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Machine learning approaches to understand and

predict rate constants for organic processes in
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Cite this: Phys. Chem. Chem. Phys.,

2021, 23, 2742 mixtures containing ionic liquids†
Tamar L. Greaves, *a Karin S. Schaffarczyk McHale,b Raphael F. Burkart-Radke,b
Jason B. Harper *b and Tu C. Le*a

Received 10th August 2020,
Accepted 14th January 2021
DOI: 10.1039/d0cp04227g
rsc.li/pccp
The ability to tailor the constituent ions in ionic liquids (ILs) is highly advantageous as it provides access
to solvents with a range of physicochemical properties. However, this benefit also leads to large
compositional spaces that need to be explored to optimise systems, often involving time consuming
experimental work. The use of machine learning methods is an effective way to gain insight based on
existing data, to develop structure–property relationships and to allow the prediction of ionic liquid
properties. Here we have applied machine learning models to experimentally determined rate constants
of a representative organic process (the reaction of pyridine with benzyl bromide) in IL–acetonitrile
mixtures. Multiple linear regression (MLREM) and artificial neural networks (BRANNLP) were both able to
model the data well. The MLREM model was able to identify the structural features on the cations and
anions that had the greatest effect on the rate constant. Secondly, predictive MLREM and BRANNLP
models were developed from the full initial set of rate constant data. From these models, a large number
of predictions (49000) of rate constant were made for mixtures of different ionic liquids, at different
proportions of ionic liquid and molecular solvent, at different temperatures. A selection of these predic-
tions were tested experimentally, including through the preparation of novel ionic liquids, with overall
good agreement between the predicted and experimental data. This study highlights the benefits of
using machine learning methods on kinetic data in ionic liquid mixtures to enable the development
of rigorous structure–property relationships across multiple variables simultaneously, and to predict
properties of new ILs and experimental conditions.

Introduction consuming and often difficult to prepare, characterise and trial

Ionic liquids (ILs) are salts that are liquid below B100 1C.1–4
Simple ILs consist of one type of cation and one type of anion
and, even with these simple systems there are a vast number
of possible combinations.2,3,5,6 The benefit of these many
combinations is that the properties of ILs can be modified
through changing their chemical structure.7 However, it is time
a
College of Science Engineering and Health, RMIT University, Melbourne, VIC
3001, Australia. E-mail: tamar.greaves@rmit.edu.au, tu.le@rmit.edu.au
b
School of Chemistry, University of New South Wales, Sydney, NSW 2052,
Australia. E-mail: j.harper@unsw.edu.au
† Electronic supplementary information (ESI) available: Summary of the ionic
liquids used in the training models; quantitative values of each descriptor used
for the ionic liquid constituents; comparison of the predicted versus experimental
values for k2 and log(k2) for other models considered; analysis of MLREM model
using 18 descriptors; general experimental methods; complete synthetic details
for the ionic liquids 1–17, composition of stock solutions and measured rate
constant data for mixtures containing ionic liquids 1–17; comparison of predicted
and experimental data for ionic liquids 1–17. See DOI: 10.1039/d0cp04227g
meaningfully large sets of ILs. This compositional space rapidly
increases for ILs in most applications, where they are typically
mixed with a molecular solvent (where the nature of that
solvent and the proportion of each solvent in the reaction
mixture are important), have solutes present (once again, the
nature and concentration are important), and the process can
be carried out under different conditions (such as tempera-
ture). There are a few approaches that have been used in the
IL field to address this issue, including the use of high
throughput techniques to experimentally screen libraries of
ILs and IL containing systems,8–17 and computational methods
to predict physicochemical properties.18–21 With the expansion
of data available on various IL physicochemical properties,
machine learning methods have been used to build predictive
models for such properties; these properties include
density,22–28 viscosity,25,26,29–31 surface tension of neat ILs,32,33
surface tension of binary26,30,34–36 or tertiary IL mixtures,26,37–40
toxicity,41,42 and gas solubilities in neat ILs or IL containing
solvents.43–51

