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\begin{document}

\title{Theoretical Studies to Estimate the Skin Sensitization Potential
of Chemicals of the Schiff Base Domain.}



\author[1]{Duangkamol Gleeson}%
\author[1]{Matthew Gleeson}%
\affil[1]{King Mongkut's Institute of Technology Ladkrabang}%


\vspace{-1em}



  
  \date{May 07, 2024}


\begingroup
\let\center\flushleft
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\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Skin sensitization occurs when an exogenous chemical substance forms a
covalent adduct with a dermal protein electrophile or nucleophile. This
instigates an immune response which leads to inflammation. The local
lymph node assay (LLNA) is an in-vivo model used in the assessment of
relative skin sensitizing potency of chemicals. The method is time
consuming and expensive, as well as poses ethical questions given that a
number of mice must be sacrificed for each compound assessed. In this
work we investigate the use of an inexpensive, rapid and ethical method
to predict the skin sensitization potential of Schiff base chemicals. We
employ quantum chemical methods to rationalize the sensitization
potential of 22 compounds with a diverse range of activities. To this
end we have evaluated the mechanistic profile associated with this type
of reaction using gas-phase models. We subsequently use the predicted
rate determining barriers and key physico-chemical parameters (such as
logP) to establish SAR guidelines to predict the skin sensitization
potential for new chemicals. We find that the predicted rate determining
barriers for aldehydes, ketone and 1,2 and 1,3 diones generally decrease
in the given order, which concurs with the overall trends in
sensitization. We find that lipophilicity also plays a role, with those
chemicals displaying both low barriers to reaction, and lower
lipophilicity (i.e. diones), being more likely to display undesirable
skin sensitization effects. These findings are in line with experimental
based observations in the literature and point to the value 3D quantum
chemical simulations can play in the combination of approaches used to
estimate skin sensitization potential of chemicals.%
\end{abstract}%



\sloppy


\section*{1.0 Introduction}

{\label{introduction}}

Skin sensitization is a commonly observed occupational health issue
which arises from an immunological allergic response. Skin sensitizers
are chemical substances that elicit an allergic response after exposure
to the skin, leading to allergic contact dermatitis (ACD).{[}1{]} It has
been reported that between 15-20\% of the general population will suffer
sensitization over the course of their lives. The disease is a
significant regulatory health concern and has resulted in European Union
legislation in the form of the Registration, Evaluation, Authorization
and Restriction of Chemicals (REACH). This legislation requires that the
skin sensitization potential of all chemical substances manufactured or
imported at level of one ton per annum must be assessed. A further goal
of REACH is to increase the use of nonanimal models for chemical
assessment.{[}2, 3{]}

Skin sensitization arises from the reaction of chemical sensitizer with
skin proteins triggering an immune response.{[}4, 5{]} A range of
different techniques are available to assess the skin sensitization of
chemicals. These including in-vivo, in-vitro, in-chemico and in-silico
methods have been developed.{[}6-13{]} As a result of ethical standards
set by REACH legislation there has been an increasing push away from
\emph{in vivo} models such as the gold standard \emph{in vivo} murine
Local Lymph Node Assay (LLNA),{[}7{]} towards \emph{in vitro}methods,
such as KeratinoSensTM assay,{[}14{]} and \emph{in chemico}alternatives,
such as peptide depletion assays.{[}13{]} Hoffman \emph{et al.}analyzed
128 compounds with a range of sensitization endpoints find that the LLNA
assay shows \textasciitilde{}75\% concordance between human results and
the LLNA assay, while that for the KeratinoSensTM assay was roughly
comparable.{[}15{]} Natsch \emph{et al.} {[}8{]} reported that the
latter\emph{in vitro} approach showed a 60\% concordance with the LLNA
methods for a set of 312 chemicals. Hoffman{[}16{]} and others{[}8,
17{]} report that the most effective strategy to predict
skinsensitization potential is to employ a multiple non-animal methods.
The former reports that incorporation of essentially orthogonal test
strategies comprising \emph{in vitro} , \emph{in chemico}and \emph{in
silico} inputs demonstrated the best overall performance, equivalent or
superior to the LLNA assay on their curated set of 128
datapoints.{[}16{]}

