A, 56B and optionally the accelerator plates 48A, 48B and 50A, 50B (or at least the plates 48B and 50A that are adjacent the interaction zone 22) are electrically grounded. In preferred embodiments, the interaction zone 22 comprises a volume of space bounded by one or more structures to create a zone in which the electric field can be caused to be zero or substantially zero. In this zone the chiral molecules are ionized by the light 112. The electric field in the interaction region must be zero or sufficiently close to zero to allow the forward and backward emitted electrons to spatially separate. For example in the embodiment shown in Figure 2 the structures defining the interaction zone 22 comprise electrodes 48B, 50A, 56A and 56B, which may all be maintained at ground potential during and immediately after each laser pulse, or more generally ionization event, at least until the generated photoelectrons have left the interaction zone 22, which is typically in the order of around 100 nanoseconds. These bounding structures are typically all located in a vacuum chamber. More generally, any one or more of the other components of the apparatus 20, including the particle detectors 40, 42, extraction device 56, electron accelerators 48, 60, deflection devices 44, 46, and magnetic field generators may be located inside the vacuum chamber as is convenient. Any component that is not provided inside the vacuum chamber may be coupled to the vacuum chamber in any conventional manner as required to enable it to perform its function. In typical embodiments the particle detectors 40, 42, extraction device 56, electron accelerators 48, 60, deflection devices 44, 46 are located inside the vacuum chamber. The magnetic field generator, e.g. comprising electromagnetic coils or permanent magnets, may be located inside or outside of the vacuum chamber as is convenient.

When ionization occurs, the resulting photoelectrons 114 are emitted from the respective molecule in either a forward or backward direction as described above. Because the magnetic field B is directed parallel with the light propagation axis, it has the effect of guiding the electrons 114 in either the forward or backward direction (depending on whether the electrons were emitted forwardly or backwardly respectively) towards the forward exit 52 or backward exit 54. More particularly the magnetic field causes the photoelectrons 114 to move helically along the magnetic field B but with a net motion in the forward or backward direction depending on whether the photoelectrons 114 were emitted forwardly or backwardly respectively. Hence, it may be said that the magnetic field B confines the photoelectrons 114 and separates them in the forward and backward directions. In preferred embodiments where the magnetic field is uniform it does not contribute to acceleration of the electrons. So movement out the interaction zone 22 is driven by the component of the electron’s initial momentum along the propagation axis. A slightly non-uniform magnetic field may cause a small acceleration or de-acceleration along the propagation axis.

After a period of time has elapsed after ionization (typically about 100 nanoseconds or similar order) the photoelectrons 114 have reached one or other of the exits 52, 54 from the interaction zone 22. Subsequently a suitable voltage can be applied, e.g. in one or more pulses, to the plates 56A, 56B of the extraction device 56 to extract the ions 58 from the interaction zone 22 as described above. A suitable voltage may also be applied to the accelerator plates 48A, 48B and 50A, 50B in order to accelerate the photoelectrons 114 towards the respective particle detector 40, 42. This may be done after a period of time has elapsed after ionization (e.g. at the same time as the voltage is applied to the plates 56A, 56B) or may be done earlier (e.g. during and after ionization) so long as the configuration of the acceleration devices 48, 50 is such that they do not cause an electric field in the interaction region during and immediately after ionization. Conveniently the accelerator plates 50A, 48B closest to the interaction zone 22 are kept continually at ground potential, while the accelerator plates 50B, 48A nearest the respective detector 40, 42 are kept at a positive voltage.

In typical embodiments, not only do the photoelectrons 114F, 114B emerge from the interaction zone 22 from the exits 52, 54, but the light 112 enters the interaction zone 22 by one of the exits 54 and leaves by the other 52. Consequently, at least some of the forward and backward photoelectrons 114F, 114B emerge from the respective exits 52, 54 along or close to the propagation axis. To detect the forward and backward photoelectrons 114F, 114B, they are separated from the light 112, which is achieved by applying an electric field perpendicular to the magnetic field B using the respective deflection device 44, 46. The forward and backward electrons 114F, 114B are thus directed into the respective particle detector 40, 42 by which the electrons are preferably detected one at a time.

The extracted ions 58 are pushed towards the detector 60 by which their mass can be determined by their time of flight (e.g. if the detector 60 comprises an MCP detector), or which may be configured to perform mass spectrometry by other conventional means, thereby enabling chemical analysis of the target sample 30.

