iterScience CHRALTY00 Chirality Forum Chirality and Chemical Processes:A Few Afterthoughts PEDRO CINTAS Departamento de Quimica.Facultad de Ciencias-UEX.Badajoz Spain ARSTRACT and chiral have e science Although terms that p chirality.yet thesis a hot igthighledbyrenonedsteres mists,it has bec ome a recurring keyword and forums such as the pres ing urher ions nat may oth begin but rar and the use of st to crit nts,which should versally correct.Chirality20:4,2008 2007 Wiley-Liss,Inc KEY WORDS ereo tive:stereodiscrimina INTRODUCTION ceptua basis of chirality and emphasizes the prope menclatu end emistry.Its termino and ster CHIRALITY AND DISCRIMINATION In their authoritative manual on organic stereochemis and related while estricted to molecules and f life enario,the ap train image obe。 actually cal aspects).Accordingly,chirality e or ahi retation rate,chiral cata st or ven worse when the term chiral is accompanied by when ar ed to proces the term chiral eng ders th ambiguous conoation as the situation with a mac rant semantic tion that h found wides pread us 即hemists..ishe mation,etc.The present note reexamines again the 2007 Wiley-Liss.Inc
Chirality Forum Chirality and Chemical Processes: A Few Afterthoughts PEDRO CINTAS Departamento de Quı´mica Orga´ nica e Inorga´ nica, Facultad de Ciencias-UEX, Badajoz, Spain ABSTRACT Chirality and chiral have become terms that pervade a wide range of disciplines in physical and life sciences. Although such terms are precisely defined, their use often engenders confusion and ambiguity. Perhaps, the most improper use of chirality, yet widely accepted, is related to its association with stereodynamics and physico-chemical transformations, such as chiral discrimination, chiral resolution, chiral recognition, chiral synthesis, and so on. Even though this conceptual perversion has been highlighted by renowned stereochemists, it has become a recurring keyword and a hot message in modern literature. It is timely to renew the correct use and context in forums such as the present journal, adding further reflections that may help both beginners and practitioners. This short article is not intended to criticize or highlight errors, but rather to encourage a level of rigor and the use of statements, which should be universally correct. Chirality 20:2–4, 2008. VC 2007 Wiley-Liss, Inc. KEY WORDS: asymmetry; chirality; enantioselective; diastereoselective; stereodiscrimination; synthesis; terminology; transformation INTRODUCTION If nomenclature jeopardizes a scientific discipline, this should most likely be stereochemistry. Its terminology possesses a strong ideographic content, i.e., representing concepts or ideas that are intellectually apprehended as precise structural information and molecular relationships. Stereochemical nomenclature is by no means pedantic stuff as a given audience or readership should interpret a concept and its implications regardless of the context, and not what the speaker or writer chooses it to mean. The paradigmatic misuse of stereochemical terms is best exemplified by chirality and related terms. This is largely influenced by the fact that chirality itself and the occurrence of chiral structures and morphologies have become hot topics linked to exciting and far-reaching fields, ranging from biomedicine to the origin of life. But in such an interdisciplinary scenario, the appropriate training in organic stereochemistry may be actually scarce. Some authors have already dealt with the common misinterpretation of chiral and homochiral, especially as equivalent or associated to single enantiomers.1–4 The situation is even worse when the term chiral is accompanied by adjectives such as nonracemic intended to draw attention to an enantiomeric imbalance.5 But, perhaps the most important semantic aberration that has found widespread use through papers and monographs, often written and reviewed by chemists and stereochemists, is the use of the word chiral, or chirality, applied to processes and reactions: chiral amplification, chiral catalysis, chiral chromatography, chiral discrimination, chiral inversion, chiral recognition, chiral resolution, chiral synthesis, chiral transformation, etc. The present note re-examines again the conceptual basis of chirality and emphasizes the proper interpretation recommended by some leading scholars and stereochemistry pioneers. Their lessons should provide a fresh look at chirality as a linguistic tool for communicating precise terminology, useful to all of us. CHIRALITY AND DISCRIMINATION In their authoritative manual on organic stereochemistry, Eliel and Wilen discourage the use of chirality or chiral for the separation or transformation of stereoisomers, while such terms should be restricted to molecules and models.5 The obvious reason lies in the concept itself, as chirality simply describes the nonidentity of two-mirror image objects by translation and rotation in a given Euclidean space (if one disregards other topological and statistical aspects). Accordingly, chirality constitutes a geometrical property and as such, it should only (let us say, strictly) applied to molecules or objects in general, i.e., chiral substrate, chiral catalyst, or chiral stationary phase. Before going any further, it should also be argued that, when applied to processes, the term chiral engenders the same ambiguous connotation as the situation with a macContract grant sponsor: Ministry of Science and Education; Contract grant number: CTQ2005-07676 Correspondence to: Prof. Pedro Cintas, Departamento de Quı´mica Orga´nica e Inorga´nica, QUOREX Research Group, Facultad de Ciencias, Universidad de Extremadura, Avenida de Elvas s/n, E-06071 Badajoz, Spain. E-mail: pecintas@unex.es Received for publication 30 May 2007; Accepted 10 August 2007 DOI: 10.1002/chir.20480 Published online 1 October 2007 in Wiley InterScience (www.interscience.wiley.com). CHIRALITY 20:2–4 (2008) VC 2007 Wiley-Liss, Inc