\emph{In silico} methods are desirable alternatives to \emph{in
vivo}models since a prediction on an unknown chemical can be made from
its chemical structure alone. While this means the methods generally
cost resource and time efficient, they are generally of lower accuracy
than their experimental alternatives. \emph{In silico} models can range
from similarity or substructural methods{[}5, 18, 19{]} that allow the
identification of like-molecules with experimental data (read-across) or
statistical models that can relate 2D chemical descriptors to a
qualitative or quantitative prediction of activity. {[}20-22{]} Methods
TIMES, Toxtree, Derek Nexus \emph{etc.} {[}17, 23, 24{]} have proved
useful in compound assessment in their own right,{[}21, 25{]} and as
part of multi-tiered testing strategies with \emph{in silico} models as
the first tier approach.{[}21, 26{]}

A number of different statistical models that relate chemical properties
to the degree of sensitization have been reported in the literature.
Guidelines that all \emph{in silico} models must meet are: (a) a defined
endpoint, (b) an unambiguous QSAR model, which is (c), mechanistically
interpretable. In addition the model must have (d) predictivity that is
fit for purpose and (e) a defined domain of applicability.{[}5, 27{]}
Notable models include the relative alkylation index (RAI) of Roberts
\emph{et al.}{[}28{]}, models built on individual chemical domain
basis{[}12, 29-32{]} or global basis.{[}21, 22, 33, 34{]} Global models
are generally desirable due to their greater applicability
domain,{[}35{]} however in many cases focusing a QSAR model on
individual chemical classes (i.e. Schiff bases, Michael acceptors,
SN1/SN2, SNAr, Acyl,\emph{etc.} ){[}12{]} we can obtain better ``local''
performance.{[}36{]} These mechanistically interpretable models can
offer increased confidence over black box models which may be important
in a regulatory situation.

There has been a general trend towards more information rich 3D
specific, or use of quantum chemical descriptors in QSAR modelling
studies associated with ligand bioactivity.{[}37-45{]} This includes the
incorporation of dynamical effects \emph{via} descriptors derived from
MD simulations{[}46-48{]} and interaction energies and conformational
energies \emph{via} quantum mechanics (QM).{[}49-53{]} and chemical
reactivity.{[}54, 55{]} Indeed, these trends towards more information
rich descriptors have been observed in studies related to skin
sensitization prediction given that chemical reactivity can be encoded
much effectively with quantum chemical derived descriptors than those
that are empirical derived. For example, Miller \emph{et al.} {[}34{]}
have used semi-empirical HOMO-LUMO energies for their QSAR studies,
Enoch \emph{et al.} used density functional theory energies of key
reaction intermediate as surrogates for the rate determining barriers of
Michael acceptors {[}55{]} while Promkatkaew \emph{et al.}fully profiled
all intermediates and transition states in the reaction mechanism of
SNAr chemicals.{[}54{]} Additional efforts have been spent investigating
ligand conformational effects on sensitization - given that molecules
are not perfectly described by a single conformation. Yu \emph{et al.}
have used 4D fingerprints in their studies{[}33{]} while Kostal \emph{et
al.} have incorporated Monte Carlo conformational sampling in their
hybrid QSAR models with good results.{[}56{]}

In this work we apply quantum chemical methods to rationalize the
sensitization potential of chemicals in the Schiff base (SB) domain
(Scheme 1). Roberts \emph{et al.} have previously reported a
quantitative mechanistic model to predict the LLNA pEC3 using the Taft
\selectlanguage{greek}σ\selectlanguage{english}* values and logP.{[}32{]} We were interested in expanding on this work
by (a) employing a more diverse datasets to cover a wider range of SB
functional groups as well as (b) investigate whether QM derived
estimates of chemical reactivity could prove useful. In our previous
work we showed that DFT derived barrier estimates did indeed perform
comparably well for the SNAr domain.{[}54{]} A key advantage of such
methods are that prediction can be made for functional groups where the
experimental Taft \selectlanguage{greek}σ\selectlanguage{english}* values are not readily available. To this end we
have collected 22 SB base chemicals covering aliphatic and aromatic
aldehydes and ketones, 1,2 diones and 1,3 diones, expanding considerably
the domain of applicability of the model over the previous study (11 out
of 16 were aliphatic aldehydes). The full reaction energy profile
leading to the formation of the 30 possible SB products for the 22
compounds, including 8 chemicals where more than one product is
possible. The relationship between the rate determining (RDS) barrier to
reaction and the LLNA pEC3 was then assessed. Finally we constructed a
two parameter quantitative molecular model (QMM) using only the RDS
barrier and the computed logP, the latter being another property
identified as being important for skin sensitization of SBs.{[}32{]}

\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Screen-Shot-2019-11-22-at-11-57-52-AM/Screen-Shot-2019-11-22-at-11-57-52-AM}

\end{center}
\end{figure}

\textbf{Scheme 1.} Formation of the imine (Schiff base) from a carbonyl
containing compound proceeds \emph{via} a hemi-acetal/ketal-like
intermediate.