In a preferred mode of operation, the apparatus 20 is configured such that electrons 114 and their corresponding ions 58 (typically a single electron 114 and its corresponding ion 58) are detected in coincidence by the respective detectors 40, 42, 60. This may be achieved by operating the apparatus 20 in a succession of ionization and detection cycles wherein, in each cycle, a single molecule is ionized and the resulting electron 114 and ion 58 are detected. Each cycle may involve ionization by a single pulse of the light 112, or a series of two or more time-spaced pulses (which may be of same or different wavelength and/or duration, and with equal or different time spacing), successive pulses typically being separated by up to nanoseconds in time. Operation in this mode allows molecule chirality (which is determined from the detection of the electrons) to be correlated with molecule mass (which is determined by detection of the ions). This mode is particularly suited to analysis of target samples containing more than one chemical species of molecule. By detecting the electrons and ions in coincidence the asymmetry of each species of molecule present in the target sample can be assessed for chiral content. Therefore, the apparatus 20 provides an extra dimension to the analysis in comparison to conventional mass spectrometer in that the chiral as well as chemical content of samples can be determined.

More generally, the apparatus 20 may be configured to operate the light source 24 and the forward and backward particle detectors 40, 42 to implement a succession of ionization and electron detection cycles during which a plurality of molecules of said target sample 30 are ionized and the resulting forward and backward photoelectrons are detected respectively by the forward or backward particle detectors. The apparatus 20 can detect the chirality of the molecules depending on the difference between the number of forward photoelectrons detected by the forward particle detector and the number of backward photoelectrons detected by the backward particle detector. For example, the chirality of the molecule can be detected by determining that the proportion of either one of the detected forward and backward photoelectrons exceeds the proportion of the other by more than a threshold amount (which is typically between 1% and 20%). This mode of operation is well suited to cases where the target sample is known to comprise molecules of a single chemical species but can be refined as described above (where single molecules are ionized in each cycle and the electrons 114 and their corresponding ions 58 are detected in coincidence) to better suit cases where the target species may comprise more than one chemical species.

In some embodiments, for example when the target sample is known to comprise only one chemical species, it may not be required to perform any chemical analysis of the sample and so it may not be required to extract the ions 58. In such embodiments, the detector 60 and ion extraction device 56 may be omitted, although they may be included and used to verify that the sample is pure.

In any event, it will be apparent that for any given chiral molecule its chirality can be assessed by comparing the respective number of photoelectron events detected in each electron detector 40, 42, since this provides an indication of the respective proportions of photoelectrons that are emitted forwardly and backwardly. In particular, for any given chiral molecule an asymmetry parameter G can be measured from the respective number of photoelectron events detected in each electron detector 40, 42. If F is the number of photoelectron events recorded in the forward detector 40 and B is the number of photoelectron events recorded in the backward detector 42, then G may be defined as G=4*(F-B)/(F+B).

The magnitude of the parameter G is unique to each chiral molecule and each enantiomer has an opposite value to its mirror image (i.e. if the right hand enantiomer is +G, the left hand enantiomer is -G). Therefore the value of G measured can be used to determine the enantiomeric proportions of the sample.

Analysis of the data recorded by the detectors 40, 42, 60 may be performed by any conventional control system (not shown), typically comprising one or more suitably programmed computing device which may be provided integrally with the apparatus 20 and/or connected to the apparatus 20 as is convenient. The control system may also be configured to allow an operator to control the operation of the apparatus 20 as described herein, although a separate control system may be provided for this purpose. In any event the or each control system may include or be connected to one or more user interface (e.g. display, keypad or other output or input device) to allow the operator to operate the device and to render the results to the operator. The or each control system may take any convenient conventional form, e.g. comprising one or more suitably programmed computing device and/or logic controller.

The components of the apparatus 20 may be assembled and powered in any convenient manner, for example comprising a body structure defining an enclosure in which the interaction zone 22 is located and to which the other components can be mounted or connected. Any suitable electrical power source may be used, e.g. one or more batteries or electrical mains connection.

By way of specific example, circularly polarised laser pulses with a wavelength of 395 nm and pulse length of 250 fs were focused into a gas jet comprising the chiral molecule camphor emanating from a 0.5 mm capillary 36 opening in the interaction region 22 with an intensity of 4 x 10 Worn . With signal rates of several kHz, data for one sample was acquired in about 5 minutes. By measuring Gvalues for samples with different enantiomeric proportions, the graph in Figure 3 was produced showing the asymmetry parameter G for camphor measured for different enantiomer proportions in the sample, where the enantiomer excess (e.e.) in a sample is the excess of one enantiomer over the other. The results show that the apparatus 20 is capable of measuring the relative proportions of a pair of enantiomers to an accuracy of a few percent within about 5 minutes.

Compared to conventional techniques for measuring PECD, preferred embodiments of the invention are advantageous in that they can: provide relatively high sensitivity (which is essential for small samples and trace analysis); analyse impure, native or contaminated samples; lead to reduced preprocessing of samples; measure enantiomer excesses accurately and quickly. In addition preferred embodiments are relatively simple in design, require simpler data analysis, are easier to operate and cheaper to produce.