CHIRALITY AND CHEMICAL PROCESSES ros Yet another potential problem linked to the term chiral rightha clear what wea are about.It fers to both)In most s.the authors refer to an asy discrimination alludes to differenc ewemltenteCianiofoneenantiomerofagireng eR sus R bot lenot ealed in both 2D and 3D spaces.However.heterochira one Mo there is ctions may lead to a mes resu eterochir Note that the 6enenchiralamdahirnlemties g t and S e tin (or hings n two nons ever,as n ted by these authors.these meanings be vels of struc fusing as only a areful reading reve the les from achiral pr rs or having mer o r.of various cules that are chiral but they wed in the y or may not be enanti omer well that the propertie e trans of thei components and th state of the syste in oth as tn hiral p or a mixture of ativ for e on e th a part ne e wel as by sepa tion ochiral interactions maydi that the terms dia suc Thto be the ded mean s of chiral or edconversion a ster mer.but the is ARE THERE MEASURABLE CHIRALITY CHANGES crimination,chiral re involved refers iral ontent.This subjec the lact th an analys scope of th tan not er reaction 4: tereochemical education emphasizes the role of diaster ormati measurable change inter to thent ons. acquired am must be found in the effects produ the tions.The molecula situation shor ld the fore be denoted that the causes that e symmetrica Chirality DOI 10.1002/chi
roscopic sample of molecules (in stark contrast to an individual entity that may be labelled as left- or right-handed). If a reaction is claimed to be chiral, it is not completely clear what we are talking about. It is not the reaction that is chiral, but the material present (substrates, products, or both). In most cases, the authors refer to an asymmetric induction or asymmetric transformation (accepted names in the IUPAC glossary, even though numerous reagents possess C2 symmetry and are not asymmetric in an etymological sense)6 leading to an enantioenriched sample (i.e., with complete or partial enantiomeric excess). Moreover, one often discloses that behind expressions like chiral discrimination or chiral resolution there is actually formation of homochiral or heterochiral aggregates. Note that the term homochiral does certainly imply a nonracemic sample (made up of molecules with the same sense of chirality), whereas a heterochiral sample is still chiral, but racemic. It is equally relevant in this context the conceptual difference between enantiomorphism (or enantiomerism) and chirality, again misused as synonyms. The former refers to the relationship between two nonsuperposable mirror-image objects, while chirality denotes the phenomenon that indicates the existence of such objects.7 In the light of this observation, expressions like chiral synthesis, chiral reaction, or chiral transformation are extremely confusing as only a careful reading reveals the meaning intended by the authors; formation of a single chiral stereoisomer or, of various molecules that are chiral but they may or may not be enantiomers. Another compelling reason to use the never-obsolete concepts of asymmetric synthesis and asymmetric transformation is their functional character. They tell us how an achiral precursor or a mixture of stereoisomers give rise to a single stereoisomer, for instance on introducing new chiral elements (e.g., reactions at prochiral centers) as well as by separation following equilibration such as in crystallization-induced enrichments. It is in such contexts that the terms enantioselective or diastereoselective appear to be the correct adjectives for the intended meaning. The term chiral has merely a structural connotation (a feature equally applicable to the cases of chiral or asymmetric centers)8 as chirality does not involves any idealized conversion leading to a stereoisomer, but the distinction between the self and nonself; i.e., one knows what stereoisomers, chiral or achiral, may exist as the result of a given transformation. It is also pointed out that the imperfect use of chiral discrimination, chiral recognition, or chiral amplification to name a few, stems from the fact that there is nothing chiral per se about these processes, which are exhibited by chiral substances but caused by diastereomeric, not enantiomeric interactions.9 It is perhaps an irony that, while stereochemical education emphasizes the role of diastereomeric transition structures in asymmetric syntheses or biological activity resulting from drug-enzyme interactions,10 research scientists have acquired a particular amnesia overlooking the origin of such molecular interactions. The molecular situation should therefore be denoted as stereoisomer discrimination (vide