The Israel Chemist and Chemical Engineer ICE Issue 9 · January 2023 · Tevet 5783 https://doi.org/10.51167/ice00000 The Israel Chemical Society הימיכל תילארשיה הרבחה The Israel Chemical Society (ICS: www.chemistry.org.il)
3 The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 Table of Contents Editorials 4 Letter from the Editor Arlene D. Wilson-Gordon 5 Letter from President of ICS Ehud Keinan Scientific Articles 6 Low-frequency Raman spectroscopy – a versatile technique for material characterization and detection Hagit Aviv et al. 15 Novel molecular architectures for “multicolor” magnetic resonance imaging Amnon Bar-Shir History of Chemistry Article 24 César Milstein (1927-2002) and monoclonal antibodies: Father of modern immunology Bob Weintraub 29 The story of a chess set – a scientific detective story for Holocaust Remembrance Day Arie Gillon 34 Shimon Vega in the eyes of his students and postdocs Amir Goldbourt et al. Profile 44 Interviewwith Leeor Kronik Arlene D. Wilson-Gordon Reports 46 Agency, advocacy, and attention: A Tale of encouraging women into careers in the chemical sciences Mindy Levine 49 Report on the 86th Annual Meeting of the Israel Chemical Society Ehud Keinan Front cover: Figure 9 of Aviv et al.'s article that appears in this issue. The contents of this issue of ICE are published under license CC-BY-SA.
4 Letter from the Editor Dear Readers, The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 Welcome to the ninth issue of the Israel Chemist and Engineer (ICE) online magazine, a publication of the Israel Chemical Society (ICS). We hope you will find the magazine interesting and will be inspired to contribute to future issues. We start with Hagit Aviv, Vinayaka Harshothama Damle and Yaakov Tischler of Bar-Ilan University who contribute an article on their latest research on low-frequency Raman spectroscopy as a versatile technique for material characterization and detection. Amnon Bar-Shir of the Weizmann Institute (recipient of the 2021 ICS outstanding young scientist prize) contributes a fascinating review of his work on novel molecular architectures for “multicolor” magnetic resonance imaging. Bob Weintraub continues to inform us about the history of science, this time with a timely article on “César Mi l stein (1927-2002) and monoclona l ant ibodies: Father of modern immunology.” Arie Gillon, the founder of Bargal Analytical Instruments, presents a fascinating scientific detective story in which he uses his analytical skills to investigate the origin of a chess set that has been in his family for many years. I had the pleasure of interviewing Leeor Kronik of the Hebrew University for this issue of the ICE. Leeor is a recipient of the 2021 ICS outstanding scientist prize. His call to educate young scientists in ethical standards is of particular importance. Prof. Shimon Vega OBM of the Weizmann Institute passed away in 2021. Some of his students and postdocs got together to share their recollections of the time spent in his group and the lasting impression he made on them. The collection was edited by Gil Goobes of Bar-Ilan University and Amir Goldbourt of Tel Aviv University. After the recollections of Shimon’s students and postdocs, Yona Siderer, a specialist in the history of science at the Hebrew University, contributes her own appreciation of Shimon’s friendship and hospitality. Mindy Levine of Ariel University, the recipient of the ACS award for encouraging women into careers in the chemical sciences, sponsored by the Camille and Henry Dreyfus Foundation, contributes an article based on her talk at the ACS symposium celebrating her award, “Agency, advocacy, and attention: A tale of encouraging women into careers in the chemical sciences.” If you have suggestions for future editions, comments on the current issue, or would like to contribute an article, please contact me at gordon@biu.ac.il. Arlene D. Wilson-Gordon Professor Emerita Chemistry Department, Bar-Ilan University ICE Editor
The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 5 Letter from President of ICS Dear Colleagues, With the Covid-19 pandemic and its consequences fading away, we are back on track. Skipping the 2021 Annual Meeting of the ICS was painful, but we kept our traditional award ceremony and held it at the Open University campus on July 1, 2021. The 86th ICS Meeting, which took place on September 12–13, 2022, 2.5 years after the 85th Meeting, was a happy gathering of many ICS members, with long-missed in-person networking and exchanging ideas and recent discoveries. Unfortunately, the Chinese delegation we expected to host canceled their arrival due to the pandemic. We all thank the chairpersons of the organizing committee, Profs. Charles Diesendruck and Saar Rahav of the Technion. We look forward to the 87th Meeting, which will take place on July 4–5, 2023, at the International Convention Center, Jerusalem, as part of the International Chemistry Congress (ChemCon2023). The event, which will include the two-day 87th ICS Meeting, a one-day “Good Carbon” symposium (July 3, 2023), and a three-day international exhibition, reflects a fruitful collaboration between the ICS and the Haaretz/ TheMarker Group. The ChemCon2023 wil l create high interest and synergism among chemists, chemical engineers, businesspeople, venture capitalists, government agencies, startup entrepreneurs, chemical industry leaders, and the public. The 87th ICS Meeting will include nearly 100 lectures in four parallel sessions, over 300 posters, and various social events. The traditional ICS Prize Ceremony will recognize outstanding scientists, graduate students, teachers, and the prominent green chemical industry. Following our long tradition, we’ll host a large delegation from Denmark, consisting of 11 professors including Nobel Prize Laureate Morten P. Meldal, and 20 graduate students from the University of Copenhagen, the Technical University of Denmark, and Aarhus University. The Meeting is organized by a joint team from Ariel University, Tel Aviv University, and the Hebrew University, chaired by Profs. Alex Schechter and Flavio Grynszpan. The “Good Carbon” Symposium wi l l focus on using compounds of a single carbon atom, such as natural gas and carbon dioxide emissions, as feedstock for the chemical industry. The symposium will highlight the methanol-based economy, methanol-to-olefins (MTO) processes, synthetic fuels, novel fuel cells, and clean energy. 2023 will be my second year as Vice President and Presidentelect of the International Union of Pure and Applied Chemistry (IUPAC), and in 2024 I’ll start my two-year term as the Union’s 41st President. In this capacity, I wish to promote the Chemist’s Oath as a global initiative, planning to run the first pilot in Israel. As is the case for the Hippocratic Oath, the Chemist’s Oath will have a moral value rather than a legally binding commitment. It will enhance the newly graduated chemist’s ethical behavior and professional pride. The following text of 57 words is my proposed draft of the Chemist’s Oath. Believing in collective wisdom, I invite you to modify the text while keeping it clear and concise. ‘Bywhat I holdmost sacred, I solemnly swear to pursue scientific truth and expand knowledge ethically and responsibly. I will promote diversity, equity, inclusivity, and mutual respect for all. As a member of society at large, obligated to all my fellow human beings, I will use my chemical expertise to sustain life and protect the environment.’ With your help, I wish to crystallize the final version and offer it as a pilot among the 2023 chemistry graduates in one or two countries before proposing it through IUPAC to the global community. Finally, please help develop the ICE magazine under the leadership of Prof. Arlene Wilson-Gordon, and contribute an article to the ICE on any topic you like, including popular science, history of science, report on an event, opinions, etc. Please, don’t hesitate to contact Arlene or me on these matters. Enjoy your reading, Ehud Keinan President, the Israel Chemical Society