The invention is not limited to the embodiment(s) described herein but can be amended or modified without departing from the scope of the present invention.

Claims

CLAIMS:

1. An apparatus for detecting molecular chirality, the apparatus comprising:

an evacuated interaction zone for containing at least one molecule of a target sample;

a electromagnetic radiation source configured to generate circularly polarised ionizing radiation in a forward direction along a propagation axis that extends though said interaction zone;

a forward particle detector having a receiving part located forwardly of said interaction zone;

a backward particle detector having a receiving part located backwardly of said interaction zone; and a magnetic field generator configured to generate a magnetic field in said interaction zone, said magnetic field extending substantially parallel with said propagation axis.

2. The apparatus of claim 1, wherein said interaction zone has a forward particle exit and a backward particle exit, said receiving part of said forward particle detector being positioned to receive electrons that emerge in use from said forward particle exit, and said receiving part of said backward particle detector being positioned to receive electrons that emerge in use from said backward particle exit.

3. The apparatus of claim 1 or 2, further including focusing means for focusing said ionizing radiation on an ionizing location in said interaction zone.

4. The apparatus of any preceding claim, wherein said interaction zone has a forward particle exit, the apparatus further including a forward electron deflection device located between said interaction zone and said forward particle detector, said forward electron deflection device being operable to deflect electrons that emerge in use from said forward particle exit away from said propagation axis.

5. The apparatus of any preceding claim, wherein said interaction zone has a forward particle exit, the apparatus further including a forward electron deflection device located between said interaction zone and said forward particle detector, and wherein said forward electron deflection device is operable to deflect electrons that emerge in use from said forward particle exit to said receiving part of said forward particle detector.

6. The apparatus of claim 4 or 5, wherein said forward deflection device comprises at least two electrodes, each electrode preferably comprising a plate, that are spaced apart in a direction perpendicular to said propagation axis and positioned such that, in use, said electrons from said forward particle exit, and typically also said ionizing radiation, pass between said at least two electrodes.

7. The apparatus of any preceding claim, wherein said interaction zone has a backward particle exit, the apparatus further including a backward electron deflection device located between said interaction zone and said backward particle detector, said backward electron deflection device being operable to deflect electrons that emerge in use from said backward particle exit away from said propagation axis.

8. The apparatus of any preceding claim, wherein said interaction zone has a backward particle exit, the apparatus further including a backward electron deflection device located between said interaction zone and said backward particle detector, and wherein said backward electron deflection device is operable to deflect electrons that emerge in use from said backward particle exit to said receiving part of said backward particle detector.

9. The apparatus of claim 4 or 5, wherein said backward deflection device comprises at least two electrodes, each electrode preferably comprising a plate, that are spaced apart in a direction perpendicular to said propagation axis and positioned such that, in use, said electrons from said backward particle exit, and typically also said ionizing radiation, pass between said at least two electrodes.

10. The apparatus of any preceding claim, wherein the respective receiving part of at least one of and preferably each of said forward and backward particle detector are spaced apart from said propagation axis.

11. The apparatus of any preceding claim, wherein said interaction zone has a forward particle exit, the apparatus further including a forward electron accelerating device located between said interaction zone and said forward particle detector, preferably at said forward particle exit, and wherein said forward electron acceleration device is operable to accelerate electrons that emerge in use from said forward particle exit towards said receiving part of said forward particle detector.

12. The apparatus of any preceding claim, wherein said interaction zone has a backward particle exit, the apparatus further including a backward electron accelerating device located between said interaction zone and said backward particle detector, preferably at said backward particle exit, and wherein said backward electron acceleration device is operable to accelerate electrons that emerge in use from said backward particle exit towards said receiving part of said backward particle detector.

13. The apparatus of any preceding claim further including an ion extraction device operable to extract ions from said interaction zone.

14. The apparatus of claim 13, wherein said ion extraction device comprises first and second spaced apart extraction electrodes, typically in the form of plates, operable to create an electric field for accelerating ions away from the interaction zone.

15. The apparatus of claim 14, wherein said extraction electrodes are configured to accelerated said ions in a direction that is substantially perpendicular to, or oblique to, said propagation axis.

16. The apparatus of claim 14 or 15, wherein said extraction electrodes are located at opposite sides of the interaction zone, spaced apart in a direction perpendicular with the light propagation axis, preferably being disposed substantially parallel with the light propagation axis.

17. The apparatus of any one of claims 14 to 16, wherein at least one of said extraction electrodes includes an aperture providing an outlet for extracted ions.

