Chirality as a phenomenon in nature has always been present. As a concept in science, it has been around for some time. It began as a curiosity, then became a fundamental component in scientific research, and today, it is a crucial consideration in medicine. It is important in crystallography, though not always recognized explicitly; for example, it does not appear in the Subject Index of the excellent Historical Atlas of Crystallography [1].
The main thrust of our research careers has been determining and modeling molecular structures. We were not concerned with chirality when using gaseous electron diffraction to determine internuclear distances because the same set of internuclear distances characterizes both chiral versions. However, chirality has fascinated us due to our broader interest in symmetry [2−4]. This essay surveys a set of selected examples of chirality.
Many objects, both animate and inanimate, have no symmetry plane but occur in pairs that are related by a symmetry plane. They are each other's mirror images but cannot be superimposed. This is called chirality or handedness from the Greek word for hand, cheir (χέρι). Below, we present examples of a homochiral pair, a heterochiral pair of hands and a heterochiral pair of feet — the concept could just as well be called 'podality' (from pódi — πόδι). The phenomenon belongs to the more general concept of dissymmetry, which signifies the absence of certain symmetry; in the case of chirality, it is the absence of a symmetry plane.
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From left to right: homochiral pair of hands: Auguste Rodin, The Cathedral, Rodin Museum, Paris; heterochiral pair of hands: tombstone in the Jewish cemetery, Prague; legs: detail of the sculpture Wave, by Kay Worden, Newport, Rhode Island. Photographs by the Hargittais.
Not only material objects can have handedness: there is a beautiful example in Johann Sebastian Bach's (1685−1750) The Art of the Fugue.
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Chiral pair: J. S. Bach, Die Kunst der Fuge, detail.
The German philosopher Immanuel Kant (1724−1804) wrote about the puzzle of the isometric left and right hands that cannot be made to coincide in space. He called the non-superposable mirror images "incongruente Gegenstücke" (incongruent counterparts) [5].
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Immanuel Kant: stipple engraving by J. Chapman, 1812 (Wellcome Collection).
In 1811, D. François J. Arago (1786−1853) described the optical activity of quartz crystals. Some rotated the plane of polarized light in one direction, while other quartz crystals rotated it to the same extent but in the opposite direction. [6]. This discovery was one of Arago's many discoveries in several areas of science. For one of them, on the magnetic properties of substances not containing iron, he received the most prestigious Copley Medal of the Royal Society (London) in 1825.
In 1812, Jean Baptiste Biot (1774−1862) discovered the optical activity of quartz crystals [7] and observed that some solids, even when dissolved in water, showed the same effect. Biot's genius manifested in his conclusion that the effect is a molecular property. It was then left to Louis Pasteur (1822−1895), decades later, to understand the correlation of dissymmetric crystals and the optical activity in solution. Chirality and optical activity have been intimately related, and laevo-active (L) and dextro-active (D) chiral substances have been distinguished. Optical activity does appear among the entries in the Subject Index of the Historical Atlas of Crystallography [1]. Indeed, it is a more general concept than chirality. If a molecule or a crystal is chiral, it is necessarily optically active, whereas the converse is not true. There are symmetry classes of crystals that are non-enantiomorphous yet may exhibit optical activity.
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D. François J. Arago and Jean Baptiste Biot: lithographs (Wellcome Collection).
What Pasteur did in this connection in 1848 may be called the reverse experiment. He crystallized sodium ammonium tartrate from a solution he prepared from the optically inactive salt. He obtained crystals of two kinds, which were each other's mirror images. One of the two was identical with the crystals of the naturally occurring optically active tartrate — a product of the fermentation of wine. But the other, its mirror image, had never been seen before. Pasteur separated the two forms by hand. Tartrate was a lucky choice because manual separation is rarely possible. In his next experiment, Pasteur dissolved the two kinds of crystals separately in water, and the two solutions showed optical activity of the same magnitude but opposite in direction. The old Biot presented Pasteur's findings of crystal and molecular dissymmetry (today, we prefer the term chirality) to the French Academy of Sciences. Biot realized the magnitude of Pasteur's discovery, so he had Pasteur first demonstrate it to him in the laboratory before reporting about it to the Academy. When Biot could see the experiment with his own eyes, in Pasteur's words [8] he became: "...very visibly affected, the illustrious old man took me by the arm and said, 'My dear child, I have loved science so much throughout my life that this makes my heart throb.'"