6 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 Hagit Aviv is a researcher at the Department of Chemistry, Bar-Ilan University and a co-founder of the Center for Energy and Sustainability. Until recently, as the lab manager of the Device Spectroscopy Laboratory, Hagit initiated projects and collaborations to develop spectroscopy techniques using Raman spectroscopy, specifically LFRS. Previously, her post-graduate work was centered on the field of polymers, and her doctoral research dissertation focused on synthesis and characterization of iodinated nano- and macro-particles for CT and MRI imaging. Abstract: Low-frequency Raman spectroscopy (LFRS) is a branch of vibrational spectroscopy that allows easy interpretationand highly sensitive structural identification of trace amounts of chemicals based on their unique vibrational characteristics. Due to the continuous technical improvement in Raman spectroscopy, advanced development of the device has been achieved and more applications have become possible. This article illustrates the use of LFRS for unique applications such as crystalline phase identification, enantiomeric identification, and enantiomeric separation. We present a general summary of our different research efforts in the field of polarised LFRS. The aim of this article is to highlight potential applications of different types, especially applications developed to characterize organic crystalline materials. Low-frequency Raman spectroscopy – a versatile technique for material characterization and detection Hagit Aviv,a†* Vinayaka Harshothama Damle,a,b† and Yaakov R. Tischlera aDepartment of Chemistry, Institute for Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 5290002, Israel bFaculty of Information Technology and Electrical Engineering, University of Oulu, Finland †Authors with equal contribution *Email: hagit.aviv@biu.ac.il Overview of Raman Spectroscopy Raman spectroscopy (RS) is an optical means of probing the vibrational modes of materials. The spontaneous Raman effect is a scattering phenomenon where photons, i.e. electromagnetic radiation of a specific wavelength, interact with the analyte i.e. the material under observation in either the ground state or one of the excited rotational-vibrational states. This interaction results in promoting the molecule into a so-called “virtual energy state” for a very short period before an inelastic photon is scattered. The resulting inelastically scattered photon which is “emitted”/“scattered” can be either of higher (anti-Stokes) or lower (Stokes) energy than the incoming photon. The probability of such inelastically scattered photons is much lower than elastically scattered photons, called Rayleigh scattered photons. Upon such interaction, the resulting rotational-vibrational state of the molecule differs from its original state, before interaction with the incoming photon. The difference in energy between the original state and the new state leads to a shift in the emitted photon’s frequency, resulting in a Raman shift [1]. RS displays several advantages over other techniques such as infrared spectroscopy. For example, the quality of the signal collected is barely affected by the presence of water, allowing for its use in many applications where infrared analysis is not reliable. A representative case study is the in-situ monitoring of a fermentative process where Raman techniques outperforms any other spectroscopic approach. Nonetheless, Raman analysis in addition to its intrinsic property of lower signal strength compared to fluorescence or absorption, suffers from some difficulties such as the
7 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 Vinayaka Harshothama Damle is a visiting researcher at the Faculty of Information Technology and Electrical Engineering, University of Oulu. Before that, he was a doctoral researcher at the Institute for Nanotechnology & AdvancedMaterials, Bar-Ilan University, Israel. Hemoved to Israel for his PhD after completing his MSc in Physics from National Institute of Technology Karnataka, India and gaining 2 years of industrial experience in various roles parting as an electron microscopy technologist of a research facility. His doctoral research dissertation mainly focused on engineering Raman scattering phenomena to probe light-matter interactions, emphasizing development of spectroscopic techniques for material detection. His research focuses onmolecular photonics and spectroscopy, with special emphasis on device spectroscopy, nanometrology, and energy materials. challenge of developing quantitative robust and trustworthy methods of data analysis. However, many methods have been developed for enhancement of these signals over the years by many research groups. These include chemical, surface, and cavity enhancement techniques that were reported by us [2– 4]. Furthermore, the presence of highly active Raman species such as carbon particles can mask the presence of other species. Several studies have been devoted to overcoming these drawbacks. Among these different approaches, it is known that polarized Raman spectroscopy provides information on molecular orientation and bond vibrational symmetry, in addition to general chemical identification [5]. In general, in polarized RS the spectra captured are either parallel or perpendicular to the inherent polarization of the excitation laser. However, Raman optical activity deals with the polarization phenomenon differently by observing the evolution of the Raman spectrum at different polarization angles. Polarizationmeasurements provide useful information about molecular shape and the orientation of molecules in ordered materials, such as crystals, polymers, and liquid crystals. The RS modes at lower wavenumbers (< 200 cm-1) are called low-frequency Raman (LFR) modes and the technique used to analyse this region of the spectrum is called low-frequency Raman spectroscopy (LFRS); the technique is very similar to spontaneous RS. LFRS is possible due to recent development of much sharper optical filters called volume holographic filters (VHFs). These filters facilitate easy observat ion of wavenumber shifts that are as low as 5 cm-1 away from the laser line. The LFR region is rich in information relating to lattice vibrations, crystallinity, symmetry, and inter-molecular acoustic modes, as well as phonon modes [6]. LFRS for identification of crystalline phases in methylammonium lead iodide Energy conversion from light to electricity has remained a major research area since the discovery of the photo-electric effect. While many materials and technologies have been developed over the years for this purpose, semiconductorbased solar cells have been spearheading the solar cell world due to their considerably higher efficiencies in spite of being expensive. The higher cost of existing technology has led to the expansion of research beyond conventional crystalline semiconductor materials. Organo-inorganic hybrid perovskites (OHPs) have remained promising in these efforts due to their exceptional performance resulting from their intrinsic properties such as high absorption coefficient, tunable band gap, long charge carrier diffusion, low exciton binding energy etc. Methylammonium lead iodide (MAPbI3) is the most widely used perovskite solar cell material. While the performance of the perovskite solar cells (PSCs) is commendable, the stability of OHPs remain questionable due to their high sensitivity to humidity, light, and temperature. The instability affects the crystal structure of the material and leads to degradation of crystal structure [7]. Here, we Figure 1. (a) Low-Frequency Raman Spectra and (b) PL spectra of tetragonal and cubic phases of MAPbI3 confirming laser-induced phase transition. §
