CHIRALITY (2015)

Adding Only One Priority Rule Allows Extending CIP Rules to Supramolecular Systems IBON ALKORTA,1* JOSÉ ELGUERO,1 AND PEDRO CINTAS2 1 Instituto de Química Médica (CSIC), Madrid, Spain 2 Departamento de Química Orgánica e Inorgánica, Facultad de Ciencias-UEX, Badajoz, Spain

ABSTRACT There are frequent situations both in supramolecular chemistry and in crystallography that result in stereogenic centers, whose absolute configuration needs to be specified. With this aim we propose the inclusion of one simple additional rule to the CahnIngold-Prelog (CIP) system of priority rules stating that noncovalent interactions have a fictitious number between 0 and 1. Chirality 00:000-000, 2015. © 2015 Wiley Periodicals, Inc. KEY WORDS: chirality; hydrogen bonding; nomenclature; stereogenicity; supramolecular chemistry Since its introduction nearly 60 years ago, the Cahn-IngoldPrelog (CIP) nomenclature has become the standard and reliable set of rules, embedded in a tree-graph hierarchical exploration, to denote the configurations of molecules whose handedness arises from stereogenic elements such as centers, axes, and planes.1,2 Although this system of stereodescriptors has become an indispensable pedagogical tool of chemistry textbooks, specific aspects remain largely unnoticed not only by advanced students but also by stereochemistry practitioners. Leading experts have recognized and discussed vividly the inconsistencies and limitations of the CIP system, especially when dealing with the stereogenicity of chiral axes and planes.3,4 Some concerns were primarily addressed by Prelog and Helmchen in their 1982 revision, thus removing some ambiguity with cyclanes, in particular, and highlighting the connotation of pseudoasymmetry in such systems.5 Despite the existence of well-established definitions and the International Union of Pure and Applied Chemistry (IUPAC) recommendations,6 stereochemical wording has significant misunderstandings and misconceptions, often related to the improper usage of chirality and stereogenicity.3,7,8 There is ample consensus, in line with the stereochemistry pioneers,5,9 that we have enough rules, and descriptors like R and S may suffice to clearly identify the configuration of stereoelements other than centers. At this stage, one should wonder whether the CIP system shows enough robustness against noncovalent entities, characteristic of supramolecular systems, which could not be foreseen in early proposals as the field grew and later matured. Obviously, stereoisomerism at a supramolecular level is hardly new. The helical motif is ubiquitous in nature and as a prototypical example the configuration of double-stranded DNA can be unambiguously denoted by stereodescriptors of axial chirality (P and M). The notation is also applicable to H-bonded helical chains generated from small molecules.10 Helical descriptors, however, are considered rather conformational elements of stereogenicity within the CIP nomenclature,3 which adds extra confusion in naming complex structures. In contrast, the R/S notation often provides unambiguous configuration of chiral axes.11 It seems to us, nevertheless, that discrete aggregates, most linked by H-bonds and susceptible to enantio- and diastereomorphism, could still require additional sequential © 2015 Wiley Periodicals, Inc.

rules, yet not affecting the CIP framework, as more than one configurational assignment could be envisaged. Thus, we were motivated in writing this communication by a desire to put the problem at the forefront and recommending the adoption of simple rules that will lead to further clarification. Taken structures from our own work and of others on such noncovalent-bonded systems, this article will exemplify situations commonly encountered in real cases. It may be amazing that even though the growth of supramolecular chemistry as an interdisciplinary discipline is indeed spectacular, with recent emphasis on dynamic libraries,12 its stereochemical features and implications often possess a secondary interest. Probably, a starting point was the multiauthor volume, edited by Jay Siegel in the mid-1990s, which reflected the importance of weak interactions as controlling forces in large molecules and crystals.13 The vacuum regarding a descriptive framework for supramolecular stereochemistry was first highlighted by Gibb,14 who lamented the lack of a systematic approach in terminology, and remarked that "as the number of supramolecular isomers increases, so will the need for describing them (assuming the phrase, a picture says a thousand words, is not always true). Precisely what sort of framework that will appear remains to be seen, but it will not be as simple as R and S determinations." Certainly, this sentence may be an appropriate caveat, at least for topological structures (interlocked systems for instance) or complex Platonic solids, for which the hierarchy of a given geometrical feature is a subtle ingredient. This does not detract from a general interest in applying conventional rules, provided that identification of stereogenic elements can be easily accomplished. Besides stereocenters, a supramolecular structure may display complex issues of stereogenicity, including directionality facilitated by intermolecular interactions such as hydrogen or halogen bonds, which can remain unaltered in the crystalline state forming larger networks. Such noncovalent bonds (NCBs) might indeed be the source of conformational