\par\null

\section*{2.0 Computational Methods}

{\label{computational-methods}}

Twenty two molecules with the potential to react as Schiff bases (Scheme
1) were taken from data reported by ICCVAM (Interagency Coordinating
Committee on the Validation of Alternative Methods){[}57{]} and Kern
\emph{et al.} {[}58{]} as described previously.{[}54{]} All SB compounds
with non-zero EC3 values were chosen, covering a different chemical
substructures (Table 1). Some of the substrates contained chemical
functionality associated with other chemical domains (SNAr, SN2 and
Acyl) or had more than one position capable of forming a SB product. The
compounds can be sub-classified as aliphatic and aromatic aldehydes,
ketones, 1,2 diones and 1,3 diones. In the case of 1,2 and 1,3 diones,
each molecule contains two carbonyl groups leading to two plausible
points for nucleophilic attack.

Calculations were performed using a model consisting of the substrate,
two water molecules and two methylamine molecules to approximate the
biological reaction. The simulated reaction leading to the imine product
(Schiff base) involves three distinct steps as shown in Scheme 2. The
first step involves nucleophilic attack of the substrate by methylamine
giving rise to a carbinolamine or hemiacetal-like intermediate (INT1).
Proton transfer from the protonated intermediate, \emph{via} water,
leads to the elimination of water and the formation of the protonated
imine product (INT2). The final step involves the deprotonation of INT2
to give the deprotonated imine (PROD).

\par\null\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Screen-Shot-2019-11-22-at-11-58-03-AM/Screen-Shot-2019-11-22-at-11-58-03-AM}

\end{center}
\end{figure}

\textbf{Scheme 2} Individual sequences simulated in this study; (a)
substitution by an amine nucleophile (b) elimination of water to form
the imine and (c) deprotonation.

\par\null

All calculations were performed using DFT method implemented in the
Gaussian G09. {[}59{]} All structures were optimized using hybrid meta
exchange-correlation functionals, M06-2X with a 6-311+G(d,p) basis
set.{[}60, 61{]} The reaction mechanism associated with SB formation was
studied in the gasphase following the mechanism described in Scheme 2.
In this model, a methylamine molecule acts as both the nucleophile and
base in the reaction. Two explicitly modelled water molecules provide
additional stabilization and facilitate proton transfer steps. The
vibrational frequency calculations were performed to confirm all
transition states (TS). TSs are characterized by having a single
imaginary frequency and minima having none. The rate determining barrier
were subsequently determined. Additional substrate properties (MWT and
clogP) were obtained using the Chemaxon JChem.{[}62{]}

The correlation between independent and dependent variables was assessed
using linear regression. The data was partitioned into a training (M=14)
and test set (N=8) and a QMM was fitted using the RDS barrier and the
logP using multiple linear regression. All statistical analyses were
performed in Statistica 12.{[}63{]}

\section*{3.0 Results and Discussion}

{\label{results-and-discussion}}

The reaction energetics for compounds \emph{\textbf{1}-\textbf{22}} are
displayed in Table 1. The compounds simulated include aldehydes,
ketones, 1,2 diones and 1,3 diones. In addition, some molecules contain
more than one position that can undergo Schiff base (SB) reaction and
the results for these positions are noted.

