Axial chirality isn't the first thing most chemists come up with when they think of indole. Yet a recent J. Org. Chem. article by Kamikawa et al. describes not only axially chiral indoles, but an enantioselective method for their synthesis.

Axial chirality has been largely ignored by the cheminformatics community. There was once a time when the phenomenon was esoteric enough that it could be reasonably ignored. However, that time has long since passed, as the Kamikawa study, and many others demonstrate.

Several years ago, Andreas Dietz proposed a conceptual framework for solving this problem. More recently, it was put into practice in the FlexMol language and the Octet framework. These may not represent the best solutions to the axial chirality problem, but they clearly demonstrate that a practical solution, fully compatible with modern information technologies, does exists.

Axially chiral molecules like those in the Kamikawa study will increasingly find their way into chemical databases as they continue to become more synthetically accessible. When this happens, users will want to be able to distinguish stereoisomers, just as they wanted (and got) this capability for tetrahedral chirality ten to twenty years ago. When the inevitable request to distinguish axially-chiral stereoisomers in your database comes, how will you respond?

-Ken Tanaka, Hiromi Sagae, Kazuki Toyoda, Keiichi Noguchi, and Masao Hirano J. Am. Chem. Soc.

Previous articles have highlighted FlexMol's ability to represent nearly all forms of molecular chirality, including many that are alien to popular cheminformatics tools. FlexMol provides just a few basic elements and rules for their combination, resulting in a system that is both extensible and systematic. For example, similar elements are used to represent the axial chirality of biaryls, the geometrical isomerism of alkenes, and the configuration of square-planar metal complexes. In this article, we'll see how FlexMol can encode an example from the very recent literature: planar-chiral metacyclophanes as described by Tanaka and coworkers.

Configuration or Conformation?

The question we have to answer is what form of stereochemistry needs to be represented - configuration or conformation. We follow the simple rule that isomers interconvertable through bond rotations are treated as conformations and conclude that to represent a metacyclophane, we'll be dealing with conformation. See the original Dietz specification for a more rigorous analysis.

A FlexMol Representation

Let's choose a specific molecule to encode in FlexMol (Y,Z=CH₂) . Using the atom numbering given in the figure above, we can construct the complete FlexMol representation. Rather than reproduce it completely here, I'll just highlight the stereochemically-relevant part:

<!-- snip -->
<conformation>
  <conformationWheel>
    <gammaSequence source="17" target="8">
      <connections>
        <atomPair source="17" target="8"></atomPair>
      </connections>
    </gammaSequence>
    <halfPlane>
      <lower atom="16"></lower>
    </halfPlane>
    <halfPlane>
      <upper atom="9"></upper>
    </halfPlane>
    <halfPlane></halfPlane>
    <halfPlane>
      <upper atom="7"></upper>
    </halfPlane>
  </conformationWheel>
  <conformationWheel>
    <gammaSequence source="11" target="10">
      <connections>
        <atomPair source="11" target="10"></atomPair>
      </connections>
    </gammaSequence>
    <halfPlane>
      <lower atom="12"></lower>
    </halfPlane>
    <halfPlane>
      <upper atom="2"></upper>
    </halfPlane>
    <halfPlane></halfPlane>
    <halfPlane>
      <upper atom="9"></upper>
    </halfPlane>
  </conformationWheel>
</conformation>
<!-- snip -->

This conformation contains two conformationWheels, each corresponding to one of the two bonds about which rotation is restricted. Notice the similarity of this FlexMol code compared to the examples for BINOL, and an N-arylacrylanilide. To better visualize the relationships among atoms, axes, and half-planes, consider the following cartoons:

It should be clear that the enantiomeric representation of our molecule would produce an arrangement of half-planes that was the inverse of those shown here, and distinguishable by manual inspection or software implementation. One such implementation is contained in the open source framework Octet

Conclusions

As the example in this article demonstrates, FlexMol can fully encode the planar-chirality of the new class of axially-chiral metacyclophanes reported in a recent J. Am. Chem. Soc. article. Exactly the same FlexMol elements were used as in previous examples illustrating axial chirality and alkene geometry. Systematic and extensible methods for encoding diverse forms of chirality are not only feasible - one of them already exists.

... To discover high-performance asymmetric catalysts, developing an excellent chiral ligand is crucial. Attracted by its molecular beauty[Chemica Scripta 1985, 25, 83], we initiated the synthesis of BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)[J. Am. Chem. Soc. 1980, 102, 1932] in 1974 at Nagoya with the help of H. Takaya, my respected long-term collaborator. BINAP was a new fully aromatic, axially dissymmetric C₂ chiral diphosphine that would exert strong steric and electronic influences on transition metal complexes. Its properties could be fine-tuned by substitutions on the aromatic rings. ...