8 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 present LFRS as a handy tool to identify and characterize phase transformations within such highly sensitive materials. Our preliminary work showed that the LFR modes are dependent on the crystallinity of the analyte material. It was observed that even in-situ changes in the material matrix upon laser excitation can successfully be captured with the right optical set-up and laser power. This was observed in examination of MaPbI3 single crystals. It is well-known from the literature that MAPbI3 exhibits different stable crystalline phases at different temperatures. At temperatures below 164 K it is orthorhombic, between 165-330 K tetragonal and at higher temperatures cubic. Additionally, there is a general agreement within the literature on thermally induced phase transitions in MAPbI3 [8]. In one of our earlier works, we presented a photoinduced phase transition [9]. A mere 2-minute excitation of MAPbI3 single crystals in the tetragonal phase with a 532 nm laser above 15 mW power resulted in the formation of cubic phase at ambient conditions and this phase transformation was confirmed using the photoluminescence (PL) shift as shown in Figure 1. Such dynamic phase transitions are hard to capture in conventional crystallographic techniques such as XRD. However, LFRS makes a good candidate for such thermal and photo-induced phase transition observations. When lower laser power can be used for characterizing the former, sufficiently high laser power facilitates both phase transition and detection. In addition to these unique characteristics of phase identification and phase transition detection, the study also revealed some interesting characteristics of the material such as Raman stimulation of iodine vapor signals in addition to stimulated spontaneous Raman signals. The overlap of the excitation laser with the electronic absorption band of the material results in resonance Raman scattering (RRS). This overlap results in a higher scattering intensity compared to the fundamental spontaneous Raman bands and in many cases leads to appearance of overtone bands [10]. On the other hand, stimulated Raman scattering (SRS) is a third-order nonlinear process that exhibits narrow-line emission from existing Raman shifts. In a regular experimental framework, this process is induced using two synchronized pulsed lasers as single-frequency excitation sources, or a narrowband source synchronized with a broadband source for multiplex excitation [11]. Certain materials under certain specific conditions self-induce SRS when subjected to a high enough laser power, even when the exciting laser is continuous wave (CW). This self-stimulated phenomenon is generally referred to as impulsive stimulated Raman scattering, or cascaded Raman process. Self-induced SRS is extensively investigated for ionic crystals, and it is understood that non-linear Raman gain is governed mainly by large crystal size and ionic radius of the cation; both of which are true for the MAPbI3 crystals used for this study [12]. Figure 2 represents the SRS from the resonant vibrational modes when the excitation laser power exceeds 15 mW. Yaakov R. Tischler leads the Device Spectroscopy Laboratory (DSL) at Bar-Ilan’s Institute for Nanotechnology and Advanced Materials. The lab is focused on studying and tailoring light-matter interactions in nanoscale devices and nanostructured materials. This involves research on microcavity polaritonic devices, organicbased lasers, near-field scanningmicroscopy, and applied vibrational spectroscopy. One of themain thrusts of DSL is Raman spectroscopy, which includes development of new spectroscopic techniques and applications thereof. Yaakov opened DSL 12.5 years ago and personally holds 13 US Patents. His former students and post-docs have gone on to make an impact in government, academic and high-tech sectors, particularly in the semiconductor and photonics industries as well as in start-ups. Figure 2. SRS from the resonant vibrational mode when laser power crosses 15 mW (green plot), and RRS obtained from high laser power excitation of PbI2(s) (pink plot).§ § Figure 1 and Figure 2 are reprinted with permission under © license 5338940298014.
9 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 LFRS for differentiation of enantiopure and racemic chiral molecules Chiral molecules form the basis of biological systems. Their occurrence is universal in the living world. They are present in the form of basic structures such as sugars and proteins and more complex ones such as amino acids, enzymes, and nucleic acids. The left- and right-handed chiral compounds exhibit different physiological effects and biological activities in biotic systems due to their contrasting interactions with proteins and enzymes [13]. It is therefore important to accomplish separation of enantiopure products from their counterparts. While various forms of chiral chromatography are widely used for enantiomeric separation, the identification of enantiopurity is achieved by studying their optical rotation or different forms of circular dichroism. While these studies are simple, they demand the analyte to be in solution form. Although X-ray diffraction, differential scanning calorimetry, inelastic neutron scattering etc. enable identification in the solid form, they are much more complex and expensive [14]. Most of the work on LFR for chiral analysis was conceived together with our colleague Prof. Mastai. In these works, we demonstrated that LFRS can be used for crystal chirality investigations, particularly for distinguishing between racemic and enantiopure organic crystals [15]. Enantiopure chiral crystals are those comprising only one type of chiral crystal among the two possible forms. However, when a crystal contains equal amounts of each enantiomer constituting an enantiomeric pair, it is called a racemate. Most racemic mixtures crystallize as racemic crystals; however, in some cases (5% to 10% in nature), racemic compounds crystallize in a conglomerate form that is a mixture of homochiral crystals. It is known from the literature that racemic crystals are denser than the corresponding enantiopure crystals. This is generally explained by the difference in their hydrogen bonding. In the case of an enantiopure material, crystallization is dictated Figure 3. LFR spectra of (a) L-Alanine, DL-Alanine crystals, and (b) L-Valine, DL-Valine crystals‡. Figure 4. LFR spectra of (a) L-Aspartic acid, DL-Aspartic acid crystals, and (b) L-Arginine, DL-Arginine crystals‡. ‡ Figure 3 and Figure 4 are reprinted with permission from J. Phys. Chem. A 2017, 121, 7882-7888 ©2017 American Chemical Society.
