Depth-First: Tag dietz

Can Your Cheminformatics Tool Do This?

Rich Apodaca — Wed, 13 Jun 2007 08:36:00 -0400

Can Your Cheminformatics Tool Do This?

Rich Apodaca — Thu, 05 Apr 2007 12:46:00 -0400

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?

A Molecular Language for Modern Chemistry: FlexMol and Planar-Chiral Metacyclophanes

Rich Apodaca — Mon, 22 Jan 2007 15:16:00 -0500

-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.

The Axial Chirality Problem

Rich Apodaca — Mon, 08 Jan 2007 14:57:00 -0500

... 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.

40085-070108-317986-10

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A Molecular Language for Modern Chemistry: FlexMol and Alkene Geometrical Isomerism

Rich Apodaca — Tue, 02 Jan 2007 15:39:00 -0500

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.

A Molecular Language for Modern Chemistry: Getting Started with FlexMol

Rich Apodaca — Wed, 20 Dec 2006 15:16:00 -0500

Existing molecular languages are limited in their ability to represent such commonplace features as multi-center bonding and axial chirality. The practical outcome of these limitations can be seen in PubChem's four separate entries for ferrocene and the inability to fully represent many molecules now in common use by organic chemists.

A recent article touched on a molecular representation system that was capable of far greater expressive power than those currently in use. In this article, I'll introduce FlexMol, an XML implementation of this advanced molecular representation system.

What is FlexMol?

FlexMol is an XML-based molecular language that's designed to allow the faithful representation of any molecule, regardless of its peculiarities. The following is a list of features that FlexMol can encode:

Multi-atom, multi-electron bonds
All known forms of stereochemistry, including axial chirality (e.g., allenes and biarlys), planar chirality (e.g., metallocenes), and non-tetrahedral stereocenters (e.g., square planar and octahedral metal complexes)
Non-natural isotopic distributions and pure isotopes
Virtual hydrogens (similar to "implicit hydrogens") through mandatory, explicit enumeration
Electronic spin, enabling the differentiation of spin states

What Does FlexMol Look Like?

Let's start with the simple example of benzene:

<!-- Benzene, represented as "1,3,5-cyclohexatriene" -->
<?xml version="1.0" standalone="yes"?>

<molecule>
  <constitution>
    <atoms>
      <atom id="C0" symbol="C" hydrogens="1" 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="1" ionization="4"></atom>
      <atom id="C4" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C5" symbol="C" hydrogens="1" 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="4"></bond>
      <bond source="C4" target="C5" bondingElectrons="2"></bond>
      <bond source="C0" target="C5" bondingElectrons="4"></bond>
    </bonding>
  </constitution>
</molecule>

The above representation divides the structure of benzene into two main elements - atoms and bonding. Both of these elements are in turn subelements of the constitution element, which specifies atom connectivity. Had we been representing a molecule with stereochemical features, the above document could have also contained a configuration element, a conformation element, or both.

Within the atoms element are definitions for each of the six degenerate carbon atoms of benzene. Each atom is assigned a unique ID for use elsewhere in the document, an atomic symbol, the number of hydrogens bonded to each atom, and the effective ionization state of each atom. The mandatory hydrogens attribute specifies "virtual" hydrogens, or those associated with an atom without being full-fledged nodes in the graph representation.

The bonding element defines all of the bonding arrangements within benzene. In this case, benzene is being represented as "cyclohexatriene" with alternating single and double bonds; below we'll see how to use FlexMol to represent delocalized (aromatic) bonding. Each bond specifies a source atom, a target atom, and the number of bonding electrons.

In many situations, the above representation of benzene will not suffice. What if we want to describe the one-electron ionization of benzene to form the benzene radical cation? Using the "cyclohexatriene" form of benzene makes it impossible to select the correct bond from which to take electrons.