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The key benefits of using machine learning methods are the
ability to extract complex trends for multivariate systems, to
develop robust predictions, and to gain insight into the sys-
tems, allowing the design of new ones to achieve a desired
outcome. There are many different machine learning methods
such as support vector machine,52 relevance vector machine,53
and random forest,54 but none of these methods has been found
to always outperform others.55–59 The most effective method has
been found to be dependent on the dataset. We have previously
reported that the surface tension and liquid nanostructure of
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ternary mixtures of non-stoichiometric protic ionic liquids with
water can be modelled well by multiple linear regression (MLR)
and artificial neural networks (ANN).60 The MLR models have the
benefit of providing quantitative structure–property relationships
that can be used for designing new systems. In contrast, the ANN
provided better agreement with both the test and training set data
but could not allow the quantitative comparison of different
factors on the property being modelled.
In this paper we have employed machine learning methods
on the use of ILs as co-solvents in a substitution reaction.
Specifically, we have used second order rate constant (k2) data
for the substitution reaction between pyridine and benzyl
bromide (Scheme 1) that has been systematically collected by
Harper et al.61–69 In this series of papers, they have quantified
the effect on k2 of IL–acetonitrile mixtures, exploring how
varying the cation structure, the anion structure, the proportion
of IL, and the temperature affects the reaction outcome. Most
of the ILs trialled led to an increase in the rate constant, which
was identified as being due to an entropic gain from loss of IL
structure around the precursors on moving to the transition
state; this benefit offset a smaller enthalpic cost. Variation of
the nature of the cation showed that accessibility to the charged
centre was important and resulted in rate constant increases
relative to acetonitrile, whereas the reaction had a lower k2 than
in neat acetonitrile if the added IL had a sterically hindered
charge centre.61,64,66 The importance of the charged centre was
further demonstrated by increased rate constants in cases with
electron withdrawing group on the cation.66,68 Consequently,
there is significant quantitative data available for this reaction
in mixtures of ionic liquids and acetonitrile that are suitable for
analysis using machine learning methods. Herein, we investigated
whether further trends in the rate constant data can be identified,
and if robust models can be developed that can be used to predict
rate constants for this reaction in other ionic liquid mixtures.
While we are not aware of any previous research into using
machine learning methods to analyse the outcomes of organic
reactions in ILs, the suitability of such methods has clearly been
shown for analysing data on organic reactions in molecular
Scheme 1 The bimolecular nucleophilic substitution reaction between
pyridine and benzyl bromide, which has been examined extensively in
mixtures containing an ionic liquid.61–69
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solvents, where much literature is available, with the focus on
predicting reaction products.70–74 Similarly, machine learning has
been used to optimise specific reactions, where the reaction
conditions (including the catalyst, solvent, reagent and tempera-
ture) were included as inputs. As an extension, some groups have
developed integrated high throughput synthesis robots that can
interact directly with the machine learning models, feeding in
new information, and learning from the previous data.74,75 How-
ever, it has been noted that, while these models and high
throughput approaches are very beneficial, there are still limita-
tions. These limitations included the need for some human
supervision,74 and the importance of nuanced descriptors that
can represent more complex reaction features, such as the three
dimensional conformations of the molecules.76 In work closely
related to this study, the reaction rate of a similar substitution
process was explored through integrating quantum mechanical
(QM) calculations with computer-aided molecular design (CAMD)
to identify solvents that might lead to faster reaction rates.77 Their
algorithm was able to successfully identify nitromethane as a
solvent that would result in a 40% rate constant increase com-
pared to acetonitrile, which was the solvent that gave the greatest
rate constant initially.78,79
However, while successful, these methods require high quality
computational input. While these integrated QM approaches have
the advantage of requiring less experimental data, they do need to
be able to model effectively the solvent mixture (and hence the
resultant solvent effects). The use of IL–molecular solvents signifi-
cantly increases the complexity of the system and appropriate
models are still in development.80,81 As such, solvent effects are
explored in this paper using available experimental data, and ML
methods on such experimental data has the potential to provide
greater understanding of the microscopic origin of the rate
constant change, to predict reaction outcomes, and perhaps even
to lead to IL solvent design.
In this paper we have used 160 pieces of rate constant data
for the reaction outlined in Scheme 1, in different ionic liquid–
acetonitrile mixtures to develop MLR and ANN models‡. The
MLR model was used to enable complex structure–property
relationships to be developed. The ANN model was used for
prediction of rate constants for the reaction in ionic liquid–
acetonitrile mixtures where the ionic liquids were based on
each possible combination of cations and anions used in this
study, along with other variables including temperature and
proportion of ionic liquid in the reaction mixture. From this
extensive list, a representative set of 17 reactions (with condi-
tions that spanned the range used in initial evaluations) were
then used to validate the model.
Experimental
Rate constant data on the reaction in Scheme 1 has been
reported by Harper et al.61–69 A total of 160 data points
‡ The effect of variations in the electrophile and nucleophile have also been
considered,61,66,67,95,96 but these data have not been included in this study as
there are limited data on the addition of a number of other variables.
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Table 1 Descriptors used in these models, their description and what is described by that descriptor. Cation descriptors are from Dragon82