\textbf{Table 1:} Structures, IDs and energetics associated with SB
formation for compounds 1-22 . Energy reported relative to the reactant
in kcal/mol. Absolute barriers are given in parenthesis.\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
\begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{ID}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Name}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Structure}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{CAS-No.}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{TS1}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{INT1}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{TS2}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{INT2}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{TS3}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{PROD}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
6-methoxy-2,6-dimethyloctanal\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
929253-05-4\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.75\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-12.75\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
15.39 (28.14)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-8.85\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-7.60 (1.25)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-10.09\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3-chloro-4-methoxy benzaldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4903-09-7\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.42\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-10.20\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
19.44 (29.63)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-8.45\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-5.87 (2.58)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-9.71\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
benzaldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
100-52-7\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.62\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-11.38\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
18.68 (30.06)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-7.55\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-6.72 (0.84)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-10.75\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1-(3-chlorophenyl) propan-1-one\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
34841-35-5\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
6.14\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-4.40\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
25.15 (29.55)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-1.35\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-0.78 (0.57)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-2.38\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
5-methylhexane-2,3-dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
13706-86-0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.67\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-13.01\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
20.63 (33.64)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-1.04\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.38 (1.42)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-9.54\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.09\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-9.68\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
20.24 (29.92)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-4.61\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-4.60 (0.01)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-8.63\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2-methyl-1-phenyl butane-1,3-dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
6668-24-2\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.07\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-0.98\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
27.35 (28.33)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.81\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.94 (0.12)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.07\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
14.58\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-3.92\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
21.15 (25.07)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-2.42\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-2.16 (0.26)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-4.44\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
7\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
6-nonenal\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2277-19-2\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.36\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-11.14\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
15.33 (26.47)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-7.08\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-6.67 (0.41)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-9.64\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
8\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2,2,6,6-tetramethyl heptane-3,5-dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1118-71-4\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
7.37\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.66\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
25.33 (21.66)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-2.56\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-2.43 (0.13)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-6.55\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
butane-2,3-dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
431-03-8\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.24\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-14.24\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
19.82 (34.06)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-0.81\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-0.68 (0.13)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-2.57\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
10\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4,4,4-trifluoro-1-phenylbutane-1,3-dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
326-06-7\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-*\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
24.31 (24.31)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
11.76\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
12.43 (0.67)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-5.42\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
25.86\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
14.56\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
37.24 (22.68)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
7.93\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
7.96 (0.03)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
5.52\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
11\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2-methylundecanal\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
110-41-8\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.87\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-12.32\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
14.87 (27.19)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-7.03\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-6.08 (0.96)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-10.06\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2-phenylpropanal\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
93-53-8\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.42\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-11.88\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
17.25 (29.13)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-7.57\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-2.20 (5.37)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-11.14\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
13\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
undec-10-enal\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
112-45-8\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.35\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-11.24\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
15.55 (26.79)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-7.13\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-6.65 (0.48)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-9.61\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
14\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1-(2,3,4,5-tetramethylphenyl)butane-1,3-dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
167998-73-4\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
7.65\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.02\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
20.70 (20.67)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.51\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
5.40 (2.89)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-3.16\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
18.02\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.22\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
27.91 (25.69)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-6.23\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-5.72 (0.52)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-6.96\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2-phenyl acetaldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
122-78-1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.03\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-9.57\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
18.34 (27.91)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-6.74\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-0.98 (5.76)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-10.46\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
16\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
glyoxal\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
107-22-2\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-*\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
31.54 (31.54)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-**\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-2.45\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
methyl 2-oxopropanoate\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
600-22-6\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.14\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-3.64\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
17.85 (21.49)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.45\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.21 (1.75)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-3.33\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
13.08\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
10.53\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
37.43 (26.90)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
9.92\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
12.83 (2.91)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
12.00\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
18\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2-bromo-5-hydroxy benzaldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2973-80-0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.71\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-12.97\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
17.88 (30.85)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-6.30\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-5.21 (1.10)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-11.97\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
19\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
N-(4-methoxyphenyl)-3-oxobutanamide\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
5437-98-9\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4.10\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-7.59\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
16.87 (24.45)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.15\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
6.05 (2.91)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-2.63\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
16.10\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
10.46\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
39.45 (28.99)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-0.67\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-0.62 (0.06)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-0.80\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
20\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
acetyl benzoyl\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
579-07-7\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.83\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-12.58\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
22.51 (35.09)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-1.83\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-1.24 (0.59)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-1.96\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
8.35\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-8.38\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
21.76 (30.14)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4.61\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
5.30 (0.69)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.72\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
21\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
glutaraldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
111-30-8\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
7.56\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-2.94\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
23.03 (25.97)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-5.28\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-5.16 (0.12)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-6.50\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1,3-butanedione, 1-phenyl-\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
93-91-4\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
9.30\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-3.04\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
23.87 (26.91)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
5.35\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
11.70 (6.35)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-0.33\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
21.30\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
9.88\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
28.62 (18.74)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.35\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.51 (0.16)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.61\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

* no barrier to formation of INT1 from REACT, ** no barrier to formation
of PROD from INT2