Instead, we could use a more physically meaningful representation of benzene, such as that shown below:

<!-- Benzene, represented with a delocalized pi-system -->
<?xml version="1.0" standalone="yes"?>

<molecule>
  <constitution>
    <atoms>
      <atom id="C0" symbol="C" hydrogens="1" 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="1" ionization="4"></atom>
      <atom id="C4" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C5" symbol="C" hydrogens="1" ionization="4"></atom>
    </atoms>
    <bonding>
      <bond source="C0" target="C1" bondingElectrons="2"></bond>
      <bond source="C1" target="C2" bondingElectrons="2"></bond>
      <bond source="C2" target="C3" bondingElectrons="2"></bond>
      <bond source="C3" target="C4" bondingElectrons="2"></bond>
      <bond source="C4" target="C5" bondingElectrons="2"></bond>
      <bond source="C0" target="C5" bondingElectrons="2"></bond>
      <bondingSystem bondingElectrons="6">
        <connections>
          <atomPair source="C0" target="C1"></atomPair>
          <atomPair source="C1" target="C2"></atomPair>
          <atomPair source="C2" target="C3"></atomPair>
          <atomPair source="C3" target="C4"></atomPair>
          <atomPair source="C4" target="C5"></atomPair>
          <atomPair source="C0" target="C5"></atomPair>
        </connections>
      </bondingSystem>
    </bonding>
  </constitution>
</molecule>

This is certainly more verbose, but what does it buy us? Notice the bondingSystem subelement at the end of the bonding element. Here we define an extended six-atom, six-electron bonding system that much more closely reflects the true nature of benzene's pi-system. Now it's obvious that this is the bonding motif from which to take an electron to make the benzene radical cation.

Next, consider the cyclopenadienyl anion, which possesses a five-atom, six-electron Hueckel aromatic bonding system. We can apply the same principles in representing benzene's pi-system to the representation of the cyclopentadienyl anion's pi-bonding:

<!-- Cyclopentadienyl Anion -->
<?xml version="1.0" standalone="yes"?>

<molecule>
  <constitution>
    <atoms>
      <atom id="C0" symbol="C" hydrogens="1" 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="1" ionization="4"></atom>
      <atom id="C4" symbol="C" hydrogens="1" ionization="4"></atom>
    </atoms>
    <bonding>
      <bond source="C0" target="C1" bondingElectrons="2"></bond>
      <bond source="C1" target="C2" bondingElectrons="2"></bond>
      <bond source="C2" target="C3" bondingElectrons="2"></bond>
      <bond source="C3" target="C4" bondingElectrons="2"></bond>
      <bond source="C0" target="C4" bondingElectrons="2"></bond>
      <bondingSystem bondingElectrons="6">
        <connections>
          <atomPair source="C0" target="C1"></atomPair>
          <atomPair source="C1" target="C2"></atomPair>
          <atomPair source="C2" target="C3"></atomPair>
          <atomPair source="C3" target="C4"></atomPair>
          <atomPair source="C0" target="C4"></atomPair>
        </connections>
      </bondingSystem>
    </bonding>
  </constitution>
</molecule>

In the above representation, all carbon atoms are equivalent - something difficult, if not impossible, to achieve with most other molecular languages. Furthermore, the representation of delocalized bonding closely matches what most chemists would describe. We could get even more sophisticated and place individual electrons into three separate bonding systems in analogy with molecular orbitals - it really depends on what we'd like to emphasize.

This is well and good for aromaticity, but how can all of this help solve the Ferrocene Problem? Just as with cyclopentadienyl anion and benzene, in the representation of ferrocene below, we're taking advantage of FlexMol's support for multi-atom bonding. In this case, we define three bondingSystems, each of which contain six electrons. We could have just as easily created a single eighteen-electron, eleven-atom bonding system. Our choice of representation again depends on what we're trying to emphasize.