Descriptor Description Portion described Initiala MLREMb BRANNLPc

Intercept n/a | | ‘
ILmolefraction Mole fraction of ionic liquid in the reaction mixture n/a | | |
InverseT Inverse temperature n/a | | |
AnionTotalNsingle Number of sp3 hybridised nitrogen Anion | ‘ ‘
AnionTotalC Number of carbon atoms Anion | ‘ |
AnionTotalS Number of sulphur atoms Anion | ‘ ‘
AnionTotalO Number of oxygen atoms Anion | ‘ ‘
AnionTotalF Number of fluorine atoms Anion ‘ ‘ |
AnionTotalB Number of boron atoms Anion ‘ | |
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AnionTotalNTriple Number of sp hybridised nitrogen atoms Anion ‘ | |

AnionTotalP Number of phosphorus atoms Anion ‘ ‘ |
nDB Number of double bonds Cation ‘ ‘ |
nAB Number of aromatic systems (ring size) Cation | ‘ |
RBN Number of rotatable bonds Cation | | |
RBF Rotatable bond fraction Cation | ‘ |
ARR Aromatic ratio in the cation Cation | ‘ |
nCIC Number of rings (cyclomatic number) Cation | | |
nCIR Number of circuits Cation | | ‘
nCp Number of primary sp3 hybridised carbon atoms Cation | | |
nCs Number of secondary sp3 hybridised carbon atoms Cation | | ‘
nCrs Number of secondary sp3 hybridised carbon atoms Cation | | |
in ring structures
nCar Number of sp2 hybridised carbon atoms in Cation | ‘ |
aromaticsystems
nO Number of oxygen atoms Cation | | |
nCL Number of chlorine atoms Cation | ‘ ‘
N-073 Number of sp3 hybridised nitrogen atoms attached to Cation | | |
anaromatic ring
N-075 Number of sp2 hybridised nitrogen atoms Cation | | |
N-079 Number of nitrogen centres with a positive charge Cation | | ‘
nHAcc Number of acceptor atoms for hydrogen bonds (N, O, F) Cation | | |
Hy Hydrophilic factor Cation | | |
Ui Unsaturation index Cation | ‘ |
AMR Ghose–Crippen molar refractivity Cation | | ‘
MLOGP Moriguchi octanol–water partition coefficient (log P) Cation | | |
TPSA Total polar surface area Cation | ‘ ‘
a
Removed descriptors were underrepresented in the data sets. b Removed descriptors had no effect on the standard error of prediction in the
model using MLREM. c Removed descriptors had zero weighting in the prediction model using BRANNLP.