\par\null

\subsection*{3.1 General Reaction Scheme}

{\label{general-reaction-scheme}}

The reaction simulated is described in Scheme 1 where methylamine is
used to simulate a generic amine nucleophile. The reaction involves an
acid catalyzed process through the inclusion of a methylammonium cation
and two water molecules. The first step sees the SN2 based substitution
of the carbonyl of the substrate by the methylamine, the breaking of the
carbonyl double bond with concomitant proton transfer from the
methylammonium cation to give the corresponding carbinolamine. As can be
seen from Figure 1, the transition state (TS1) associated with the
nucleophilic attack at position-a of compound 22 has a short C-N
nucleophilic distance of 2.0 \selectlanguage{ngerman}Å. However, it does not involve noticeable
proton transfer to the oxyanion being formed, this occurring after the
barrier has been traversed. Furthermore, it is found that nucleophilic
attack of the carbonyl directly connected to the phenyl ring
(position-b) results in a dramatically higher barriers to reaction (9.3
vs 21.3 kcal/mol) as a result of the loss of resonance effects with the
carbonyl bond not observed at the other position. This also helps to
explain why the corresponding intermediate at position-a is considerably
lower in energy (-3 vs 9.9 kcal/mol).

Despite position-a having the lowest barrier to substitution, it is
found that position-b has the lowest barrier associated with the
elimination of water and the formation of the imine. This can be
explained by the resonance stabilization afforded by the phenyl ring
attached to position-b. The reaction proceeds with shuttling of a proton
from the amine of the carbinolamine intermediate to its hydroxy
group\emph{via} a water molecule. The proton transfer step is
essentially complete at the transition state with the C-O carbinolamine
bond being 1.5 Å. The barrier to reaction for position-a is found to be
26.9 kcal/mol compared to 18.7 kcal/mol for position-b. The final step
in the reaction requires the abstraction of the remaining proton on the
imine nitrogen to generate the neutral product. This step is found to be
a low energy process (\textasciitilde{}0.1-10 kcal/mol) and sees the
regeneration of the methylammonium catalyst.

All compounds simulated follow the same general trends as compound 22 .
Two exceptions are compounds 10 and 16 which do not display a barrier to
substitution (TS1) for positions containing strongly electron
withdrawing groups. Furthermore, 16 forms product directly from INT2
without the formation of INT3. More detailed analysis of the complete
reaction profiles of all molecules in Table 1 showed clearly that the
barrier to water elimination (TS2) was observed to be the rate
determining step for the conversion of the substrates to the
corresponding SB. The TS2 barrier heights for the main chemical classes
present ranged from \textasciitilde{} 18-25 kcal/mol for 1,3 diones (6),
\textasciitilde{}21-34 kcal/mol for 1,2 diones (5),
\textasciitilde{}25-32 kcal/mol for aliphatic aldehydes (7),
\textasciitilde{}29-30 kcal/mol for aromatic aldehydes and ketones (4).

\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image25/Screen-Shot-2019-11-22-at-12.00.16-PM}

\end{center}
\end{figure}

\textbf{Figure 1:} Optimized 3D structures for 22 (position a only, top)
and the corresponding energetic profile.

\par\null

A subset of molecules contain additional SNAr functionality (2 , 4 \& 18
){[}54{]} and Michael acceptor groups (7 \& 13 ).{[}55{]} We also
predicted the SNAr reactivity of compounds 2 , 4 and 18 using our
previously reported QM-QSAR method (Figure 4).{[}54{]} All 3 compounds
were re-simulated using the methodology previously described and it was
observed that only compound 18 was predicted to have a barrier to
reactivity likely to result in a significant LLNA response. Compound 18
, which contains bromide leaving group was predicted to have a barrier
of 10.5 kcal/mol while compounds 2 and 4 , the chloride leaving groups,
have predicted barriers of \textgreater{}16 kcal/mol. Compounds 7 and 13
were not simulated as they consist of Michael acceptors connected to
aliphatic carbons and couples with their small solvent accessible
surfaces are not predicted to be sensitizers.

\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image27/Screen-Shot-2019-11-22-at-12.01.20-PM}

\end{center}
\end{figure}

\textbf{Figure 2.} Plot of the SNAr reaction profiles for compounds 2 ,
4 and 18 .

\par\null

It should be acknowledged that such analyzes are further complication by
the fact that the LLNA response is not always a result of direct
sensitization the molecule itself, rather an effect of reactive
metabolites. This issue further complicates the construction and
validation of computational methodologies such as these reported
here.{[}21, 64{]} In particular, it is known that 1,2 diones such as
compound 16 , glyoxal are not commonly encountered because it can form a
hydrate, which can then undergo oligomerization.