10 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 by the chirality, and thus the hydrogen bond network is limited, whereas for racemic crystals, there is an extremely large availability of hydrogen bonding modes [16]. Hence the structure is stochastically defined. These considerable differences in the crystalline structure result in differences in the intermolecular interactions of racemic and enantiopure crystals. As a result, distinct vibrational modes exist in enantiopure and racemic crystals that are detectable by LFRS. Some examples of enantiomeric differentiation from their racemic mixtures are presented in Figure 3 and 4. Hence, it is observed that LFRS produces completely different spectra for racemic and enantiopure crystals. Moreover, LFRS offers faster and more sensitive chiral characterization in crystals than currently used methods, enabling facile measurements for microcrystals and detection of defects in chiral crystals. More detailed study can be found elsewhere [15]. Polarization dependence of LFRS in organic single crystals Crystal lization is a very unique phenomenon in pure compounds. Post nucleation, under a conducive environment, crystal lization results in formation of highly ordered structures and adaptation of a unique three-dimensional orientation. The crystal structure governs physical and chemical properties in materials [17]. Therefore, it is extremely important to investigate and understand the structure and orientations of intermolecular interactions in crystals. Over the years, many different physical techniques hav e been used to characterize crystalline structures, such as X-ray diffraction (XRD), thermal analysis, and electron diffraction. In general, each face of a single crystal provides detailed structural information. The most common experimental method that al lows resolution of individual atoms is single crystal X-ray diffraction (SCXRD) [18]. However, it requires a sufficiently large crystal that is at least partially transparent i.e. in general is bright looking, having clear edges and faces, and is free of inclusions. Another method for characterizing crystals that uses X-rays is near-edge X-ray absorption fine structure, a technique which determines the molecular orientation for non-transparent samples. Raman spectroscopy, with established higher sensitivity than XRD in crystal purity investigations, provides information on both covalent bonds based on intramolecular vibrations and intermolecular interactions [19]. At the same time, intermolecular interactions that result in shear modes, breathing modes, and hydrogen bond stretching modes are lower in energy and are observed in LFRS. The LFR modes are generated by weak interactions including molecular degrees of freedom and shear modes, and are observed in the lower range of LFRS, while vibrational modes that are generated by stronger intermolecular interactions such as hydrogen bonds exhibit larger LFR shifts within the LFRS spectral range. Theoretical and computational efforts have successfully assigned these larger LFR modes to hydrogen bond stretching vibrations using density functional theory (DFT) calculations. Previous studies have used polarized Raman spectroscopy for various applications in material characterization. Polarization dependence in Raman, along with transmission electron microscopy, is used to investigate the crystallographic orientation of dark crystals [20]. Polarization-dependent contrast in the interaction cross section of LFR modes was primarily probed in this study. We observe that investigation of crystal structures is indeed possible by studying vibrational modes obtained from each face of a single crystal using LFRS. Unlike other methods, Figure 5. (a) Photo of L-aniline single crystal and measured planes. (b) L-aniline crystal structure constructed using the program “Mercury” along with the measured planes (101), (002), and (011).
11 The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 Scientific Article Figure 6. (a) Hydrogen bonds’ simulation (dotted lines) in the L-alanine single crystal relative to the (101) plane. (b) LFRS of crystals excited from (101) direction with three different polarization angles. Figure 7. (a) Hydrogen bonds’ simulation (dotted lines) in the L-alanine single crystal relative to the (002) plane. (b) LFRS of crystals excited from (002) direction with three different polarization angles. Figure 8. (a) Hydrogen bonds’ simulation (dotted lines) in the L-alanine single crystal relative to the (011) plane. (b) LFRS of crystals excited from (011) direction with three different polarization angles. (a) (a) (a) (b) (b) (b)
12 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 due to the reflection geometry of the optical set-up, even lack of transparency does not affect the ability to characterize the structural properties of a crystalline material. The only known governing factors for successful characterisation is presence of hydrogen bonds in addition to other low energy modes. The contrast in polarizability of hydrogen bond in the crystal in different directions resulted in characterizability of the structure using LFRS. The variation of polarizability of the hydrogen bonds and resulting spectral contrast is presented in Figures 5–8. A detailed report of this can be found elsewhere [21]. Polarized LFRS for identification of enantiomers An overview of enantiomers and chirality is presented in earlier sections. Enantiomers being molecules with mirror symmetries have right-handed or left-handed symmetry in their structure. This results in antiparallel polarizabilities. In other words, when plane-polarized laser excitation along a particular polarization plane is incident on D- and L-enantiomers, the polarizabilities induced in the molecule are opposite to one another [22]. With LFR modes in general being orientation dependent, the LFR interaction cross-section is therefore dependent on the polarization angle of the excitation laser [23]. This counterintuitively results in different scattering cross sections along different polarization directions. Observation of this contrast is impossible in RS systems that have normal angle of incidence. This work is the realization of a theoretical study of the polarization phenomena with respect to the laser and Raman signal propagation in optically active samples, which was proposed elsewhere [24]. In our work, we engineered an asymmetry into the optical set-up in both excitation and collection geometries and constructed an offaxis excitation collection set-up. In addition to the engineered asymmetry, the excitation and collection geometries were modified to accommodate polarizers to allow capture of orthogonal ly polarized signals. This resulted in enantio-contrasting interaction cross sections along excitation geometry and enantio-selective LFR spectrum in collection geometry. Figure 9 represents the schematics of asymmetry induced into the optical system by virtue of modification and resulting asymmetrical interaction cross sections and induced contrast into the collection signal. Experimental details can be found elsewhere [25]. The study was the first of its kind for identification of enantiomers in their solid form using LFRS. For representation purposes, we present the spectra showing enantioselective contrast between enantiomeric pairs in Figure 10. A detailed explanation of the experimental set-up can be found elsewhere. Figure 9. (a) Schematic representation of conventional Raman excitation and collection and (b) its collected focal area. (c) Schematic representation of the modified Raman setup and (d) its collected focal area. The modified Raman collects different intensities from the polarization planes after excitation of optically activematerials. The schematics are approximate representations directed to understand the processes. The colored squares are a guide to the eye, representing (a) a symmetric interaction cross section for both D and L enantiomers and (b) relative asymmetric interaction cross section for D and L enantiomers*.