(covering 36 different ILs, a range of proportions of ionic liquid
in the IL–acetonitrile mixtures and a range of temperatures; for
a summary and link to the Figshare repository see ESI†). The
data were randomly partitioned three independent times – 80%
for training (128 points in the set) and 20% for testing (32
points in the set). For each partitioning, modelling and statis-
tical analysis were done independently.
The ILs and reaction conditions were represented by 33
descriptors, which are summarised and described in Table 1.
Most descriptors are only for either the cation or the anion, and
this is specified in the ‘portion described’ column. An addi-
tional intercept term for fitting was included for the Multiple
Linear Regression with Expectation Maximization (MLREM)
models. The ILmolefraction and InverseT described the mole
fraction of the IL in the ionic liquid reaction mixture and the
inverse of the temperature, respectively. The inverse of the
temperature was used since there is a linear relationship with
ln(k).83 The ILs were described by the remaining 30 descriptors,
which were taken from the Dragon descriptor data base,82,84
with eight descriptors for the anions, and 22 for the cations.
These Dragon descriptors include constitutional indices, func-
tional group counts, atom-centered fragments and molecular
properties such as log P, unsaturation index, hydrophilic factor,
molar refractivity and polar surface area. Descriptors that had
the same values for different ILs were excluded. The quantita-
tive value of each descriptor is provided in Tables S2 and S3 of
the ESI† for the cations and anions, respectively. Descriptors
that were highly correlated, with a correlation coefficient of
greater than 0.98, or did not have much variation across the
data set (only changed for one or two samples) were removed by
the BioModeller package85–87 that was used for constructing the
machine learning models; descriptors with correlation between
0.9 and 0.98 are not automatically removed, but subject to
human screening to avoid the exclusion of unrelated descrip-
tors. The correlation coefficient between the secondary sp3
hybridised carbon atoms (nCs) and the number of rotatable
bonds (RBN) had a correlation coefficient of 0.96, however
these were both retained due to the chemically different
features they represent. The correlation matrix of the initial
pool of descriptors is provided in Table S4 of the ESI.†
Sparse feature selection algorithms including Multiple
Linear Regression with Expectation Maximization (MLREM)88
and Bayesian Regularized Artificial Neural Networks with
Laplacian prior (BRANNLP)89 were employed to further prune