-Ryoji Noyori, Nobel Lecture, December 8, 2001

Axial chirality results, not from a tetrahedral chiral center, but from a chiral axis. This form of chirality most frequently occurs in biaryls and allenes. The importance of axial chirality to organic chemistry was recognized in 2001, when Ryoji Noyori was co-awarded the Nobel Prize in Chemistry, in part for his work with highly selective catalysts derived from the axially-chiral BINAP ligand.

Since the early 1980s, axial chirality has played an increasingly significant role in organic chemistry. Much of this research has focused on catalysis; consider two recent reviews, one on modified BINOLs, and one on modified BINAPs. But axial chirality isn't just restricted to catalysts; it's also a feature of numerous natural products.

Once merely a curiosity, axial chirality now plays a role in virtually every subdiscipline of organic chemistry. At the same time, this important concept is alien to most molecular languages and toolkits. Consider, for example, that the specifications of all four of the most popular molecular languages (SMILES, InChI, Molfile, and CML) are silent on the representation of axial chirality. In other words, axial chirality is undefined in these languages. Although support for axial chirality could be "hacked" into these languages, this would require nonstandard conventions that would be unintelligible to any third party.

This situation poses a significant problem for those needing to discriminate axially chiral stereoisomers in molecular databases or other applications. For example, PubChem's entry on the axially-chiral drug gossypol is devoid of stereochemical information. If PubChem used an internal representation of molecular structure capable of encoding axial chirality, coupled with a suitable molecular language to be used by depositors, separate entries for each gossypol enantiomer would be feasible. After all, PubChem users have come to expect the same of other chiral drugs containing stereogenic atoms.

To address this problem, a new XML-based molecular language called FlexMol has been developed. Recent articles have highlighted FlexMol's use with the multi-atom bonding found in metallocenes, and E/Z alkene geometrical isomerism. Based on a specification by Andreas Dietz, Flexmol can represent all forms of axial chirality using a single flexible formalism..

Chemical informatics is beginning to embrace the concepts of Open Source and Open Data already in widespread use elsewhere. This shift will bring into sharp focus the need for robust and open methods for accurately encoding molecular structure. Existing technologies have not kept up with the chemists themselves, as the axial chirality problem demonstrates. Future articles in this series will show how FlexMol can offer a solution to this and other important molecular representation problems.

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The fundamental idea behind our representation of stereochemistry is to really describe the relative spatial arrangements of the atoms of a chemical structure. For a given constitution, we obtain a unique and unambiguous stereochemical representation. No limitation to predefined types or steregenic units exits; any conceivable relative spatial arrangement of atoms may be uniformly represented by one universally applicable formalism. ...

-Andreas Dietz, J. Chem. Inf. Comput. Sci. 1995, 35, 787-802

A recent article introduced FlexMol, a molecular language designed to encode the multi-atom bonding arrangements present in molecules being increasingly made and used by today's chemists. But FlexMol was designed with much more than bonding in mind. Of all of the difficult areas in molecular representation, perhaps none are more daunting than stereochemistry. This article will introduce the basic ideas behind FlexMol's stereochemistry capabilities using the geometrical isomers of 2-butene as an example.

The Difference Between Configuration and Conformation

FlexMol distinguishes between two complementary stereochemical concepts - conformation and configuration. The difference between the two lies in whether isomers can be interconverted through bond rotations. To paraphrase Dietz:

• Conformation. Two molecules with identical atom connectivities and bonding differ with respect to their conformation if if they possess different relative spatial arrangements of atoms that can be interconverted by rotations about bonds.

• Configuration. Two molecules with identical atom connectivities and bonding differ with respect to their configuration if they possess different relative spatial arrangements of atoms that can not be interconverted by rotations about bonds.

Notice that these definitions say nothing about whether a bond rotation is likely to occur; they simply refer to the possibility of isomer interconversion through bond rotation. Clearly, double bond geometrical isomerism arises from restricted bond rotation. So we'll be relying on FlexMol's support for conformational stereochemistry.