13 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 Conclusion Raman spectroscopy is a well-known powerful analytical tool that has become increasingly important in recent years. More recently, the development of VHFs has led to high impact research in LFRS. The main aim of this article is to summarize unique characterization efforts using LFRS and polarized Figure 10. LFR spectra of (a) D-arginine, (b) L-arginine, (c) D-leucine, (d) L-leucine, (e) D-serine, and (f) L-serine. All powders were excited using P-Polarization. Red curves present the signal collected along P-Polarization, and blue curves present the signal collected along S-Polarization*. * Figure 9 and Figure 10 are reprinted with permission from Anal. Chem. 2022, 94, 3188−3193 ©2022 American Chemical Society. LFRS, leading to evolution of the technique into a versatile characterisation and material detection tool. In this article, we have summarised four of our distinct research efforts leading to the unique application of LFRS for enantiomeric identification in solid form.
14 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 References 1. C. V. Raman, “A new radiation,” Indian J. Phys, 1928, 2, 387–398. 2. V. H. Damle, L. Gouda, S. Tirosh, and Y. R. Tischler, “Structural Characterization and Room Temperature Low-Frequency Raman Scattering from MAPbI3 Halide Perovskite Films Rigidized by Cesium Incorporation,” ACS Appl. Energy Mater., 2018, 1, 6707–6713. 3. T. ben Uliel, L. Gouda, H. Aviv, A. Itzhak, and Y. R. Tischler, “Microcavity enhancement of low-frequency Raman scattering from a CsPbI3 thin film,” J. Raman Spectrosc., 2019, 50, 1672– 1678. 4. V. H. Damle, M. Sinwani, H. Aviv, and Y. R. Tischler, “Microcavity Enhanced Raman Spectroscopy of Fullerene C60 Bucky Balls,” Sensors, 2020, 20, 1470. 5. V. Sereda, N. M. Ralbovsky, M. C. Vasudev, R. R. Naik, and I. K. Lednev, “Polarized Raman Spectroscopy for Determining the Orientation of di-D-phenylalanine Molecules in a Nanotube,” J. Raman Spectrosc., 2016, 47, 1056–1062. 6. L. Liang, J. Zhang, B. G. Sumpter, Q. H. Tan, P. H. Tan, and V. Meunier, “Low-Frequency Shear and Layer-Breathing Modes in Raman Scattering of Two-Dimensional Materials,” ACS Nano, 2017, 11, 11777–11802. 7. B. P. Dhamaniya, P. Chhillar, B. Roose, V. Dutta, and S. K. Pathak, “Unraveling the Effect of Crystal Structure on Degradation of Methylammonium Lead Halide Perovskite,” ACS Appl. Mater. Interfaces, 2019, 11, 22228–22239. 8. Q. Wang, M. Lyu, M. Zhang, J. H. Yun, H. Chen, and L. Wang, “Transition from the Tetragonal to Cubic Phase of Organohalide Perovskite: The Role of Chlorine in Crystal Formation of CH3NH3PbI3 on TiO2 Substrates,” J. Phys. Chem. Lett., 2015, 6, 4379–4384. 9. T. Ben-Uliel et al., “Raman scattering obtained from laser excitation of MAPbI3 single crystal,” Appl. Mater. Today, 2020, 19, 100571. 10. R. S. Czernuszewicz and M. B. Zaczek, “Resonance Raman Spectroscopy,” 2011, in Encyclopedia of Inorganic and Bioinorganic Chemistry (Wiley). 11. 11. R. C. Prince, R. R. Frontiera, and E. O. Potma, “Stimulated Raman Scattering: From Bulk to Nano,” Chem. Rev., 2017, 117, 5070–5094. 12. Xiaoli Li, Andrew J. Lee, Yujing Huo, Huaijin Zhang, Jiyang Wang, James A. Piper, Helen M. Pask, and David J. Spence, “Managing SRS competition in a miniature visible Nd:YVO4/ BaWO4 Raman laser” Opt. Exp., 2012, 17, 19305-19312. 13. N. M. Davies and X. W. Teng, “Importance of Chirality in Drug Therapy and Pharmacy Practice: Implications for Psychiatry,” Adv. Pharm., 2003, 1, 242–252. 14. T. B. Freedman, X. Cao, R. Dukor, and L. A. Nafie, “Absolute Configuration Determination of Chiral Molecules in the Solution State using Vibrational Circular Dichroism,” Chirality, 2003, 15, 743–758. 15. H. Aviv, I. Nemtsov, Y. Mastai, and Y. R. Tischler, “Characterization of Crystal Chirality in Amino Acids Using Low-Frequency Raman Spectroscopy,” J. Phys. Chem. A, 2017, 121, 7882–7888. 16. A. R. Kennedy, C. A. Morrison, N. E. B. Briggs, andW. Arbuckle, “Density and Stability Differences between Enantiopure and Racemic Salts: Construction and Structural Analysis of a Systematic Series of Crystalline Salt Forms of Methylephedrine,” Crystal Growth and Design, 2011, 11, 1821–1834. 17. O. Sichevych et al., “Crystal Structure and Physical Properties of the Cage Compound Hf2B2-2δIr5+δ,” Inorg. Chem., 2020, 59, 14280–14289. 18. K. Hasegawa, “Introduction to Single Crystal X-ray Analysis,” The Rigaku Journal, 2012, 28, 14–18. 19. I. Nemtsov, Y. Mastai, Y. R. Tischler, and H. Aviv, “Chiral Purity of Crystals Using Low-Frequency Raman Spectroscopy,” ChemPhysChem, 2018, 19, 3116–3121. 20. J. Kim, J. U. Lee, andH. Cheong, “Polarized Raman Spectroscopy for Studying Two-Dimensional Materials,” J. Phys: Condens. Matter, 2020, 32, 343001. 21. I. Nemtsov, H. Aviv, Y. Mastai, and Y. R. Tischler, “Polarization Dependence of Low-Frequency Vibrations fromMultiple Faces in an Organic Single Crystal,” Crystals, 2019, 9, 425. 22. A. Yachmenev and S. N. Yurchenko, “Detecting Chirality in Molecules by Linearly Polarized Laser Fields,” Phys. Rev. Lett., 2016, 117, 033001. 23. X. Ling et al., “Low-Frequency Interlayer Breathing Modes in Few-Layer Black Phosphorus,” Nano Lett., 2015, 15, 4080–4088. 24. J. Kiefer and K. Noack, “Universa l enant ioselect ive discrimination by Raman spectroscopy,” Analyst, 2015, 140, 1787–1790. 25. V. H. Damle, H. Aviv, and Y. R. Tischler, “Identification of Enantiomers Using Low-Frequency Raman Spectroscopy,” Anal. Chem. 2022, 94, 3188–3193.