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Louis Pasteur's bust in front of the central building of the Institut Pasteur, Paris, and his models as exhibited there. Photographs by the Hargittais.
Pasteur's discovery had broad implications. J. Desmond Bernal (1901−1971) pointed out that it arose at a meeting place of three great distinct disciplines: crystallography, physics, and chemistry. In his treatise Molecular Asymmetry [9], Bernal charted the developments that could be related to Pasteur's discovery. Here and already once above, the term 'molecular asymmetry' figures, whereas the term 'molecular dissymmetry' often occurs in describing chirality. It is a little confusing, so we better define them: asymmetry means the complete absence of symmetry and dissymmetry means the absence of certain symmetry. Accordingly, in this case, indeed, dissymmetry and asymmetry could be used interchangeably. When Bernal discusses the significance of Pasteur's discovery, he reaches back to other classics of science, to R. J. Haüy, J. F. W. Herschel, J. J. Berzelius, and Auguste Bravais. He shows how they contributed to the development of the concept and to the development of X-ray crystallography in the early 1910s.
Lord Kelvin (1824−1907) wrote [10]: "I call any geometrical figure, or group of points, chiral, and say that it has chirality if its image in a plane mirror, ideally realized, cannot be brought to coincidence with itself."
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William Thomson, Lord Kelvin: photograph by Harry Herman Solomon (Wellcome Collection).
Pierre Curie (1859−1906) formulated the most general and fundamental concept related to symmetry that involves dissymmetry, including chirality: "c'est la dissymétrie qui crée le phénomène" (dissymmetry creates the phenomenon) [11]. A phenomenon is expected to exist and can be observed only if certain elements of symmetry are absent from the system. A forerunner of this concept was put forward in 1833 by Franz E. Neumann (1798−1859) in his studies of the physical properties of crystals: "The physical properties of crystals always conform to the symmetry of the crystal" [12].
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Statue of Marie and Pierre Curie in the Marie Curie Garden, Paris 5 — Latin Quarter, photograph by the Hargittais; and Chiral Pierre Curie by and courtesy of the graphic artist Istvan Orosz [3].
The emergence of stereochemistry could be a direct consequence of Pasteur's discovery. Its birth was in 1874, which is 150 years ago [14, 15]. The basic concepts were proposed by J. H. van 't Hoff (1852−1911) and J. A. Le Bel (1847−1930). Van 't Hoff published a booklet, La Chimie dans l'Espace (Chemistry in Space). Viktor Meyer (1848−1897) first used the term stereochemistry in 1890. The idea of extending the description of materials structures into the third dimension reaches back at least to Johannes Kepler in the early 18th century [16] and John Dalton in the early 19th century [17] in their discussions of the stacking of the building elements in water and ice. Still, even as late as 1956, the distinguished crystallographer Albert F. Wells (1912−1994) felt the need to stress that the description of "...the three-dimensional arrangements of atoms in crystals was an integral part of structural chemistry" [18].
The possibility that chirality leads to two different versions of the molecules of the same substance causes a well-defined isomerism in molecular structures. This is shown in the scheme below summarizing molecular isomerism. According to Vladimir Prelog (1906−1998), Hans Erni's ex libris, shown below, contains all three basic paraphernalia necessary for dealing with chirality. They are human intelligence, a pair of left and right hands, and two enantiomorphous tetrahedra [19]. Prelog was a co-recipient (with John W. Cornforth) of the 1975 Chemistry Nobel Prize "...for his research into the stereochemistry of organic molecules and reactions."
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Hans Erni's ex libris bookplate for Vladimir (Vlado) Prelog with a dedication to one of the present authors (courtesy of the late Vladimir Prelog). A peculiar feature of this drawing is that the two hands appear inverted due to the two arms being crossed [13]. Erni made other versions of this drawing in which the two hands appear non-inverted.
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Hierarchy of molecular isomerism ([2], p. 100).
Returning to the multitudes of consequences of Pasteur's discovery, it brought about the realization that biologically important substances occur in one of the two possible versions in living organisms. The Nobel laureate biologist George Wald (1906−1997) noted: "No other chemical characteristic is as distinct of living organisms as is optical activity" [20]. The great question is: how did it start, and how was one version of the two possibilities chosen? Already, Pasteur contemplated this, and Vladimir Prelog called this a question of molecular theology in his Nobel lecture titled Chirality in Chemistry [21]. Prelog gave his own definition to chirality: "An object is chiral if it cannot be brought into congruence with its mirror image by translation and rotation. Such objects are devoid of symmetry elements which include reflection: mirror planes, inversion centers or improper rotational axes."