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out irrelevant descriptors. Unlike the basic multiple linear
regression (MLR) and Bayesian Regularized Artificial Neural
Networks with Gaussian Prior (BRANNGP), which make use of a
Gaussian prior and minimize the sum of the squares of errors
between the measured and predicted values, MLREM and
BRANNLP use Laplacian prior to automatically set the weights
of irrelevant descriptors to zero and minimize the modulus
between the measured and predicted values. A detailed expla-
nation of these algorithms can be found elsewhere.85–90 These
BRANN based methods are difficult to overtrain since they have
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an objective Bayesian criterion for stopping training, and are
unlikely to overfit since they train on a number of effective
network weights and remove those that are not relevant. The
neural networks had three layers, input, hidden and output.
The number of nodes in the input layer was equal to the
number of descriptors, while the hidden layer had 3 nodes
and the output layer had one single node corresponding to the
rate constant of the organic reactions. The rate constant, k2,
was initially used as the output in the models, however it was
quickly identified that log(k2) was more appropriate for the
MLREM models, which is consistent with ln(k) being propor-
tional to the activation energy.83 Consequently, log(k2) was used
as the output for the MLREM models, while k2 and log(k2) were
used for the neural network models. We randomly partitioned
the data set into a training and a test set which consisted of
80% and 20% of the data, respectively. This process was done
three times to ensure generalized results. Note that no valida-
tion set was used because the Bayesian regularization provides
a criterion for stopping training and therefore eliminates the
need for a validation set.85,86 The quality of the models was
assessed using the square of the correlation coefficient between
the predicted and measured values (R2) as well as the standard
error of estimation (SEE) and prediction (SEP) for the training
set and test sets. Good models have R2 of close to 1.0 together
with low SEE and SEP.
Preparation of ionic liquids and determination of
rate constants
Pyridine and benzyl bromide were distilled91 and stored over
activated molecular sieves (3 Å) at 4 1C prior to use. Acetonitrile
was distilled91 and stored over activated molecular sieves (3 Å)
at room temperature under nitrogen. All other chemicals were
purified through literature methods91 and used immediately.
The ionic liquids used were generally prepared through the
N-alkylation of the appropriate precursor, followed by
anion metathesis (complete synthetic procedures are given in
the ESI†).
All kinetic measurements were obtained by monitoring
reaction progress using 1H NMR spectroscopy with either a
Bruker Avance III 400 (400 MHz, 1H), a Bruker Avance III 500
(500 MHz, 1H) or a Bruker Avance III 600 (600 MHz, 1H)
spectrometer equipped with either a BBO, BBFO or TBI probe.
The results were shown to be reproducible regardless of the
NMR spectrometer and probe used. The temperature of the
NMR spectrometer was calibrated using a thermocouple con-
taining ethanol.
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The reaction mixtures for the kinetic studies were prepared
under pseudo first order conditions such that they contained at
least a 10-fold excess of pyridine relative to benzyl bromide.
Reaction progress was monitored to 495% completion using
1
H NMR spectroscopy, noting depletion of the signal corres-
ponding to the benzylic protons of benzyl bromide at d ca.
4.0. The exceptions were the kinetic data determined in mix-
tures containing either (i) the ionic liquid [bmim][PF6] 2, where
the reaction was monitored as above but only to ca. 10%
completion and analysed using initial rates methodology; or
(ii) the ionic liquid [bmpi][PF6] 11, where reaction progress was
monitored (again to 495% completion) using 1H NMR spectro-
scopy following formation of the signal corresponding to
the benzylic protons of the product of the reaction shown in
Scheme 1 at d ca. 5.6.
Results and discussion
The modelling process was conducted on the rate constant data
for the reaction shown in Scheme 1 that included data for
36 different ILs (33 variants of the cation and four variants for
the anion of the ILs, see Fig. S1, ESI†). It is important to note
that not all ILs have the same number of data points (based on
available literature) and that the chemical space covered by the
ions considered is limited. The latter is a function of the
structural requirements for the components to ensure a liquid
phase, but also the practicalities of preparing the ionic liquids.
Whilst this feature should not preclude analysis, it should be
borne in mind in subsequent discussions.
The 160 data points were randomly partitioned into 80%
training and 20% test sets. This process was done three times
to remove bias and improve the generalisation of the model,
with all three sets giving comparable results. The MLREM,
BRANNGP and BRANNLP models were run independently on
each training set, and then tested on the corresponding test set.
The descriptors used for each model are provided in Table 1.
The BRANNGP had a similar performance to the BRANNLP
(see ESI†). In the algorithms, the MLREM model minimises the
sum of the squares of error, where the BRANNLP minimises the
magnitude of the absolute errors.
The comparison of the predicted versus experimental values
for k2 and log(k2) for MLREM are shown in Fig. S2 (ESI†) for one
of the three training/test sets. There is clearly a poor correlation
between predicted and experimental values when k2 is used as
the output (Fig. S2a, ESI†), which is vastly improved by using
log(k2) (Fig. S2b, ESI†). The squared correlation coefficients (R2)
for the use of k2 and log(k2) for MLREM were 0.77 and 0.96,
respectively. This large difference in the correlation quality is
consistent with log(k2) having a more linear relationship
with the descriptors than k2. Consequently, log(k2) has been
used as the output for all MLREM models. The predicted versus
experimental values for log(k2) are provided in Fig. 1a for the
MLREM models, and in Fig. 1b and c for log(k2) and k2 for the
BRANNLP models. The comparison plots for the BRANNGP
models are provided in Fig. S3 of the ESI.† The predicted versus
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Table 2 The bimolecular rate constants for the reaction shown in

