COSMO-RS with multi-species components
**************************************

COSMO-RS Conformer Association

Sometimes molecules behave in solution in ways that are not accurately
captured by the "one-molecule-one-structure" paradigm of standard
COSMO-RS theory.  The single-structure picture of standard COSMO-RS
represents much of the chemical space reasonably well but often fails
to accurately describe solutions with more complex behavior.  Examples
of systems with complex behavior may include:

* Compounds that exist as multiple conformers

* Compounds that may dimerize, trimerize, etc.

* Compounds that can dissociate into multiple species

* Compounds or species that explicitly associate with other molecules
  (e.g., solvent) in solution

Multi-species COSMO-RS aims to describe the inherent complexities in
these types of systems by allowing users to directly input multiple
representations for a single component.  The ratios of all of these
species in solution are calculated and final, "apparent" values are
reported for important thermodynamic values with respect to the
compounds.

The following tutorial aims to guide the user in setting up and
running calculations containing multi-species compounds.  This guide
will also discuss a few tips and point to a few GUI features that may
be useful in understanding the results of the multi-species
calculations.  Additionally, we will walk the user through a number of
practical examples demonstrating the benefits of this approach.


Building multi-species compounds
================================

The multi-species compounds input is used to organize information
about a compound that can exist in multiple forms.  It can be accessed
in the COSMO-RS GUI with a single step:

In this window, we can input ".coskf" files in specific boxes which
convey a relationship between a .coskf file and a single molecule of
the parent compound or a molecule which must be present for an
associated form to occur.  ".coskf" files can be used directly from
the AMS sigma profile database or calculated with ADF by following
this tutorial.  A basic guide for inputting ".multipleform" compounds
is given below:

   Select **Compounds → Compound with multiple forms**
   Input all conformers under conformers
   If there are any dimers, trimers, etc., select the dropdown box next to multimers and choose the appropriate value
   Enter the .coskf file and any enthalpy or entropy corrections
   If the compound dissociates, place the appropriate dissociated species in the boxes under the dissociated compound section
   Pay attention to the stoichiometry.  Note MgCl_2dissociates into 1 Mg^2+and 2 Cl^-ions
   If any structures contain other compounds in the mixture (for association or solvation) place them in the association section.
   Also, be sure to indicate which additional compounds are required in the following (1 or 2) boxes
   Finally, click save to save your .multipleform file


Enthalpy and entropy corrections
================================

A chemical structure's energy in solution is calculated as the sum of
two energies: (1) The "bond energy", which can be seen in the
**Compounds → List of Added Compounds.** menu; and (2) the solvent-
specific corrections calculated by COSMO-RS.  While this procedure
generally provides acceptable relative energies for different
unassociated conformers, it is usually insufficient to calculate
relative energies for compounds that associate or dissociate.

It is often necessary to provide corrections for these energies.  For
example, in the case of acetic acid dimerization, the "bond energy"
alone doesn't accurately represent the enthalpy and entropy changes
involved in dimerization.  For this reason, we can add a correction
term to the enthalpy ("Hcorr") value.  Of course, there is a large
entropic effect associated with dimerization, but for this simple
example, we'll assume we're performing a constant-temperature
calculation and the "Hcorr" can effectively represent the entire
correction to the free energy.  Setting Hcorr to a value of 9.25 for
the acetic acid dimer looks like the following:

[image]


Example multi-species calculations
==================================


Conformers and dimers in the acetic acid/hexane system
------------------------------------------------------


Relevant files for example
^^^^^^^^^^^^^^^^^^^^^^^^^^

".coskf files"

In this example, we'll investigate the acetic acid/heptane system.  In
this system, acetic acid prefers to dimerize, making it a good test
case to demonstrate the advantages of including multiple forms in a
COSMO-RS calculation.  We'll also perform this calculation using only
conformers of single acetic acid molecules.  Both of these
calculations will be compared to the standard COSMO-RS approach using
a single structure.