18. The apparatus of any one of claims 13 to 17 further including a particle detector for receiving extracted ions.

19. The apparatus of claim 18, wherein said ion extraction device is configured to accelerate ions from said interaction zone to said particle detector.

20. The apparatus of claim 18 or 19 wherein said particle detector comprises a microchannel plate detector (MCP) and/or a mass spectrometer.

21. The apparatus of any preceding claim, wherein said radiation source is a light source, preferably a laser, typically a short pulse laser.

22. The apparatus of any preceding claim configured to cause said radiation source to emit said circularly polarised ionizing radiation along said propagation axis in pulses.

23. The apparatus of any preceding claim configured to operate said radiation source and said forward and backward particle detectors to implement a succession of ionization and electron detection cycles during which a plurality of molecules of said target sample are ionized and the resulting photoelectrons are detected by said forward or backward particle detector, said apparatus being further configured to make a determination on the chirality of said molecules depending on the relative number of photoelectrons detected by said forward and backward particle detectors.

24. The apparatus of any one of claims 18 to 23, wherein said apparatus is configured to operate said radiation source, said forward and backward particle detectors and said extracted ion particle detector in a succession of ionization and detection cycles wherein, in each cycle, a single molecule is ionized and the resulting photoelectron and corresponding ion are detected.

25. The apparatus of claim 24, wherein said extracted ion particle detector is configured to identify a chemical species for the respective molecule ionized in each cycle, and wherein said apparatus is configured to make a determination on the chirality of the or each molecule of the or each identified chemical species depending on the relative number of photoelectrons detected by said forward and backward particle detectors in respect of each identified chemical species.

26. The apparatus of any preceding claim, wherein said magnetic field generator configured to generate said magnetic field such that it extends at least from said receiving part of said backward particle detector to said receiving part of said forward particle detector.

27. The apparatus of any preceding claim, wherein said magnetic field generator comprises one or more electromagnets and/or one or more permanent magnets.

28. The apparatus of any preceding claim further including means for introducing said target sample into said interaction zone in a gaseous form.

29. The apparatus of claim 28 wherein said introducing means includes an inlet, optionally comprising a capillary, formed in a structure bounding said interaction zone.

30. The apparatus of claim 28 or 29, wherein said introducing means includes an injector for injecting said target sample into said interaction zone in a gaseous form.

31. The apparatus of any one of claims 28 to 30, wherein said introducing means includes an energy source configured to vaporise said target sample.

32. The apparatus of any one of claims 23 to 31, wherein in each cycle the apparatus causes ionization by a single pulse of said electromagnetic radiation.

33. The apparatus of any one of claims 23 to 31, wherein in each cycle the apparatus causes ionization series of two or more time-spaced pulses of said electromagnetic radiation.

34. A method of detecting molecular chirality of the molecules of at least one chemical species of a target sample in an evacuated interaction zone, the method comprising:

generating a magnetic field in said interaction zone, said magnetic field being directed substantially parallel with a propagation axis that extends through said interaction zone;

ionizing said molecules using an electromagnetic radiation source configured to generate circularly polarised ionizing radiation in a forward direction along said propagation axis;

detecting, at a location forward of said interaction zone, each forwardly travelling photoelectron generated by said ionizing radiation;

detecting, at a location backward of said interaction zone, each backwardly travelling photoelectron generated by said ionizing radiation; and determining the chirality of said molecules depending on the relative number of photoelectrons detected respectively at said forward and backward locations.

35. The method of claim 34 further including deflecting said forwardly travelling photoelectrons away from said propagation axis.

36. The method of claim 34 or 35 further including deflecting said backwardly travelling photoelectrons away from said propagation axis.

37. The method of any one of claims 34 to 36, further including causing substantially no electric field to be present in said interaction zone during said ionization and fora period of time after said ionization.

38. The method of claim 37, further including applying an electric field to said interaction zone after said period of time has elapsed, said electric field being configured to direct ions in said interaction zone out of said interaction zone.

39. The method of claim 38, further including detecting and/or analysing said ions directed out of said interaction zone.

40. The method of any one of claims 34 to 39, including implementing a plurality of ionization and electron detection cycles during which a plurality of said molecules are ionized and the resulting forward and backwardly travelling photoelectrons are detected.

41. The method of any one of claims 38 to 40, including implementing a plurality of ionization and detection cycles wherein, in each cycle, a single one of said molecules is ionized and the resulting photoelectron and corresponding ion are detected.

42. The method of claim 41, further including identifying a chemical species for the respective molecule ionized in each cycle, and making a determination on the chirality of the or each molecule of the or each identified chemical species depending on the relative number of detected forwardly travelling and backwardly travelling photoelectrons in respect of each identified chemical species.

Intellectual

Property

Office

Application No: Claims searched:

GB1616382.6

1-42