Encoding Cis/Trans Isomerism: 2-Butene

Consider the two isomers of 2-butene. The cis isomer can be encoded in FlexMol as follows:

<!-- cis-2-butane -->
<?xml version="1.0" standalone="yes"?>

<molecule>
  <constitution>
    <atoms>
      <atom id="C0" symbol="C" hydrogens="3" ionization="4"></atom>
      <atom id="C1" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C2" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C3" symbol="C" hydrogens="3" ionization="4"></atom>
    </atoms>
    <bonding>
      <bond source="C0" target="C1" bondingElectrons="2"></bond>
      <bond source="C1" target="C2" bondingElectrons="4"></bond>
      <bond source="C2" target="C3" bondingElectrons="2"></bond>
      <bond source="C3" target="C4" bondingElectrons="2"></bond>
    </bonding>
  </constitution>
  <conformation>
    <conformationWheel>
      <gammaSequence source="C1" target="C2">
        <connections>
          <atomPair source="C1" target="C2"></atomPair>
        </connections>
      </gammaSequence>
      <halfPlane></halfPlane>
      <halfPlane>
        <lower atom="C0"></lower>
        <upper atom="C3"></upper>
      </halfPlane>
    </conformationWheel>
  </conformation>
</molecule>

In contrast to previous FlexMol examples, this representation contains a conformation element, which in turn contains a conformationWeel subelement. The conformationWheel is composed of a gammaSequence and two halfPlanes. The relationship among these elements can be seen in the diagram below.

Stereochemical representation in FlexMol boils down to placing atoms into a set of half-planes intersecting a given axis (Dietz refers to this arrangement as a "pencil of planes"). In the case of cis-2-butene, this axis, or gamma sequence, is the atom pair between atoms C1 and C2. A gamma sequence can consist of two or more atoms, a very useful feature for representing allene stereochemistry, for example. Half planes are specified in clockwise order about this axis. Because half planes always occur in pairs separated by 180 degrees about their common axis, the number of half planes will always be even. Each conformational half plane is further subdivided into two regions labeled appropriately enough "upper" and "lower".

A conformation wheel will always have an equivalent, but opposite representation. For example, cis-2-butene could also be represented with an axis of opposite orientation (C2->C1), opposite ordering of half planes (in this case the same ordering because there are only two half planes), and inverted upper/lower designations. FlexMol only requires that one of these two equivalent arrangements be specified.

In a similar fashion, we can generate a FlexMol representation for trans-2-butene:

<!-- trans-2-butane -->
<?xml version="1.0" standalone="yes"?>

<molecule>
  <constitution>
    <atoms>
      <atom id="C0" symbol="C" hydrogens="3" ionization="4"></atom>
      <atom id="C1" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C2" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C3" symbol="C" hydrogens="3" ionization="4"></atom>
    </atoms>
    <bonding>
      <bond source="C0" target="C1" bondingElectrons="2"></bond>
      <bond source="C1" target="C2" bondingElectrons="4"></bond>
      <bond source="C2" target="C3" bondingElectrons="2"></bond>
      <bond source="C3" target="C4" bondingElectrons="2"></bond>
    </bonding>
  </constitution>
  <conformation>
    <conformationWheel>
      <gammaSequence source="C1" target="C2">
        <connections>
          <atomPair source="C1" target="C2"></atomPair>
        </connections>
      </gammaSequence>
      <halfPlane>
        <upper atom="C3"></upper>
      </halfPlane>
      <halfPlane>
        <lower atom="C0"></lower>
      </halfPlane>
    </conformationWheel>
  </conformation>
</molecule>

This representation contains a conformationWheel with two filled half planes containing the atoms C3 and C0, respectively. The arrangement among the conformational elements can be better seen in the following diagram:

So What?

There are many ways to represent alkene geometrical isomerism, most of which are far simpler than the one outlined here. So what does this additional complexity buy us? In FlexMol, we can use exactly the same formalisms we used for 2-butene isomers to represent the stereochemistries of molecules that simply can not be represented in other systems. Two specific examples include the axial chirality of allenes and biaryls. If you'd like some hints on how to accomplish this, see the allene and binaphthyl FlexMol examples contained in the flexmol directory of the Octet source distribution.

Notice how FlexMol does away with the need to define conformation in terms of sterochemical descriptors, which are quite limited. Instead, FlexMol provides a small set of modular concepts that, when used together, actually describe the underlying conformational features of a molecule. Of course, (E) and (Z) descriptors (and a host of others as well) can be derived from a FlexMol representation given the right software.

Conclusions

We've covered the essentials for conformational representation in FlexMol, and we've seen how to differentiate double bond geometrical isomers. The same principles described here are also used in encoding stereochemical configuration, which will be the subject of a future tutorial.