15 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 Novel molecular architectures for “multicolor” magnetic resonance imaging Amnon Bar-Shir Department of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot, 7610001, Israel Email: amnon.barshir@weizmann.ac.il 1. Introduction The complexity of biological processes, as well as their tightly controlled regulation, attracts researchers from a wide range of scientific fields. Such multiplexity is apparent in almost every aspect of life, in health and in disease, from enzymatic activity to protein-protein interactions, frommetal ion homeostasis to cell function, from gene expression to neuronal activity, or from gene networks to disease onset and therapeutics mechanisms. Although our accumulated knowledge allows us to understand many aspects of these processes, some are still elusive, unknown, or cannot be studied in an intact live organism. In this regard, luminescent sensors (small molecules [1], proteins [2], or nanoformulations [3]) have been the “highlighter pens” of science for decades, since they enable molecules (or cells) of interest to be tagged, enabling mapping of their location, levels, and functions in multiple distinguishable colors. This capability has advanced our ability to reveal the complexity of cellular events, study their tight regulation, and explore a wide range of biological processes concurrently. Perfecting the chemical and optical properties of luminescent materials, in addition to dramatic improvements in microscopy technologies, provide scientists with the ability to visualize multiple biological targets simultaneously within the same imaging frame. However, the light signal source of these materials remains an obstacle when information is desired from the deep tissue of a live subject. MRI, with its unlimited tissue penetration capabilities and ability to combine information from biological targets with high-resolution anatomical images, has become a valuable imaging technology for molecular and cellular imaging. Amnon Bar-Shir earned his BSc (2002) and MSc in chemistry from Tel Aviv University (2004, under Michael Gozin), both magna cum laude. His PhD (2009, under Yoram Cohen) focused on advanced diffusion NMR and MRI to study the structure and function of the central nervous system. As a postdoc at the Johns Hopkins University School of Medicine under Assaf Gilad he developed genetically engineered reporters for MRI. In 2014 he joined the Weizmann Institute, where he created new kinds of biosensors with artificial “multicolor” features for MRI applications. His lab uses synthetic chemistry, nanofabrication, and protein engineering to generate novel molecular formulations, such as small molecules, nanocrystals, supramolecular assemblies and proteins, as MRI sensors of high sensitivity, specificity, and orthogonality. He has used thesemethods for in-vivo molecular and cellular MRI studies for mapping inflammation, multiplexed in-vivo MRI, imaging orthogonal reporter genes, and sensing metal ions. In addition, he used his techniques to study fundamental questions in supramolecular chemistry, including kinetic features of dynamically exchanging molecular systems and control over nanocrystal formation. Amnon’s research achievements were recognized recently by the 2019 Krill Prize, and the 2021 ICS Excellent Young Scientist Prize. Abstract: Luminescent materials with their rich color palettes have revolutionized the field of bioimaging through the ability to distinguish between spectrally resolved colors and, thus, to map the complexity of biological systems. Yet, advanced solutions to overcome the restricted tissue penetration of light are still needed to allow in vivo mapping of tissue multiplexity in both health and disease. Among the diverse capabilities and many advantages of MRI, the ability to encode specific frequencies of imaging agents and, by that, to allow pseudo-color display of MRI maps, is unique. Here, I summarize our recently developed molecular probes that are capable of generating artificial MR-based colors. To this end, the use of nanofabrication, supramolecular chemistry, and protein engineering approaches to generate novel molecular formulations (inorganic nanocrystals, supramolecular assemblies, and enzyme/substrate pairs) as MRI sensors with uniquemulticolor display characteristics is reviewed.