infra), either enantiomer or diastereomer discrimination.11 Yet another potential problem linked to the term chiral discrimination is that discrimination may actually occur in the presence of achiral species. Thus, enantiomer discrimination refers to measurable differences between homochiral and heterochiral interactions (RR against RS), while diastereomer discrimination alludes to differences between the interactions of one enantiomer of a given species with the two enantiomers of a different species (i.e. RI RII versus RI SII). Collectively, both can be denoted as manifestations of stereoisomer discrimination and revealed in both 2D and 3D spaces. However, heterochiral interactions may lead to a meso aggregate and as a result, enantiomer discrimination would involve a difference between chiral and achiral entities. Agranat and Sarel have suggested to replace chiral discrimination by chiral distinction invoking that, while discrimination is associated with differences between two things as being equal, distinction implies the lack of resemblance between two like things.12 Chiral distinction might then be equivalent to diastereomeric interactions in a stereochemical context. However, as noted by these authors, these meanings appear to be rooted in human psychology and are too broad to be universally accepted in a scientific context. Since chirality can be observed at different levels of structure and organization, processes leading to chiral supramolecules from achiral precursors or having chiroptical properties different from those of their chiral monomers are likewise viewed in the literature as examples of chiral amplification or discrimination. We however know well that the properties of chiral substances depend on the composition and proportion of their components and the state of the system, in other words, the system does not behave as the sum of the individual components. As a representative example, formation of helical structures with a particular handedness is again a manifestation of stereoisomer discrimination where homoand hetero-chiral interactions may differ substantially with respect to their source and energy. This situation does not imply a chirality change, but a different stereochemical outcome (hence asymmetric or stereoselective, not chiral). There is no such a thing called chirality transfer as we cannot transfer handedness on shaking hands. ARE THERE MEASURABLE CHIRALITY CHANGES? A final point that deserves attention and discourages the use of chiral still further when transformations or syntheses are involved, refers to the chiral content. This subject obviously requires an analysis beyond the scope of this article, although a few considerations also evidence the improper usage of, for instance chiral reaction or chiral amplification. Intuitively, one could interpret that such transformations involve measurable changes in chirality content or, alternatively in symmetry contents according to the symmetry principle: the elements of symmetry of the causes must be found in the effects produced; although the effects produced may be more symmetrical that the causes that produce them.13–16 However, quantification of chirality in terms of chiroptical or thermodynamic parameters is not immediately CHIRALITY AND CHEMICAL PROCESSES 3 Chirality DOI 10.1002/chir
4 CINTAS onsid ered withou ulny mas Only the magnitude of a ch clea Arguments based on enantiomeric evidence of chirality contents.and hence of chiral e res ACKNOWLEDGMENTS The issu of chirality,its history and significance has the py y pe talented colle to all of then in particular Mark tha al. flhksandcistobalWeina,he ction ctions in sym LITERATURE CITED rea ctions,where the exc 1.eEIInfelicusermc omenreChirality19 lem nuence by the 3.H matic terms in orga jority rule as rathe depends s GP.B Appl Chem 1996.68219 nistry.IUPAC recommend rding t general sym e of for an d s the but eithe the av s ymmety of the lt this ple and the se d are isom entropy and degree of symmetry.Thus,even though the ystem may be very 13.Cune P.Su CONCLUSIONS We have long misused the terms chiral and chirality to 161 and practitio 3171317 orchiral discrimination.which inundate the hemical literture suggest ignoring the more accurate and pre cise terms that charac 19. 20 ony of s hem rtainythe hall mark o 21 flue 8800 200417719-73. e pr vide 22 Chirality DOI 10.1002/chir
obvious as chirality is by definition a geometrical property of molecules or objects, thereby requiring an algebraic treatment of models viewed as collections of points considered without any mass. Only the magnitude of a chirality function could be used as a quantitative measure of chirality.17,18 Arguments based on enantiomeric excesses as well as chiroptical and other spectroscopic measures as evidence of chirality contents, and hence of chiral change, amplification, or discrimination, may certainly be flawed. One should note the dichotomy between chirality per se and the physical observables that support the existence of that concept.19 Consider for instance the fact that chiral molecules may have null optical rotation (within conventional detection); reductions in symmetry going from molecules to crystals; or processes, often highlighted as chirality memory reactions, where the enantiomer excess of substrate and