*Correspondence to: Ibon Alkorta, Instituto de Química Médica (CSIC), Juan de la Cierva, 3, E-28006 Madrid, Spain. E-mail: [email protected] Received for publication 10 December 2014; Accepted 12 February 2015 DOI: 10.1002/chir.22438 Published online in Wiley Online Library (wileyonlinelibrary.com).

ALKORTA ET AL.

cyclostereoisomerism, although the latter is usually neglected. It is true, according to Mislow and associates, that directionality is superfluous so long as it does not increase the number of possible stereoisomers.15,16 In fact, complex H-bonded polyhedral and capsules show enantiomorphism that can be unequivocally defined by P and M stereodescriptors.17 Moreover, chiral knots and axles, as exemplified by rotaxanes, have also been adequately specified by the CIP rules.18 Chiral suprastructures are indeed involved in various subjects such as racemization, chiral memory, dynamic stereochemistry, or crystal growth, among others.17,19,20 Also, enantio- and diastereoselective supramolecular processes represent a valuable approach to obtain optically active materials and biomimetic substances.21

Fig. 1. Noncovalent coordination of lone pairs in amines, ethers, and alcohols.

RESULTS AND DISCUSSION

An assessment of priority rules for NCBs could be inferred from the IUPAC recommendations, yet adhering to the CIP nomenclature22: i. ‘ Duplicate atoms and phantom atoms: There is no difficulty in the expression of the connectivity between the various atoms used in a digraph of atoms or groups when they are monovalent. A special interpretation is necessary to treat multiple bonds, saturated and mancude rings and ring systems, and lone pairs of electrons in order to maintain the tetravalency indispensable to the application of the sequence rules’ (p. 91.1.4.2). ii. ‘Treatment of tetrahedral systems having a pair of electrons: A lone pair of electrons on an atom such as nitrogen or sulfur has the fictitious atomic number of zero. It is thus ranked lower than a hydrogen atom’ (p. 91.1.4.2.4) By focusing on noncovalent interactions, two situations must be considered herein: (a) those involving lone pairs (LP), and (b) those involving atoms. The former is illustrated in Figure 1, where it suffices to give the coordinated lone pair a fictitious atomic number between 0 and 1, i.e. larger than a lone pair (0) but smaller than a hydrogen atom (1). For chiral amines (the same applies to phosphines), coordination does not alter the configurational assignment that is determined unambiguously regardless of the noncovalent interaction. The latter, however, contributes to prevent further configurational inversion at the nitrogen atom.23,24 Achirality becomes obvious in alcohols and ethers devoid of noncovalent interactions. With mono-coordination the order of precedence should be formulated in terms that LP···A interaction precedes the lone pair. The presence of two noncovalent interactions (LP···A, LP···B) follows the standard rule that higher atomic number precedes lower (Fig. 1). The stereogenicity of oxygen atoms manifests itself in these particular cases.

Fig. 2. Chiral structures involving H-bonds showing stereogenic oxygen atoms. Chirality DOI 10.1002/chir