\subsection*{3.2 Reaction Barriers vs LLNA
pEC3}

{\label{reaction-barriers-vs-llna-pec3}}

The goal of the present work is to determine whether it is possible to
attribute the skin sensitization to the predicted chemical reactivity of
the functional groups present the molecules\emph{\textbf{1}-\textbf{22}}
. We first assessed whether a relationship existed between the predicted
barriers to reaction and the skin sensitivity. The expectation was that
TS2 should show the most significant correlation with the LLNA pEC3
given that this was almost exclusively the rate determining barrier for
the molecules studied here. Indeed we did see the strongest correlation
between the TS2 (lowest value of the reported positions if more than
one) and the pEC3. However, when all 22 compounds were included, the
observed correlation coefficient squared (r2) was just 0.16. This
prompted us to re-evaluate the data by excluding compound 18 , which is
a predicted to be a strong sensitizer \emph{via} the SNAr domain, and
the 1,2 dione compound (\emph{\textbf{5}, \textbf{9}, \textbf{16},
\textbf{17}, \textbf{20}} ), which potentially exist in their hydrated
form. This is similar to the approach of Roberts \emph{et al.} who
focused on compounds with a single reactive group consisting primarily
of aldehydes and ketones and may point to a need for a more restricted
domain of applicability.{[}32{]}

Re-analysis of the correlation between the 16 remaining compounds and
the pEC3 reveals an improved, albeit weak correlation, with an r2 of
0.36. It is found as the predicted barrier to reaction decreases, the
experimental sensitization is found to increase in line with expectation
(Figure 2). It can also be seen from Figure 3 there is a lipophilicity
effect operating within the dataset. Compounds, which have been colored
by logP, show a noticeable trend in that, those with a higher logP
generally have lower pEC3 for a given barrier. For example, the 1,3
dione 8 has a predicted barrier of approximately 22 kcal/mol compared to
19 which has a barrier of \textasciitilde{}25 kcal/mol (19 a). This
would suggest that 8 should be a stronger sensitizer than 19 , whereas
in fact the opposite is observed (pEC3 of 0.84 vs 1.97, respectively).
The predicted logP of 8 is 3.93 while that of 19 is 1.28 suggesting that
a lower barrier combined with a low logP leads to increased
sensitization for this set of diverse compounds.

This observation apparently contradicts the findings of the earlier QSAR
study of Roberts \emph{et al.} on Schiff bases.{[}32{]} However, since
this publication, the authors have reported an extensive analysis of 525
substances and note that logP is not simply a surrogate for permeability
and that higher logP values do not result in higher sensitization on a
diverse set of compounds.{[}65{]} The result is also consistent with
observations that the Schiff base, formaldehyde (logP=-0.51), which is
known to be highly sensitizing in sensitization based-assays. {[}66{]}
It should be noted that we are using a somewhat larger (22 vs 16
compounds), and more diverse set of chemicals (70\% were aldehydes in
the latter study). Indeed evidence for similar series specific-logP
behavior can be seen from the non-linear relationship between logP and
pEC3 for azlactones of the acyl domain.{[}5{]}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image28/image28}

\end{center}
\end{figure}

\textbf{Figure 3:} Plot of pEC3 versus the predicted rate determining
barrier for aldehydes (triangle), ketones and 1,3 diones (circles). Data
is colored by logP (red=high, green=low). R2=0.36, n=16.

\par\null

\subsection*{3.3 Quantitative molecular
model}

{\label{quantitative-molecular-model}}

Other factors such as clogP have been included in a number of QSAR
models related to LLNA. Given that the parameter also appeared possible
in further differentiating between active and inactive compounds as
shown in Figure 3, an additional 2-parameter linear regression model was
constructed on the data. The goal here is to produce a conservative
model using small numbers of descriptors that have known relevance to
skin sensitization. This is in part due to the REACH requirements for
simple, robust and interpretable QSAR models for use within a regulatory
framework, but also due to the small numbers of datapoints available for
such modelling exercises.