First, we need to generate the ".coskf" files we need for this
calculation.  We will consider 3 geometries for acetic acid: 2
unassociated conformers and 1 dimer.  These structures are shown
below:

[image][image][image]Structures used to represent acetic acid: lowest
energy conformer, higher energy conformer, and dimer (clockwise from
top left)

First, we will perform a standard COSMO-RS calculation for reference.
In this case, we will intentionally choose the higher-energy conformer
to illustrate that the results can be significantly influenced by a
poor choice of conformer.  An additional advantage of using
multispecies compounds is that the lowest-energy conformer is
preferred automatically in the calculations and the user does not have
to exercise so much caution when selecting structures.  To do a
standard calculation, we perform the following steps:

   **Properties → Binary Mixture VLE/LLE**
   Select acetic_2.coskf or compound 1
   Select Heptane for compound 2
   Set n to 20
   Click **Run**
   **Graph → Y Axis → activities**

The result of this calculation is the following:

[image]

Next, we will perform the calculation considering 2 conformers for
acetic acid.  This can be done by creating a ".multipleform" file
according to the following:

   **Compounds → Compound with multiple forms**
   Add the acetic_1.coskf under conformers
   Add the acetic_2.coskf under conformers
   Hit save in the top of the multiple forms box
   Save as acetic_acid_conformers.multipleform

Now, we perform the same steps as above in the **Binary Mixtre
VLE/LLE** module, except this time we will use the
"acetic_acid_conformers.multiform" instead of "acetic_2.coskf".

This should result in the following image:

[image]

Finally, we build the ".multipleform" file acetic acid with the dimer
included.   These steps are summarized below:

   **Compounds → Compound with multiple forms**
   Add the acetic acid conformers under conformers
   Add the acetic acid dimer under dimer
   Set the Hcorr of the dimer to 9.25
   Hit save in the top of the multiple forms box
   Save as acetic_acid.multipleform

The GUI should look like the following:

[image]

Now, we'll repeat the same steps as above, this time using the
"acetic_acid.multipleform" file (including the dimer) in place of the
previously used acetic acid file.

The result of this calculation is the following:

[image]

Additionally, we can view the relative amounts of the different forms
of acetic acid as a function of mole fraction.  To view this, do the
following:

   **Graph → Y Axis → Liquid phase composition 1**

This should produce the following:

[image]

Finally, we can compare the calculated activities to experimental
values [1] among 3 scenarios: (1) using a single structure for acetic
acid that is also *not* the lowest energy conformer; (2) using two
conformers for acetic acid; and (3) using both conformers and the
dimer.

[image]


Solvent association in the diethyl ether/chloroform system
----------------------------------------------------------


Relevant files for example
^^^^^^^^^^^^^^^^^^^^^^^^^^

".coskf files"

In this example, we'll investigate the effect of an association that
takes place in the diethyl ether/chloroform system.  This effect is
observed because the hydrogen atom in chloroform is electron deficient
and forms a H-bond with the oxygen in diethyl ether.  We begin this
example by generating ".coskf" files for the three relevant
structures: diethyl ether, chloroform, and the associated complex.
These files can be created by the user by following the steps outlined
in the COSMO result files tutorial .  Alternatively, the required
coskf files can simply be downloaded using the link above
(recommended).  The structures used in this example are shown below.

[image][image][image]Structures used in the diethyl ether chloroform
system: diethyl ether, chloroform, and the associated complex
(clockwise from top left)

First, we'll simply consider the system without association.  This can
be done by performing the following steps:

   Input Chloroform.coskf and Diethyl_ether.coskf to the AMS COSMO-RS GUI
   **Properties → Binary Mixture VLE/LLE**
   Select Diethyl_ether for compound 1
   Select Chloroform for compound 2
   Click **Run**
   **Graph → Y Axis → ln (activity coefficients)**

This should result in the following:

[image]

Now, we'll create a .multipleform file by adding the associated form
to diethyl ether (it can also be added to chloroform).  This procedure
is as follows:

   **Compounds → Compound with multiple forms**
   You may need to press 'Clear' at the top of the left window
   In the conformers section, add Diethyl_ether
   In the associated section, add the associated Diethyl_ether_chloroform
   Add chloroform to the requires box and make sure the requires value is 1
   Save the multipleform file

This should produce the following result:

[image]

Now, we'll use the multipleform file in place of the diethyl ether
file and repeat the binary mixture calculation.