EXTENDING CIP RULES

Figure 2 depicts additional examples that include a chiral diether (alkyllithium ethane-1,2-bisolate)25,26 as well as “chiral water molecules” (it is worth pointing out that this structural motif is commonly encountered in the literature).27–29 There are actually five possibilities for chiral water networks depending on the LPs and hydrogen atoms involved in the noncovalent interaction, especially hydrogen bonds; an example of (S) configuration is shown. The sequence rule applies newly as either the nonbonding interaction precedes the LP and the NCB also follows the precedence of higher atomic number and mass number. Likewise, L-lactic acid30,31 and methyl L-lactate32 yield complexes rendering an asymmetric water oxygen, even though configurational inversion at oxygen atoms occurs quickly. Another article dealing with L-lactic acid/water complexes alludes to "achiral water molecules," although these should be inherently chiral.33 When a water molecule is linked to a chiral molecule such as L-lactic acid by a single HB, then the complex is chiral but the water oxygen is not stereogenic. The existence of stereogenic oxygen atoms has been well discussed by Mitsudo et al. in the light of ruthenium complexes (Fig. 2, bottom right).34 In cases (b), i.e., noncovalent interactions involving atoms, the assignment can be achieved by means of the same rules as those applied to stereogenic central atoms, which are illustrated in Figures 3–6. Thus, hydrogen bonding or another noncovalent interaction precedes hydrogen and NCBs are sequenced by their higher atomic number. Figure 4 illustrates the situation of a prochiral isotopomer subjected to further coordination with ammonia (deuterium appears to be more acidic than H or T).35 Hydrogen bonds between cations and π-excedent aromatic rings or between anions and π-deficient aromatic rings are of great significance, because the associated stereoelectronic effects influence the reaction outcome and may be a driving

3

Fig. 5. Noncovalent bi-coordination to an sp atom.

Fig. 6. Examples involving ion-π interactions.

force for completion.36–46 Hypothetical structures featuring such key interactions are exemplified in Figure 6 for L-proline (cation-π) and for methyl phosphate dianion (anion-π). Further perusal in the CSD47,48 searching for stereogenic atoms involved in NCBs gives rise to a plethora of examples. A few, yet discrete, structures are summarized in Figure 7 (structural formulae for the sake of clarity) and Figure 8 (modified Mercury-generated ball-and-stick 3D-structures), whose configurations are assigned in agreement with the above statements. Last, but not least, it is worth pointing out that the CIP rules will also apply to metal-containing structures.54–56 Whether transition elements or not, they are ubiquitous in supramolecular aggregates (as the central part of tetrahedral or pseudotetrahedral complexes) and capable of interacting with a lone pair. A few cases have been reported herein (Fig. 1, bottom right, Figs. 7 and 8, RIHCIW), and many others are possible.

Fig. 3. NCBs in ammonium and oxonium species.

Fig. 4. NH3-coordination in isotopically labeled ammonia.

Fig. 7. Molecular representations of BEMDAZ,49 CIKCUV,50,51 FEZHOJ,52 XARZIA,53 and RIHCIW54 (acronyms used in the CSD). Chirality DOI 10.1002/chir

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Fig. 8. Mercury images of compounds shown in Figure 6 with their absolute configuration assigned to nitrogen (BEMDAZ, CIKCUV, FEZHOJ), phosphorus (XARZIA), and oxygen atoms (RIHCIW).

CONCLUSIONS

In summary, this communication is a proposal to name supramolecular aggregates decorated by noncovalent interactions, in particular hydrogen bonding. We have chosen rather small molecules and selected fragments bearing noncovalent coordination, whose chirality is properly specified by simple extension of the CIP rules. The process of working out the right assignment merely assumes that either covalent interaction has priority over a noncovalent one, and the latter is catalogued depending on its nature and atomic number. This unveils the asymmetric character of atoms, such as oxygen, ubiquitous not only in supramolecular structures but also in transient species and transition states. On revisiting the CIP system again, one should recognize a conceptual legacy that demonstrates its almost perpetual validity, especially when stereogenic atoms are involved. ACKNOWLEDGMENTS

This work was supported by the Spanish Ministry of Economy and Competitiveness (Grants CTQ2012-13129-C02-02 and CTQ2013-44787-P) and the Comunidad Autónoma de Madrid (Project Fotocarbon, Ref. S2013/MIT-2841). We thank Dr. David Fernández-Rivas for help with graphical artwork. LITERATURE CITED 1. Cahn RS, Ingold CK, Prelog V. The specification of asymmetric configuration in organic chemistry. Experientia 1956; 12: 81–94. 2. Cahn RS, Ingold CK, Prelog V. Specification of molecular chirality. Angew Chem Int Ed Eng 1966; 5: 385–415. 3. Mislow K, Siegel J. Stereoisomerism and local chirality. J Am Chem Soc 1984; 106: 3319–3328. Chirality DOI 10.1002/chir

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Chirality DOI 10.1002/chir