Starting with all 22 compounds, a multiple linear regression model was
constructed with the two variables resulting in equation 1. The model
results in an explained variance of 66\% with a p value of 0.008,
considerably better than that observed with the energy barrier
associated with TS2 alone. The model predicts that as the barrier to
reaction decreases, pEC3 will increase. In addition, as the logP
decreases, the barrier to reaction will concomitantly decrease.

pEC3=-0.377(\selectlanguage{ngerman}±0.138)*clogP -- 0.127(±0.0436)*ETS2 + 5.69 (±1.30)
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~\textbf{\emph{Equation 1}}

n=22, r2=0.66, r2adj=0.38,. p=0.008)

Subsequently, the known SNAr compound 18 , was excluded from the
analysis and the logP of 20 was corrected due to large difference
between the clogP value used here (1.82) and two other commonly used
methods (0.58 for clogP{[}67{]} and 0.82 for ACD{[}68{]}). The latter
value, intermediate between the two other value was used. SNAr compounds
2 and 4 were not excluded as they are not predicted to function
\emph{via} an SNAr mechanism according to the predicted QSAR methodology
of Promkatkaew\emph{et al.} {[}54{]} The updated multiple regression
model was developed for the 21 compounds as shown in equation 2. The
model has slightly improved prediction statistics with an r2=0.71 and a
p-value of 0.002. Again, it is found that both increasing logP and
barrier height lead to decreased sensitization.

\par\null

pEC3=-0.425(±0.124)*clogP -- 0.152(±0.0412)*ETS2 + 6.17 (±1.22)
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ \textbf{\emph{Equation 2}}

n=21, r2=0.71, r2adj =0.46, p=0.002

~

As a final exercise, the dataset of 22 compounds was partitioned into a
training (N=14) and test set (N=8). As with the work of Roberts \emph{et
al.} , we generated the QSAR model on a set consisting primarily of
nonfunctional aldehydes and ketones to avoid confounding effects. A
small number of additional exemplars that help cover the full range in
pEC3 were also included (Table 2). All compounds were predicted using
equation 3. Compounds \textbf{2} , \textbf{4} and 18 were also predicted
using our previously reported model for SNAr domain.{[}54{]} Again, a
two-parameter model was fitted using the training data resulting in
equation 3. The training set explained variance is somewhat lower than
observed with the larger combined set (r2=0.40), however the descriptor
coefficients are qualitatively similar. Prediction on the test set of
compounds show the compounds are quite well ranked (r2=0.49). A
noticeable outlier in figure 3 is compound 17 which on further analysis
of the structure can also potentially function \emph{via} the acyl
reaction domain.{[}5{]} This could account for its low predicted
activity from this Schiff-base derived model. When compounds 20 (SNAr
domain) and 17 (Acyl domain) are excluded from the test set, r2 of 0.62
is observed.