   Input the multiform diethyl ether/chloroform associated complex to the AMS COSMO-RS GUI
   **Properties → Binary Mixture VLE/LLE**
   Select the multiform file for compound 1
   Select Chloroform for compound 2
   Click **Run**
   **Graph → Y Axis → ln (activity coefficients)**

This should result in the following:

[image]

Finally, we can compare the two approaches to experiment [2].  We
observe that the inclusion of the explicit association greatly
improves the agreement with experimental values.

[image]


Conformer populations across the chloroform-water phase partition
-----------------------------------------------------------------

In this example, we will investigate the differences in conformer
populations of amphetamine between water and chloroform solvents.
Additionally, we will look at how the partition coefficient is
affected by accounting for the conformers of amphetamine. Amphetamine
has three conformers, denoted in the literature [3] as the t-form,
g-form and h-form.  These are shown below.

[image]

For each conformer we can additionally rotate the C-N bond, producing
3 additional conformers for each of the conformers above.  The figure
below shows the three conformations of amphetamine in the t-form.

[image]


Relevant files for example
^^^^^^^^^^^^^^^^^^^^^^^^^^

".coskf files"

The conformations in this example may be prepared by the user, but for
convenience we have included all relevant ".coskf" files in the link
to the right.  The filenames refer to the energy in the COSMO phase as
well as which conformer is represented.  For example, AMP_E1_t is the
t-form conformer and has the lowest energy (among the 3 C-N rotamers)
while AMP_E9_h is the h-form conformer and has the highest energy.
Next, let's prepare a ".multiform" file to use with COSMO-RS.

   **Compounds → Compound with multiple forms**
   You may need to press 'Clear' at the top of the left window
   In the conformers section, add AMP_E1_t, AMP_E2_t, ... and AMP_E9_h.
   Save the multiform file

The GUI should look like the following:

[image]

Now, we can set up a logP calculation with the ".multiform" we just
made. This procedure is as follows:

   **Properties → Partition Coefficient(LogP)**
   Select User Defined 2 components
   Select Chloroform for compound 1
   Select Water for compound 2
   Add the ".multiform" file as solute
   Set molar volume ratio 4.4170
   Click **Run**

This should result in the following:

[image][image]

Now, we can sum up the populations of all of the 3 conformations for
each of the t-form, g-form, and h-form. Comparing these results to
conformer populations derived from H-NMR data [3], we observe good
agreement with our predictions.  This is shown in the the figure
below.

[image]

We can additionally do a logP calculation for every individual
conformation. Simply delete the ".multiform" file from the solutes
window, add all the individual ".coskf" files, and then click run. The
results show that the calculated logP ranges from 1.98 to 2.92 for the
different conformations.

[image][image]

-[ References ]-

[1] Lark, Bhajan S., et al. Excess Gibbs energy for binary mixtures
    containing carboxylic acids. 1. Excess Gibbs energy for acetic
    acid+ cyclohexane,+ benzene, and+ n-heptane. Journal of Chemical
    and Engineering Data 29.3 (1984): 277-280.

[2] Becker F.; Kiefer M.; Rhensius P.; Schaefer H.D.: Interpretation
    von Dampfdruckdiagrammen binärer flüssiger Mischungen mit Hilfe
    von Gleichgewichtsmodellen. Z.Phys.Chem.(München) 92 (1974)
    169-192

[3] Noszál, B., & Kraszni, M. (2002). Conformer-specific partition
    coefficient: Theory and determination. The Journal of Physical
    Chemistry B, 106(5), 1066-1068.