Scheme 1 at 295 K in reaction statistical results for the MLREM, BRANNLP
and BRANNGP models, averaged over three training and testing sets

Training Test
Output Model Effective weights R2 SEE Q2 SEP
k2 MLREM 29.0 0.77 0.101 0.64 0.135
BRANNLP 19.7 0.90 0.055 0.88 0.067
BRANNGP 31.2 0.92 0.046 0.90 0.056

log(k2) MLREM 28.0 0.96 0.053 0.91 0.063

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BRANNLP 31.0 0.96 0.038 0.92 0.056

BRANNGP 32.0 0.97 0.035 0.94 0.086

experimental values are shown on the same training/test set for

Fig. 1 (a) Predicted log(k2) versus experimental log(k2) for the reaction
shown in Scheme 1 as analysed by MLREM, (b) predicted k2 versus
experimental k2 for the reaction shown in Scheme 1 as analysed by
BRANNLP, and (c) predicted log(k2) versus experimental log(k2) for the
reaction shown in Scheme 1 as analysed by BRANNLP. The training set is
shown by the circles and the test set by the triangles.
all three models for both k2 and log(k2).
The statistical results for the MLR, BRANNLP and BRANNGP
models are given in Table 2 for both k2 and log(k2) outputs.
These are the average of the statistics for the three training and
test sets. The effective weights give a measure of the complexity
of the model. The squared correlation coefficients (R2) and
descriptors removed were for the total number of fluorine,
boron or phosphorus atoms, and without these present, the
standard error of estimation (SEE) were obtained for the train-
ing set of data, and similarly the squared correlation (Q2) and
standard error of prediction (SEP) were obtained on the test set
of data. Consistent with Fig. S1a (ESI†), the MLREM model
using k2 as the output had poor performance, while the MLREM
with log(k2) had a high R2 and Q2, showing the model has good
predictive capability. The BRANNLP had good R2 and Q2 using
both k2 and log(k2) as the output, but noticeably better perfor-
mance using the latter for all measures. The BRANNGP had
comparable statistics to BRANNLP.
While the best model based on the statistics is the BRANNLP
model with log(k2) as the output, the MLREM model also has
excellent statistics, and an additional advantage in that it can
be used to identify structure–property relationships through
visualising the contribution from each descriptor. Of the origi-
nal set of 33 descriptors, there were 5 removed, as noted in
Table 1; one cation descriptor and four anion descriptors.
While these descriptors are relevant to represent the full set
of ILs, the random partitioning of the data into training and
test sets led to some of the training sets not having the range of
either cations or anions that required these descriptors, and
hence the algorithms removed them. This removal resulted in a
total of four descriptors for the anions and 21 for the cations. It
should be noted that the four anion tetrafluoroborate and
hexafluorophosphate anions were equivalent in the models.
The scaled weightings for each of the remaining 28 descrip-
tors for the MLREM model with log(k2) as the output are shown
in Fig. 2. The input descriptors with a positive contribution are
expected to lead to larger rate constants. It is evident that the
largest contribution is positive, and from the nCs (total number
of secondary sp3 hybridised carbon atoms in the cation). The
largest negative contributions were from the RBN (number of
rotatable bonds in the cation) and AMR (molar refractivity