The philosopher and theoretical physicist Lancelot L. Whyte (1896−1972) extended the definition of chirality: "Three-dimensional forms (point arrangements, structures, displacements, and other processes) which possess non-superposable mirror images are called 'chiral'" [22]. This extension made it convenient to describe chiral point groups, such as chiral molecules, and space groups, such as left-handed and right-handed helices. One of us (IH) discussed the possible origin of handedness in biological macromolecules in 1998 with Nobel laureate Ilya Prigogine (1917−2003), who said [23]: "Some people had proposed that the preference of left-handed amino acids may be related to electroweak interactions which stabilize very slightly the left-handed amino acids. Indeed, bifurcations are very sensitive to very small differences of energy. If the transition goes very slowly over years, then even such small differences in energy will introduce a slight effect in favor of one of the two amino acids." The polymath science historian Stephen F. Mason (1923−2007) did a great deal of pioneering studies on biomolecular homochirality and on the recognition of the electroweak origin of biomolecular handedness (see e.g. in [24]). The handedness of the biologically important helices has a vast literature.
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Left-handed and right-handed helices at the Monastery in Zagorsk (left), and in a church in Paris (right). Photographs by the Hargittais.
At the birth of stereochemistry, it was impossible to tell when there was a molecule that could exist in two mirror image forms which isomer was which, and there was no way to establish the absolute configuration. The organic chemist Emil Fischer (1852−1919) took the bold step in 1894 of arbitrarily assigning an absolute configuration to sugars [25]. There was a 50% probability that he might be right. Luckily, he was, which could be established only in the early 1950s when the crystallographer Johannes M. Bijvoet (1892−1980) and his team determined experimentally the sense of molecules [26]. Their technique was revolutionary but tedious, because for each new molecule the chemical relationship with the initial one had to be established for which they had determined the absolute configuration. Prelog succeeded in simplifying the procedure a great deal.
In conclusion, we mention two remarkable stories in connection with molecular handedness.
In Dorothy L. Sayers' (1893‒1957) detective story, The Documents in the Case, an expert identifier of wild mushrooms dies of poisoning. The question arose: was this death a consequence of accidental poisoning or even suicide, or was it foul play, i.e. intentional poisoning and murder? The analysis of the toxin in the victim's body showed the presence of only one of the two possible versions of the poisonous molecule, pointing to a man-made product, hence, murder. Sayers had a co-author for this book, Robert Eustace (pen name of Eustace Robert Barton, 1869‒1943). He was a physician and himself a prolific author whose plots often included references to scientific innovation. He probably provided the scientific basis for Sayers' detective story; everything presented in the story was correct, even from today's perspective. Sayers' book has been kept in print ever since it appeared in 1930. The date of the original publication is significant as it was anticipated for decades by the current legislation that rigorously prescribes chiral purity for pharmaceutical products. Pharmacology necessitated this legislation because the physiological impact of left-handed and right-handed versions of the same molecule may vastly differ. This is not what Sayers' story exposed. It exposed some physiological relevance of chirality, which was sufficiently pioneering to deserve our appreciation [27].
Here, we present a few examples of differences in the properties of chiral versions of the same substance. We list the names of the substances with selected properties of the right-hand/left-hand versions in that order:
(1) Ethambutol — treats tuberculosis/causes blindness.
(2) Penicillamine — treats joints/is toxic.
(3) Naproxen — reduces inflammation but risks heart disease/is toxic for the liver.
(4) Propoxyphene — pain reliever (Darvon)/cough medicine (Novrad). Note that the names of these two medications are each other's mirror images.
(5) Asparagine — bitter/sweet.
(6) Carvon — caraway smell/spearmint smell.
(7) Limonene — lemon smell/orange smell.