16 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 types, as well as on developing methods for pseudo-color in vivo MR imaging. I here provide an overview of our recent developments, emphasizing the newly proposed MRI sensors that are based on inorganic nanocrystals (NCs), host-guest systems, and engineered proteins, which have the potential to extend the MRI toolbox with features that have been, thus far, inaccessible. Principles of generating pseudo-colors for MRI Several strategies have been proposed to generate pseudocolors for MRI applications. One example is the use of the chemical exchange saturation transfer (CEST) contrast mechanism to produce artificial MRI colors (Figure 1a). By applying a saturation pulse at the specific resonance of an exchangeable proton of a putative CEST agent, it can be “tagged.” This tag (manifested by its MR signal nullification) is transferred to the water protons in the surrounding area and leads to 1H-MRI signal reduction as a result of the dynamic exchange process of the “tagged” protons with the water protons. Using multiple CEST agents with exchangeable protons that resonate at different and specific chemical shift offsets (Dws) from the resonance of the water protons (set at 0.0), artificial MRI colors can be generated, as demonstrated for several applications [6, 8]. The relatively large chemical shift range of fluorinatedmaterials in a 19F-MR framework was also exploited for spectral differentiation between different fabrications and presents this range in a pseudo-color manner (Figure 1b) [7, 9, 10]. Benefitting from the negligible tissue background in 19F-MRI and the 19F-MR signal quantifiability, multicolor 19F-MRI studies provide unique multicolor MRI features that are not accessible to a 1H-CEST-based approach. Combining the two strategies for multicolor MRI, i.e., CEST and 19F-MR to obtain 19F-CEST [11] (Figure 1c), provides a novel MRI platform that can be implemented for applications in which both 1H-CEST and 19F-MRI are not applicable. Nanofluorides Fluorine-19 is the second most NMR-sensitive nucleus (after 1H) and is therefore favorable for MR-based studies (NMR and MRI) and fluorinated materials have been proposed as 19F-MR imaging tracers [12], overcoming some of the major drawbacks (i.e., strong background signal, non-quantifiable, challenging in multiplexing, etc.) of paramagnetic contrast agents. Combining this with the fact that 19F-nuclei do not exist in soft biological tissues, the 19F-MR signal of an introduced 19F-tracer can be directly monitored and presented Moreover, the versatility of MRI contrast mechanisms [4, 5], and the variability in imaging probe identities (including non-1H tracers), create many possibilities for the design of MRI sensors. One feature that is unique to MRI is that this technique relies on MR properties, which allows, among other advantages, differentiation between molecular entities based on their chemical environment, which is reflected by a characteristic chemical shift. If spectrally resolved, the frequencies of multiple chemical shifts of properly designed molecular probes can be exploited for multiplexed imaging by introducing MRI maps with pseudo-color features [6, 7]. Such pseudo-MRI-colors can be generated using several strategies, including the use of non-1H nuclei, which frequently provide improved spectral resolution, or through magnetization transfer mechanisms that benefit from the high sensitivity of 1H-MRI. In recent years, our lab has focused on the development of novel molecular formulations of a variety of Figure 1. Strategies to generate artificial colors in 1H- and 19F-MRI frameworks. (a) Artificial colors can be generated in CEST-MRI by exploiting the different chemical shift offsets of different exchangeable protons of 1H-CEST agents. (b) In 19F-MRI, artificial colors can be generated by using different 19F-agents based on the difference in the 19F-chemical shifts of their fluorinated content. (c) In the 19F-CEST approach, which is applied on host-guest systems (termedguest exchange saturation transfer, GEST), the sameprinciples used to generate artificial colors in 1H-CEST are used. In this case, the different chemical shift offsets are obtained from the complexation of a 19F-guest with a different molecular host in the solution. 0 Frequency offset from 1H2O [ppm] ω2 ω3 R-NH R-NH2 1H2O R-OH ω1 19F chemical shift [ppm] ω1 ω2 R319F R219F R1 19F ω3 0 Frequency offset from free 19F-guest [ppm] ω2 ω3 19F-guest ω1 F F F F a) 1H-CEST b) 19F-MRI c) 19F-CEST
17 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 as a quantitative “hot-spot” map over anatomical 1H-MRI. In this regard, perfluorocarbons (PFCs), fluorine-rich materials, have been successfully used in a wide range of 19F-MRI applications [12, 13], including clinical setups [14]. Relying on the relatively large range of their chemical shift appearances in the 19F-NMR spectrum (a few tens of ppm), PFCs have been proposed for multiplexed in vivo 19F-MRI [7, 9, 10]. Nevertheless, their introduction as emulsions of a typical 100– 200 nm size (i.e., PFC nanoemulsions) and because they are organic formulations, PFC nanoemulsions are not applicable for studies for which ultrasmall (<10 nm) nanoformulations are desired, and they lack the well-established and diverse chemistries of inorganic nanocrystals (NCs). Moreover, they do not cover the whole range of 19F-NMR chemical shifts, which span over almost 200 ppm when using inorganic fluorides (as shown by solid-state NMR). An inorganic, small-size alternative to PFC nanoemulsions may, therefore, be fluoride-based NCs (MxFy, M = metal ion, F = F-), which had not been studied in solutions with highresolution 19F-NMR and were not used in 19F-MRI until very recently. This is because in NC-based formulations, the restricted mobility of the elements within the crystal frequently results in NMR line-broadening, and highresolution NMR signals from the core of the NCs’ nuclei cannot be obtained using liquid-state NMR experiments. Overcoming such l imitations and, thus, successful ly performing liquid-state 19F-NMR experiments of M xFy in solution, we offered a novel kind of 19F-nanotracers for 19FMR imaging, which are based, for the first time, on inorganic fluoride NCs, namely nanofluorides [15]. These nanofluorides combine the advantages of inorganic NCs (e.g., small and controllable sizes, dense fluoride content, monodispersity, colloidal stability, surface modifiability, designed as nonspherical materials, etc.) with the merits of 19F-MRI. In addition, the large chemical shifts of nanofluorides, which can span over almost 200 ppm, provide a platform for the