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Fig. 2 MLREM coefficients for each of the 27 descriptors (intercept not
included) used to assess the reaction shown in Scheme 1, using log(k2) as
the output, averaged for the three training sets.
for the cation calculated based on group contributions).
The reaction conditions showed that the IL mole fraction had
a weak positive contribution, and the temperature a positive
contribution (since the inverse temperature had a negative
contribution).
It is worth briefly commenting on those prominent descrip-
tors. The reaction conditions are consistent with what would be
expected based on the understanding of temperature effects on
reaction, but also observed dependencies of the reaction out-
come for the process shown in Scheme 1 on the proportion of
the ionic liquid in the reaction mixture.68 Likewise readily
explained, the number of rotatable bonds in the carbon atom
might be considered to indicate conformational flexibility and
hence difficulty for the identified key interaction between the
cation and pyridine to occur (cf. charge accessibility64,68). Molar
refractivity is a measure of the polarizability of the molecule;
a negative correlation here is consistent with the need for
localised charge in order for the key interaction to occur.64,68
The origin of the positive parameter is less clear; why having
secondary sp3 hybridised carbon atoms would enhance reactiv-
ity is not immediately apparent.
The same set of 28 descriptors were used for the BRANNLP
and BRANNGP models, again with five removed as they were
not valid for the training sets. The ANN models do not enable
contributions to be extracted for each descriptor. However,
across the three, separate training/test sets it was noted that
some of the descriptors had a zero weight. This zero weight was
due to the limited data available for some cation and anion
features, and hence for some data partitioning certain descrip-
tors had minimal variation within the training set. Specifically,
for the BRANNLP model with the log(k2) output, there were zero
weights for Hy, nO, N-075, nAB, and AMR for the first indepen-
dent training set, AnionTotalC, Ui, nO, nHAcc and nAB for the
second set and Hy, N-075 and AMR for the third set. To some
extent, this indicates that these descriptors are more limited in
their variation across the ILs, and implies that the other
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descriptors are more robust for this set of ILs and reactions.
Interestingly, these descriptors do not simply correlate with
those with negligible coefficients for the MLREM model (Fig. 2),
and hence while they may not have variation within each
training set, some do appear to have a significant contribution.
Prediction of rate constants
Additional MLREM, BRANNLP and BRANNGP models were
generated, and used to predict the rate constants of the
Menschutkin reaction (Scheme 1) in IL–acetonitrile solvents.
The data was not partitioned as training and test data to
maximise the data used as inputs for the models, and the 33
input descriptors (shown in Table 1) were used as inputs. This
methodology enabled the tetrafluoroborate and hexafluoropho-
sphate anion to be treated as distinct species, though there was
still minimal data present for them. The output log(k2) was
used since it had led to the best models in the previous section.
For the MLREM model the best results based on the standard
error of estimation were obtained when the model had 19
descriptors (including the intercept). The resulting coefficients
are shown in Fig. S4 (ESI†), and it is evident that while there are
differences compared to those generated using the data parti-
tioned into training sets, overall, they are similar. The descrip-
tors that were removed by the algorithm are identified in
Table 1. Unfortunately, the inclusion of only two anion descrip-
tors resulted in the model treating hexafluorophosphate
and bis(trifluoromethanesulfonyl)imide anions as identical.
The cations were uniquely identified by the 14 cation descrip-
tors with non-zero coefficients. For the BRANNLP model, the
coefficients for some descriptors were zero, and hence not
used in the model, and these are again identified in Table 1.
In contrast to the MLREM model there were five descriptors
retained for the anions with non-zero coefficients, which
enabled the four anions to be uniquely described. Similarly,
the cations were uniquely identified by the 16 cation descrip-
tors with non-zero coefficients. Consequently, it was expected
that the BRANNLP would be more reliable in predicting rate
constant data.
A total of 9504 predictions of log(k2) were made for the
reaction shown in Scheme 1 in mixtures containing ionic
liquids made up of all the possible binary combinations of
