*************************
Difficult Chemical Groups
*************************

This chapter describes how Grade2 tackles chemical groups that present problems
in restraint generation.

If you come across a chemical group that Grade2 does not handle properly,
then :ref:`please let us know <faq_suggestion>`.
Please note that it is unnecessary to disclose the whole of your ligand
but instead just the problematic chemical group, for instance,
by finding a compound in PubChem containing the group.

.. _sf5:

Pentafluorosulfanyl -SF\ :sub:`5`\
==================================

The pentafluorosulfanyl (-SF\ :sub:`5`\) moiety is a functional group
with useful properties, such as high electronegativity, chemical and
thermal stability, that is becoming increasing popular
`(Chan, 2019) <https://doi.org/10.1039/C9TC01949A>`_.

For restraint generation the pentafluorosulfanyl group present a challenge
as it adopts an `octahedral molecular geometry
<https://en.wikipedia.org/wiki/Octahedral_molecular_geometry>`_.


   .. figure:: images/GISVOU_labeled.png
     :width: 500
     :alt: CSD entry GISVOU with labels on CSF5
     :align: center

     CSD entry
     `GISVOU <https://www.ccdc.cam.ac.uk/structures/Search?Ccdcid=GISVOU>`_
     with labels showing Grade2 classification of the atoms in the
     CSF\ :sub:`5`\ group.

The octahedral geometry means that the fluorine atoms become non-equivalent
and produces bond angles at the sulfur atoms that are close to either 90º
or 180º. As shown in the figure above, Grade2 assigns the fluorine atoms
so that F\ :sub:`away`\  is opposite the carbon atom and F\ :sub:`next1`\
is opposite F\ :sub:`next3`\.

Restraints for the group were found by using the CSD Conquest program to
search for CSF\ :sub:`5`\  in CSD entries with R factors better than 0.05,
excluding organometallics and entries with disorder or errors. This
identified 68 CSD entries. For each of these Grade2 was used to
measure the bond angles at the sulfur atom the CSF\ :sub:`5`\
group (excluding the angles close to 180º).


   .. figure:: images/cfs5_histogram.png
     :width: 500
     :align: center
     :alt: Conquest/Grade2 CSF5 bond angle analysis

     Distribution found in the CSD database for bond angles at the sulfur atom
     of the CSF\ :sub:`5`\ group.

The distributions show that that geometry is not exactly octahedral.
From release :ref:`1.4.0 <changelog-1.4.0>`, Grade2
imposes angle restraints using the mean and standard deviation found in the
CSD distributions, as shown in the figure and table below.

.. figure:: images/GISVOU_with_restraint_ideals.png
     :width: 500
     :alt: Grade2 restraints CSF5 angles
     :align: center

     Grade2 bond angle restraints for the CSF\ :sub:`5`\   group.
     Values ideal angle and estimated standard deviation (esd or sigma)
     are shown.

.. flat-table:: Grade2 restraints for  CSF\ :sub:`5`\
   :widths: 1 1 1 1
   :header-rows: 1

   * - Angle
     - Ideal angle
     - Angle esd
     - Notes

   * - F\ :sub:`away`\ -S-F\ :sub:`next*`\
     - 87.7º
     - 0.5º
     -

   * - F\ :sub:`next1`\ -S-F\ :sub:`next2`\
     - 89.9º
     - 0.5º
     -

   * - F\ :sub:`next1`\ -S-F\ :sub:`next4`\
     - 89.9º
     - 0.5º
     -

   * - F\ :sub:`next2`\ -S-F\ :sub:`next3`\
     - 89.9º
     - 0.5º
     -

   * - F\ :sub:`next3`\ -S-F\ :sub:`next4`\
     - 89.9º
     - 0.5º
     -

   * - C-S-F\ :sub:`next*`\
     - 92.3º
     - 0.9º
     -

   * - C-S-F\ :sub:`away`\
     - 180.0º
     - 999.9º
     - inactivated

   * - F\ :sub:`next1`\ -S-F\ :sub:`next3`\
     - 180.0º
     - 999.9º
     - inactivated

   * - F\ :sub:`next2`\ -S-F\ :sub:`next4`\
     - 180.0º
     - 999.9º
     - inactivated

Note that restraints for all angles involving atoms on opposite
sides of the octahedral coordination are inactivated, as the geometry
is already heavily restrained by the other bond angle restraints.

It should be noted that
`RDKit does not handle the CSF5 group well
<https://github.com/rdkit/rdkit/issues/200#issuecomment-190210663>`_,
as it is not supported by the UFF force field as implemented in RDKit.
This means that the RDKit SMILES to 3D routine used by Grade2 fails for
CSF\ :sub:`5`\   group. As a workaround, `Open Babel <https://openbabel.org/>`_
can generate 3D coordinates for molecules with SF\ :sub:`5`\   group:

::

    $ obabel -:'CS(F)(F)(F)(F)F' --gen3D -O methyl_sf5_obabel.sdf

The resulting SDF file can be used as an input to grade2.