A tragic example was the thalidomide case — N-phthaloyl-α-aminoglutarimide (its model is shown below and here). It was known as Contergan in Europe. Originally, it was marketed as a sedative in the late 1950s. It was given to pregnant women suffering from morning sickness. The drug was marketed as a racemate (i.e. consisting of both chiral molecules), and by the early 1960s, many birth defects in Western Europe were associated with Contergan. Slowly, the correlation between its consumption and the occurrence of birth defects was recognized, and it was finally withdrawn from the market. Eventually, it was understood that one of the two chiral versions of thalidomide was teratogenic; the other was harmless. The tragedies occurred worldwide except in the Soviet bloc, where it was not available, and the United States, where the Food and Drug Administration (FDA) had never approved it. A young and conscientious official of the FDA, Frances O. Kelsey (1914−2015) [28], resisted approval and demanded more and more tests and thorough investigations. Her work contributed to establishing a regulatory regime — the Kefauver-Harris Amendments of 1962 and the Investigational New Drug Regulations of 1963. Today, and for some time, it has been the case, in the European Union and elsewhere, that molecules that may have two enantiomeric versions may be marketed for medicine only in the version that has the desired effect. This has resulted in a huge industry of chiral separation.
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Computer drawing of thalidomide molecular structure (courtesy of Ilya Yanov) and Frances O. Kelsey, 2000, in her office at the US Food and Drug Administration. Photograph by the Hargittais.
On the one hand, this has added to the costs of medicine, while, on the other hand, it has saved enormous amounts of substances that are not consumed and wasted. For fairness, we add that chiral separation would not solve the problem of thalidomide causing birth defects because the harmless version rapidly converts into the other version in the organism. Note also that thalidomide has other beneficial uses in medicine, but it should never be administered to expectant mothers.
Here, we make a big jump to allude to the enormous significance of chirality — or, more generally, dissymmetry — on a universal scale. In 1960, there was less than a half-page note in Nature [29] in which the physiologist John B. S. Haldane (1892−1964) returned to Pasteur in the wake of the recent discovery of parity violation. Haldane's starting point was T. D. Lee and C. N. Yang's discovery [30], which led to the acceptance of the notion of the asymmetrical universe. Pasteur first enunciated this [31], and Haldane quotes him in the French original.
Here, we provide the quote in English translation (courtesy of Alan L. Mackay): "It is inescapable that dissymmetric forces must be operative during the synthesis of the first dissymmetric natural products. What might these forces be? I, for my part, think that they are cosmological. The universe is dissymmetric, and I am persuaded that life, as it is known to us, is a direct result of the dissymmetry of the universe or of its indirect consequences. The universe is dissymmetric." (emphasis in the original).
References
[1] Lima-de-Faria, J. (1990). Historical Atlas of Crystallography. Dordrecht/Boston/London: Kluwer Academic Publishers for the International Union of Crystallography.
[2] Hargittai, M. & Hargittai, I. (2009). Symmetry through the Eyes of a Chemist. 3rd ed. Springer.
[3] Hargittai, I. & Hargittai, M. (2000). In Our Own Image: Personal Symmetry in Discovery. New York: Kluwer Academic/Plenum.
[4] Hargittai, M. & Hargittai, I. (2003). Eternal dissymmetry. Mendeleev Commun. 13, 91–92.
[5] Kant, I. (1905). Von dem ersten Grunde des Unterschiedes der Gegenden im Raume (1768). In Kant's gesammelte Schriften. Konigl. Preuss. Akad. Wissensch. Vol. 2, pp. 375–383. Berlin: Verlag Georg Reimer.
[6] Arago, D. F. J. (1811). Mémoire sur une modification remarquable qu'éprouvent les rayons lumineux dans leur passage à travers certains corps diaphanes et sur quelques autres nouveaux phénomènes d'optique. Mémoires de la classe des sciences mathématiques et physiques de l'Institut Impérial de France, 12, 93–134.
[7] Biot, J. B. (1812). For references, see [1], p. 103.
[8] Pasteur, L. (1897). Researches on the Molecular Asymmetry of Natural Organic Products. Alembic Club Reprints No. 14. p. 21. Edinburgh: W. F. Clay.
[9] Bernal, J. D. (1953). Molecular asymmetry. Science and Industry in the Nineteenth Century. pp. 181–219. London: Routledge & Kegan.
[10] Kelvin, L. (1904). Baltimore Lectures on Molecular Dynamics and the Wave Theory of Light. Appendix H, pp. 602-642. London: C. J. Clay & Sons.
[11] Curie, P. (1894). Sur la symétrie dans les phénomènes physiques, symétrie d'un champ eléctrique et d'un champ magnétique. J. Phys. (Paris) 3, 393-415.
[12] Neumann, F. E. (1833). Die thermischen, optischen und krystallographischen axen des krystallsystems des gypes. Annalen Phys. 103, 240–274. (See [1] p. 61.)