<!-- Ferrocene -->
<?xml version="1.0" standalone="yes"?>

<molecule>
  <constitution>
    <atoms>
      <atom id="C0" symbol="C" hydrogens="1" 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="1" ionization="4"></atom>
      <atom id="C4" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C5" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C6" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C7" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C8" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="C9" symbol="C" hydrogens="1" ionization="4"></atom>
      <atom id="Fe10" symbol="Fe" hydrogens="0" ionization="8"></atom>
    </atoms>
    <bonding>
      <bond source="C0" target="C1" bondingElectrons="2"></bond>
      <bond source="C1" target="C2" bondingElectrons="2"></bond>
      <bond source="C2" target="C3" bondingElectrons="2"></bond>
      <bond source="C3" target="C4" bondingElectrons="2"></bond>
      <bond source="C0" target="C4" bondingElectrons="2"></bond>
      <bond source="C5" target="C6" bondingElectrons="2"></bond>
      <bond source="C6" target="C7" bondingElectrons="2"></bond>
      <bond source="C7" target="C8" bondingElectrons="2"></bond>
      <bond source="C8" target="C9" bondingElectrons="2"></bond>
      <bond source="C5" target="C9" bondingElectrons="2"></bond>
      <bondingSystem bondingElectrons="6">
        <connections>
          <atomPair source="C0" target="C1"></atomPair>
          <atomPair source="C1" target="C2"></atomPair>
          <atomPair source="C2" target="C3"></atomPair>
          <atomPair source="C3" target="C4"></atomPair>
          <atomPair source="C0" target="C4"></atomPair>
          <atomPair source="C0" target="Fe10"></atomPair>
          <atomPair source="C1" target="Fe10"></atomPair>
          <atomPair source="C2" target="Fe10"></atomPair>
          <atomPair source="C3" target="Fe10"></atomPair>
          <atomPair source="C4" target="Fe10"></atomPair>
        </connections>
      </bondingSystem>
      <bondingSystem bondingElectrons="6">
        <connections>
          <atomPair source="C5" target="C6"></atomPair>
          <atomPair source="C6" target="C7"></atomPair>
          <atomPair source="C7" target="C8"></atomPair>
          <atomPair source="C8" target="C9"></atomPair>
          <atomPair source="C5" target="C9"></atomPair>
          <atomPair source="C5" target="Fe10"></atomPair>
          <atomPair source="C6" target="Fe10"></atomPair>
          <atomPair source="C7" target="Fe10"></atomPair>
          <atomPair source="C8" target="Fe10"></atomPair>
          <atomPair source="C9" target="Fe10"></atomPair>
        </connections>
      </bondingSystem>
      <bondingSystem bondingElectrons="6">
        <connections>
          <atomPair source="C0" target="C1"></atomPair>
          <atomPair source="C1" target="C2"></atomPair>
          <atomPair source="C2" target="C3"></atomPair>
          <atomPair source="C3" target="C4"></atomPair>
          <atomPair source="C0" target="C4"></atomPair>
          <atomPair source="C0" target="Fe10"></atomPair>
          <atomPair source="C1" target="Fe10"></atomPair>
          <atomPair source="C2" target="Fe10"></atomPair>
          <atomPair source="C3" target="Fe10"></atomPair>
          <atomPair source="C4" target="Fe10"></atomPair>
          <atomPair source="C5" target="C6"></atomPair>
          <atomPair source="C6" target="C7"></atomPair>
          <atomPair source="C7" target="C8"></atomPair>
          <atomPair source="C8" target="C9"></atomPair>
          <atomPair source="C5" target="C9"></atomPair>
          <atomPair source="C5" target="Fe10"></atomPair>
          <atomPair source="C6" target="Fe10"></atomPair>
          <atomPair source="C7" target="Fe10"></atomPair>
          <atomPair source="C8" target="Fe10"></atomPair>
          <atomPair source="C9" target="Fe10"></atomPair>
        </connections>
      </bondingSystem>
    </bonding>
  </constitution>
</molecule>

The same principles outlined for ferrocene apply equally to other metallocenes. FlexMol can also represent a host of otherwise tough cases such as nonclassical carbocations, allylmetal complexes, resonance-stabilized radicals and ions, and transition states.

Why XML?

XML provides several often-cited advantages:

Availability of standardized parser and output libraries
Human readability
Adequate mapping to Object-Oriented models for most purposes

Nothing about FlexMol prevents it from being built on top of another data-interchange format. Two of the most interesting alternatives to XML are JavaScript Object Notation (JSON) and YAML. JSON in particular seems to have learned from XML's experiences and so represents a platform worthy of serious consideration.

What About Chemical Markup Language?

Chemical Markup Language (CML) is a widely-used XML-based molecular language. So why invent yet another XML language for chemistry? Currently, CML does not solve the molecular representation problems discussed in this article and those preceding it. So although FlexMol and CML are both built on XML, they are nevertheless each aimed at addressing different problems. In this respect, FlexMol and CML are complementary.

Where's the Software?

Any language needs software to make it useful. To simplify the use of FlexMol, it is fully supported by Octet, an Open Source framework written in Java. Supporting FlexMol in other cheminformatics toolkits will likely be challenging due to impedance mismatch; FlexMol can precisely encode a variety of structural concepts that simply don't exist elsewhere.