development of a series of fluoride-based NCs with different 19F-NMR chemical shifts, which can serve as artificial “multicolor” tracers for multiplexed MRI. Demonstrating that high-resolution 19F-NMR spectra can be achieved by sufficient averaging of homonuclear dipolar interactions of 19F-nuclear spins within small-size fluoridecontaining NCs (i.e., nanofluorides), we showed that CaF2 NCs can be used as nano-sized molecular tracers for 19F-MRI [15]. First, small, water-dispersed CaF2 NCs were synthesized and found to be highly crystalline and monodispersed (Figure 2a) with preserved monodispersity in water, as determined by dynamic light scattering (DLS, Figure 2b). The XRD pattern of the synthetic CaF2 NCs (Figure 2c) features a typical cubicphase, fluorite-type, fcc structure, where all fluorides are expected to be magnetically equivalent, as reflected by the first coordination sphere scheme (inset, Figure 2c). Indeed, a singlet peak was observed in the high-resolution 19F-NMR spectrum of water-dispersed CaF2 NCs at -109 ppm (Figure 2d), similar to the frequency obtained for CaF2 powder with solid-state NMR [16]. Then, the potential of using the proposed CaF2 NCs as imaging tracers for in vivo 19F-MRI was evaluated in a mouse model of inflammation. To this end, polyethylene-glycol (PEG)-coated CaF2 NCs were injected into a group of inflamed mice. A clear 19F-MRI signal was observed at the region of the popliteal lymph node of NCinjected mice in the same leg as the injection site (Figure 2e) one hour post-injection. Although their potential to be used in vivo was evident, the T1 relaxation times of nanofluorides are relatively long (>10 sec) [15], which limits signal averaging and, thus, the signal-tonoise ratio (SNR) in 19F-MR images at a given imaging time. Figure 2. 19F-NMR and 19F-MRI of water-soluble CaF 2 NCs. (a) TEM images. (b) DLS histogram. (c) XRD pattern with schematic of the Ca2+ first coordination sphere (red spheres represent 19F-atoms). (d) High-resolution 19F-NMR in water. (e) In vivo imaging of PEGylated CaF2 showing anatomical 1H-MRI of a representative mouse (left) and matched 19F-MRI (middle) shown as a pseudo-color map overlaid on 1H-MRI (right). Modified from reference 15 with permission. e
18 Scientific Article The Israel Chemist and Chemical Engineer Issue 9 · January 2023 · Tevet 5783 over phospholipid coated Sm:SrF2 (i.e., PL-Sm:SrF2, and thus referred to as non-glycosylated nanofluorides), in realtime, in the same inflamed tissue by presenting their spatial distribution as a multicolor 19F-MRI map (Figure 3d-i). In addition to the ability to use them as imaging agents for 19F-MRI, in general, and the potential to use them for multicolor MRI applications in particular (Figure 3), we developed a liquid-state NMR approach with which to study the formation pathways of nanofluorides with a conventional NMR setup, without the need to disturb the reaction conditions. Synthesizing nanofluorides under in situ NMR conditions, we were able to probe their sub-nm growth over the entire course of their formation, highlighting their controllable growth mechanisms (coalescence vs. classical simple-growth), which resulted in different morphological and functional features [18, 19]. Examining the correlation between the crystallographic features of the nanofluorides and their relaxation properties, we have developed an approach to shorten the T1 relaxation times of the fluoride content in nanofluorides by 10-fold only by introducing a defect in their crystals. Such an approach for nanocrystallinedefects relaxation enhancement (NDRE) demonstrates that, while avoiding the use of paramagnetic elements and without introducing the PRE-effect to shorten T1 values, we were able to extensively enhance the longitudinal relaxation rates of small-sized fluoride NCs to improve 19F-MRI performance [20]. To overcome this pitfall, nanofluorides were doped through their fabrication with the paramagnetic dopant Sm3+, which induced a significant paramagnetic relaxation enhancement (PRE) effect. Specifical ly, the T1 of nanofluorides was shortened more than 200-fold, from a T1 of ca. 15 s for nondoped CaF2 to an ultrashort T1 of 70 ms for Sm:CaF2 resulting in an eight-fold enhancement in their 19F-MRI SNR [17]. Then, with the introduction of paramagnetic nanofluorides (with Sm:CaF2 as a putative example), the ability to classify different types of synthetic nanofluorides and present them in a “multicolor” fashion was also examined. In this regard, the large range of chemical shifts of nanofluorides, which spans from BaF2 (ca. -10 ppm) to MgF2 (ca. -200 ppm) [16], provided a platform for the development of a series of fluoride-based NCs with different 19F-NMR chemical shifts. To demonstrate this ability, paramagnetic nanofluorides of the Sm:SrF2 type were synthesized to have a size and shape similar to Sm:CaF2 (Figure 3a). Dispersed in water, well-resolved, high-resolution 19F NMR peaks that differed from one another by more than ∼20 ppm (Figure 3b) were obtained with the expected characteristic resonances for SrF2 (-88 ppm) and CaF2 (-109 ppm). Such relatively large difference in their chemical shifts allowed spatial mapping of the two types of nanofluorides (Sm:CaF2 vs. Sm:SrF2) in the same imaging frame, without overlapping signals and without affecting the two detectable 19F-MRI signals (Figure 3c). Specifically, we demonstrated the immune specificity of lactose-phospholipid coated Sm:CaF2 (i.e., LPL-Sm:CaF2, namely paramagnetic glyconanofluorides) Figure 3. Multicolor 19F-MRI with nanofluorides. (a) TEM images (scale bar: 50 nm) of Sm:SrF 2 and Sm:CaF2 nanofluorides and (b) their 19F-NMR spectra when dispersed in water. (c) Multicolor 19F-MRI of a phantom containing SrF 2, CaF2, or a mixture of these. (d) Schematic representation of nonglycosylated PL-Sm:SrF2 and glycosylated LPL-Sm:CaF2 NCs injected as a mixture into the footpad of an inflamed mouse. (e) 1H-MRI of the inflamed mouse; white arrow indicates the inflamed lymph node, and yellow arrow represents the injection site. (f) In vivo 19F-NMR spectrum (total injected PL-Sm:SrF2 and LPL-Sm:CaF2). (g) 19F-MRI acquired with the center of the frequency offset set at either −88 ppm (left, yellow) or −109 ppm (right, light blue). (h) Representative 1H/19F MRI showing the higher accumulation of LPL-Sm:CaF 2 NCs in the LN. (i) Dot graph presenting the 19F-MRI signal of either PL-Sm:SrF 2 or LPL-Sm:CaF2 in the lymph node ROI (n = 4, Student’s t test, * represents a p value <0.05). Scale bar: 50 nm. Modified with permission from ref. 17 https://pubs.acs.org/doi/10.1021/acsnano.1c01040
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