product does not match at all.20 Semantics may be particularly problematic with chiral polymers, in which a particular handedness is usually influence by the statistical domain of chiral or achiral units. However, a majority rule could lead to decreased control of the helical sense and therefore of optical activity. The conflict suggests that chirality is not an intrinsic property of the chiral moiety but rather depends on the molecular environment.21 Chirality has also remarkable relationships with concepts such as similarity and entropy, not usually handled in a chemical context. According to a more general symmetry evolution principle, for an isolated physical system the degree of symmetry cannot decrease as the system evolves, but either remains constant or increases; the degree of symmetry has to do with the initial and final symmetry groups, it does not refer to any symmetry of the states of the physical system as the latter evolves.15,22 As a result, this symmetry evolution principle and the second law of thermodynamics are isomorphic; paradoxically a monotonically ascending correlation exists between entropy and degree of symmetry. Thus, even though the chirality of a system implies the lack of certain symmetry elements, chirality and degree of symmetry of an evolving system may be very different things.18 CONCLUSIONS We have long misused the terms chiral and chirality to denote systems evolution and molecular dynamics, which deviate from the conceptual basis of chirality embedded in geometry. Some readers and practitioners will feel that, at least intuitively, expressions such as chiral reaction, chiral recognition, or chiral discrimination, which inundate the chemical literature, suggest any enantiomeric (perhaps stereoisomeric?) bias without major headaches. But, why ignoring the more accurate and precise terms that characterize stereoselective and asymmetric transformations, as well as the nature of molecular interactions? Chirality is certainly the hallmark of stereochemistry, but it can also be too much of a good thing. A few adjectives (enantio selective, diastereoselective, enantiomer, diastereomer, stereoisomer), combined as judiciously as possible provide the best illustration in the present context. In doing so, one does justice to the original Kelvinian concept, emphasizes the true origin of the stereochemical outcome, and uses clear and consistent definitions as properly vindicated by stereochemistry educators. ACKNOWLEDGMENTS The issue of chirality, its history and significance has been the subject of past and recent discussions with many talented colleagues; to all of them, in particular Mark Green, Joseph Gal, Meir Lahav, and Cristobal Viedma, the author offers his heartfelt thanks. LITERATURE CITED 1. Eliel EL. Infelicitous stereochemical nomenclature. Chirality 1997;9: 428–430. 2. Gal J. Problems of stereochemical nomenclature and terminology, Part: 1 The homochiral controversy. Its nature, origins, and a proposed solution. Enantiomer 1998;3:263–273. 3. Helmchen G. Glossary of problematic terms in organic stereochemistry. Enantiomer 1997;2:315–318. 4. Mislow K. Stereochemical terminology and its discontents. Chirality 2002;14:126–134. 5. Eliel EL, Wilen SH. Stereochemistry of organic compounds. New York: Wiley; 1994. p 5. 6. Moss GP. Basic terminology of stereochemistry. IUPAC recommendations. Pure Appl Chem 1996;68:2193–2222. 7. Gal J. Carl Friedrich Naumann and the introduction of enantio terminology: a review and analysis on the 150th anniversary. Chirality 2007;19:89–98. 8. Wade LG Jr. Precision in stereochemical terminology. J Chem Educ 2006;83:1793–1794. 9. Eliel EL, Wilen SH. Stereochemistry of organic compounds. New York: Wiley; 1994. p 154–155. 10. Mannschreck A, Kiesswetter R. Differentiations of enantiomers via their diastereomeric association complexes—there are two ways of shaking hands. J Chem Educ 2005;82:1034–1039. 11. Craig DP, Mellor DP. Discriminating interactions between chiral molecules. Top Curr Chem 1976;63:1–48. 12. Agranat I, Sarel S. Introduction. Reflections on chiral discrimination. Enantiomer 1996;1:249–250. 13. Curie P. Sur la syme´ trie dans les phe´ nome`nes physiques, syme´ trie d’un champ e´lectrique et d’un champ magne´ tique. J Phys Theor Appl (Paris) 1894;3:393–415. 14. Renaud P. Sur une ge´ ne´ ralisation du principle de syme´ trie de Curie. Compt Rend Acad Sci Paris 1935;200:531–534. 15. Rosen J. Symmetrie in science: an introduction to the general theory. New York: Springer; 1996. 16. A´ valos M, Babiano R, Cintas P, Jime´ nez JL, Palacios JC. Symmetry breaking: an epistemological note. Tetrahedron: Asymmetry 2004;15: 3171–3175. 17. Buda AB, Auf der Heyde T, Mislow K. On quantifying chirality. Angew Chem Int Ed Engl 1992;31:989–1007. 18. Petitjean M. Chirality and symmetry measures: a transdisciplinary review. Entropy 2003;5:271–312. 19. Weinberg N, Mislow K. On chirality measures and chirality properties. Can J Chem 2000;78:41–45. 20. Cozzi F, Siegel JS. Chirony of stereochemical metaphors. Org Biomol Chem 2005;3:4296–4298. 21. Cheon KS, Selinger JV, Green MM. Counterintuitive influence of microscopic chirality on helical order in polymers. J Phys Org Chem 2004;17:719–723. 22. Rosen J. The symmetry principle. Entropy 2005;7:308–313. 4 CINTAS Chirality DOI 10.1002/chir