pEC3 = -0.388(±0.150)*clogP -- 0.172(±0.061)*ETS2 + 6.671 (±1.841)~
~~~~~~ \textbf{\emph{Equation 3}}

Training set (n=14, r2=0.49, r2adj=0.40, p=0.02),

Test set (n=8, r2=0.49), Test set (n=6 (ex \textbf{\emph{17}} \&
\textbf{\emph{20}}), r2=0.62)

\par\null\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image29/image29}

\end{center}
\end{figure}

\textbf{Figure 4:} Plot of the observed vs predicted pEC3 using equation
3 for the training set (white circles) and test set (red circles). Value
for test set compound 20 using previously reported SNAr model.{[}54{]}

\par\null

\textbf{Table 2:} Descriptors, observed and predicted pEC3 values from
equation 3.\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{ID}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{CAS No.}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Chemical Class}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{pEC3}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{RDS} \textbf{Barrier}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{clogP}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Predicted pEC3}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Set}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
01\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
929253-05-4\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Aliphatic aldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.00\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
28.14\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.62\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.81\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
02\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4903-09-7\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Aromatic aldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.00\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
29.63\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.13\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.74 (0.00)a\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Test\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
03\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
100-52-7\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Aromatic aldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.00\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
30.06\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.69\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.84\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
04\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
34841-35-5\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Aromatic Ketone\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.00\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
29.55\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.84\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.48 (0.00)a\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
05\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
13706-86-0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1,2 dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.69\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
29.92\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.83\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.81\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
06\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
6668-24-2\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1,3 dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.78\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
25.07\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.30\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.46\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
07\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2277-19-2\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Aliphatic aldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.80\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
26.47\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.62\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.09\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
08\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1118-71-4\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1,3 dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.84\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
21.66\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.93\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.42\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Test\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
09\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
431-03-8\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1,2 dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.89\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
34.06\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.40\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.65\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
10\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
326-06-7\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1,3 dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.03\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
22.68\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.89\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.64\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Test\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
11\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
110-41-8\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Aliphatic aldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.27\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
27.19\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4.42\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.27\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
93-53-8\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Aliphatic aldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.33\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
29.13\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.00\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.88\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
13\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
112-45-8\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Aliphatic aldehyde/MA\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.39\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
26.79\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.57\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.67\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
14\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
167998-73-4\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1,3 dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.42\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
20.67\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.81\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.63\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
122-78-1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Aliphatic aldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.60\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
27.91\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.45\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.30\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
16\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
107-22-2\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1,2 dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.62\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
31.54\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.00\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.24\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Test\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
600-22-6\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1,2 dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.63\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
21.49\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.45\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.80\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Test\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
18\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2973-80-0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Aldehyde / SNAr\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.89\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
30.85\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.15\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.60a (0.52)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Test\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
19\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
5437-98-9\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1,3 dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.97\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
24.45\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.28\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.96\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
20\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
579-07-7\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1,2 dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.06\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
30.14\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.82 (0.82)b\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.10b (0.77)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Test\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
21\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
111-30-8\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Aliphatic aldehyde\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.00\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
25.97\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-0.27\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.30\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Train\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
93-91-4\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1,3 dione\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.61\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
18.74\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.75\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.76\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Test\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

(a) pEC3 predicted based on its SNAr potential (pEC3 = -0.31*SNAr
barrier + 4.90){[}54{]} b pEC3 predicted using ACD logP

As highlighted by other researchers the prediction of skin sensitization
is a highly challenging process and that the concordance between
different \emph{in vivo} , \emph{in vitro} and \emph{in chemico} based
methods is often no more than 60-80\% in agreement with gold-standard
methods such as the LLNA assay.{[}8, 15, 16{]} This is in part due to
the fact that the LLNA response is not always a result of direct
sensitization the molecule itself, potentially arising as a function of
reactive metabolites.{[}21, 64{]} In this case we report a purely
theoretical approach to predict a diverse set of Schiff base chemicals
-- using just two relatively simple and interpretable descriptors. The
observation that the model can explain \textasciitilde{}50-60\% of the
variance in the dataset is therefore not surprising.

\section*{4.0 Conclusions}

{\label{conclusions}}

In this paper we have reported the use of a quantum chemical-based
approach to assess the skin sensitization potential of chemicals from
the Schiff base domain. We have evaluated the mechanistic profile
associated with 22 SB substrates using a model consisting of two
methylamine and two water molecules. We find that calculating the full
reaction profile for the chemicals is important as the substrates can
often react in more than one position, while also allowing for
mechanistic exceptions to be uncovered. We find that the use of a single
computed descriptor, namely the rate determining barrier to formation of
the SB product can help us to separate sensitizer and non-sensitizer. A
RDS barrier of \textasciitilde{}28 kcal/mol indicate that a molecule is
unlikely to act as a sensitizer. We also observed that compounds with
low barriers, but higher logP values show reduced sensitization
prompting us to generate a 2 parameter QMM.

A QMM equation established suggests that SB of lower logP have a greater
propensity to react resulting in r2 of 0.50-0.60. The predicted RDS and
logP establish SAR guidelines to rationalize the skin sensitization
potential. The RDS barriers for aldehydes, ketone, 1,2 and 1,3 diones
broadly decrease in that order, in line with their increasing
experimental sensitivity. These findings agree with experimental based
observations in the literature and point to the value computational
methods can play in skin sensitization predictions. We find that the
rate determining barrier and the computed lipophilicity can be used to
estimate the skin-sensitization of unknown compounds. This orthogonal
source of information could prove useful in consensus based predictions
of likely sensitization potential.{[}21, 26{]}

The results presented here show that 3D quantum chemical simulation of
SB chemicals, while useful, will lead to the mischaracterization of some
compounds. This is not so different to the variation observed between
the different types of \emph{in vivo} , \emph{in vitro} and \emph{in
silico} methods reported to date which show predictions accuracies of no
more than 70-80\%. This is simply a reflection of the complex event
being simulated, a multitude of potential protein targets, and the fact
that the molecules may function in the form of a metabolite rather than
the dosed substrate. The utility of such simulations is that physical
insight and understanding can be garnered which could prove useful,
especially when combined in the so--called weight of evidence approach
with other methods.

\section*{Funding Information}

{\label{funding-information}}

D. Gleeson would like to acknowledge funding from the King Mongkut's
Institute of Technology Ladkrabang. (grant number KREF046104)

\section*{References}

{\label{references}}

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