[13] Hargittai, I. & Hargittai, B. (2006). Prelog centennial: Vladimir Prelog (1906–1998). Struct. Chem. 17, 1–2.
[14] Hargittai, B. & Hargittai, I. (2024). 150 years of stereochemistry – selected examples. Struct. Chem. 35, 383–392.
[15] Hargittai, B. & Hargittai, I. (2023). Kurt Mislow centennial – he changed the way people think about stereochemistry. Struct. Chem. 34, 345–349.
[16] Hargittai, I. & Hargittai, M. (2024). Johannes Kepler – the first scientific crystallographer. IUCr Newsletter, 32 (1).
[17] Hargittai, I. & Hargittai, M. (2023). John Dalton remembered. IUCr Newsletter, 31 (4).
[18] Wells, A. F. (1956). The Third Dimension in Chemistry. Oxford: Clarendon Press. (See Preface.)
[19] Hargittai, I. (2000). Vladimir Prelog. Candid Science: Conversations with Famous Chemists. Edited by Magdolna Hargittai, ch. 10, pp. 138-147. London: Imperial College Press.
[20] Wald, G. (1957). The origin of optical activity. Ann. N. Y. Acad. Sci. 69, 352–368.
[21] Prelog, V. (1976). Chem. Sci. 193, 17–24.
[22] Whyte, L. L. (1975). Chirality. Leonardo, 8, 245-248 (published posthumously); see also, Whyte, L. L. (1958). Chirality. Nature, 182, 198.
[23] Hargittai, I. (2003). Ilya Prigogine, Candid Science III: More Conversations with Famous Chemists. Edited by Magdolna Hargittai, ch. 31, pp. 422-431. London: Imperial College Press. (The quoted excerpt is from p. 428.)
[24] Mason, S. F. (1991). Chemical Evolution: Origins of the Elements, Molecules and Living Systems. Oxford University Press.
[25] Fischer, E. (1894). Einfluss der configuration auf die wirkung der enzyme. Berichte der Deutschen Chemischen Gesellschaft, 27, 2985-2993.
[26] Bijvoet, J. M., Peerdeman, A. F. & van Bommel, A. J. (1951). Determination of the absolute configuration of optically active compounds by means of X-rays. Nature, 168, 271–272.
[27] Hargittai, I. & Hargittai, M. (2021). Science in London: A Guide to Memorials. pp. 118-119. Springer Nature.
[28] Hargittai, M. (2023). Meeting the Challenge: Top Women in Science. pp. 184–188. Oxford University Press.
[29] Haldane, J. B. S. (1960). Pasteur and cosmic asymmetry. Nature, 185, 87.
[30] Lee, T. D. & Yang, C. N. (1956). Question of parity conservation in weak interactions. Phys. Rev. 104, 254–258.
[31] Pasteur, L. (1874). Comptes Rendus Acad. Sci. Paris. (Note that what 'dissymmetry' is in Pasteur appears as 'asymmetry' in Haldane. In Mackay's translation, its usage is consistent with Pasteur.)
Istvan Hargittai and Magdolna Hargittai are at the Budapest University of Technology and Economics.
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Optical rotation through a medium.
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The Max Perutz Prize awardee Professor Mariusz Jaskólski during his lecture: A path paved with crystals.
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Dorothy L. Sayers, 1925, publicity photo from her American publisher, in the public domain (
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Figure 1. The first designed novel globular protein fold by David Baker and coworkers confirmed with a 2.5 Å X-ray SAD (single wavelength anomalous diffraction) phased crystal structure, PDB code 
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Gwladys Steciuk (left) and Paul Klar (right) at ECM34, Padua, Italy, August 2024.
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Inauguration of the seventh MaThCryst School in Latin America. From left to right: Dr Arbelio Pentón, Dr Leopoldo Suescun, Dr Massimo Nespolo, Dr Justiniano Quispe, Dra Marisel Espinoza, Dr José Niño, Dr Ángel Bustamante, Mg María Luisa Cerón, Dr Mois Arroyo, Dra María Cristina Nonato and Dr Carlos Landauro.
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Dr Massimo Nespolo uses a ball to keep the attention of all students.
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Dr Mois Aroyo teaching space groups and their description in International Tables for Crystallography.
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Authors and co-authors in the poster session happy to show their work to the attendees.
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Dr Allan O. Junio from the Philippines secured first place in the poster session, while Dr Yonathan Parra from Ecuador earned second place.