Conclusions

Existing molecular languages lack the expressive power to represent many structural motifs in widespread use by today's chemists. FlexMol was designed to solve this problem. Future articles in this series will demonstrate how FlexMol documents can be read and written, as well as showing some techniques for manipulating the resulting molecular representations.

Ferrocene and Beyond: A Solution to the Molecular Representation Problem

Rich Apodaca — Tue, 19 Dec 2006 14:45:00 -0500

The representation of molecular structure decisively determines the scope of a chemical computer program. Our goal is to provide a versatile computer-oriented molecular structure representation for chemical information storage and retrieval as well as for computer-assisted synthesis design. Structural formulas describe molecular structure on the proper level of abstraction for these applications. ... It is therefore desirable that the computer-oriented representation of molecular structure be as expressive as the structural formulas.

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

A recent Depth-First article highlighted the difficulty that existing molecular languages have in communicating the generalized, multi-atom bonding present in metallocenes such a ferrocene. For software and Web services that do not interact with the outside world, the Ferrocene Problem may not be a big deal. But for the growing number that do, the Ferrocene Problem is but the tip of a very large iceberg.

Today's Weird-Looking Molecule is Tomorrow's Molecule of the Month

Consider the problem of axial chirality, such as that present in certain biaryls. None of the molecular languages currently in widespread use (InChI, SMILES, Molfile, or CML) provide a mechanism to faithfully represent and communicate this structural motif. In the 1980s, axial chirality was a novelty. Today it is ubiquitous. Consider this graphical abstract from the current issue of Organic Letters:

If you were asked to create an application capable of distinguishing substituted (R) and (S) binol enantiomers, could you do it? If your system needed to reliably interact with the outside world, could it do so? If you're working with any of the cheminformatics tools currently in widespread use, chances are good that the answers to these questions would be "no".

Do you still think of metallocenes as curiosities studied by a handful of organometallic chemists? Consider this J. Org. Chem. ASAP contents article describing one of the most fundamental transformations in organic chemistry:

The problem only gets worse as concepts like axial and planar chirality are increasingly co-mingled with multi-atom bonding. For example, consider the following graphical abstract, taken from J. Org. Chem. ASAP contents:

These molecules, and many others like them, were used in the context of organic chemistry. Moreover, the papers describing their use were published in widely-respected journals specializing in organic chemistry. Yet dozens of popular cheminformatics tools specifically designed for use with organic chemisty are incapable of faithfully representing the most interesting features of these molecules. In other words, the problem is both real and immediate.

Chemistry relentlessly marches forward, revealing even greater molecular information problems on the horizon. For software to remain relevant, it must be based on tools that are up to the challenge.

A Solution

The system proposed by Dietz offers a solution to nearly all of the bonding and stereochemistry problems of existing molecular languages. As a tradeoff, Dietz's system is significantly more complicated to implement. This places an increased burden on software to make the system as simple and understandable as possible.

Java and XML Implementations

Any specification, if it is to become more than just an academic exercise, requires a software implementation. Fortunately, for Dietz's system both a software implementation and an XML Schema have been developed and are freely-available.

The software implementation can be found in the Java framework Octet. In addition to fully-implementing Dietz's specification, Octet enables ring perception, substructure and query structure matching, breadth-first traversal, and of course, depth-first traversal. Add-on libraries are available for 2-D structure depiction, and Molfile and SMILES input and output. A CDK News article discusses CDKTools, a bridge to the Chemistry Development Kit. Octet remains, to my knowledge, the first and only implementation of the Dietz system.

The first, and to my knowledge only, XML implementation of the Dietz molecular representation system is FlexMol (Flexible Molecular Object Language). A commented W3C schema is distributed with Octet. Browser-ready HTML documentation can be found here, or from the sidebar links under "APIs and Schema Documentation." Octet is able to read and write FlexMol documents, providing an open, end-to-end solution to the problem of representing and transmitting molecules containing "nonstandard" bonding and stereochemistry.

Conclusions

Both FlexMol and Octet are convenient tools for working with the Dietz molecular representation system. Future articles in this series will show how they can be used to solve current, real-world molecular representation problems.