the 33 cations and four anions used in the training set, at mole
fractions of ionic liquid in acetonitrile in the range 0.1–0.9 and
at a temperature in the range 260–330 K. This data set included
predictions for 132 ILs, which included 36 ILs from the original
set and 96 new ILs based on the other possible cation–anion
combinations. The predicted log(k2) values were then converted
to k2. Both models resulted in predicted rate constant data in
the range ca. 10 5–10 1 mol L 1 s 1; that is, over four orders of
magnitude.
Validation of the model
The predicted rate constant data for the reaction shown in
Scheme 1 included the original 36 ILs used, along with predic-
tions for 96 new ILs made up of the constituent anions from the
original set of ILs. A series of 17 ILs (Fig. 3) was chosen,
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Fig. 3 The ionic liquids 1–17 prepared to evaluate the models developed. For details of nomenclature, see ESI.†
including 11 from these 96 new ILs;§ this set was carefully
selected to cover the range of ions used in the training set. The
rate constant for the reaction shown in Scheme 1 was deter-
mined in mixtures of one of these ionic liquids and acetonitrile,
with a range of IL mole fractions and temperatures used to test
the predictability of the model. Note that the set includes two
repeats for ionic liquids 9 and 16. The former salt was used to
see the effect for a case over two different proportions of ionic
liquid in the reaction mixture, while the latter was used to
check whether changing the temperature had a significant
effect on a poor predictability. The proportions of ionic liquid
in the reaction mixtures and temperatures used were all close
to those included in the models, with the exact IL mole fraction,
temperature and rate constants provided in the ESI.† There are
§ Where considered here, those ionic liquids that made up the initial training set
were considered under different conditions (particularly at different composi-
tions in the reaction mixture and different temperatures) to provide data not
available in the training set.
2748 | Phys. Chem. Chem. Phys., 2021, 23, 2742--2752
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some small differences between the experimental conditions
and the outputs of the models, but these are expected to have
little effect on the comparisons made.
The agreement between the predicted and experimental
values for this new data set was highly dependent on which
ions were present in the ionic liquid and varied between
extremely good and quite poor. A summary is provided in Table
S7 (ESI†), including the newly determined k2 values, the pre-
dicted k2 values from MLREM and BRANNLP methods, and
the percentage difference. A representation of the efficacy of
the models is provided in Fig. 4. It is evident from Table S7
(ESI†) and Fig. 4 that generally the predictions were close to the
experimental data, and that both models performed well.
It should be noted that the training set there were only three
ionic liquids that did not contain the bis(trifluoromethanesulfonyl)
imide anion, and these three consisted of the 1-butyl-3-
methylimidazolium cation paired with either dicyanimide,
hexafluorophosphate or tetrafluoroborate. Consequently, the
influence on the training of these three anions was limited. The
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Fig. 4 Comparison of the log(k2) values determined experimentally com-
pared to those predicted using the (a) MLREM and (b) BRANNLP models.
Numbering corresponds to the ionic liquids. The line shown is y = x.
validation set of ILs was deliberately selected to consist of a
broad range of anions and cations.
From Fig. 4 it is apparent that the majority of the predictions
had good agreement with the experimental results, and across
all of the ionic liquids considered, using either MLREM or
BRANNLP. Two ionic liquids, [bmmo][N(CN)2] 14 and [TOA][BF4]
16, are the exceptions, with both of these ionic liquids having
predicted values substantially lower than the experimental values.
While the origin of the discrepancy, and the direction of such, is
not clear, for these ILs there were limited relevant training data.
Not only were the cations for both these ionic liquids only
paired with the bis(trifluoromethanesulfonyl)imide anion in the
training set, but the dicyanimide and tetrafluoroborate anions
were only paired with the 1-butyl-3-methylimidazolium cation in
the training set.
It is worth noting, however, that in contrast, the predictions
for other ionic liquids containing these anions (including salts
6, 8, 10 and 13) all matched the experimental data well.
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Overall there is excellent agreement considering the broad
range of cations and anions included in the validation set, the
relatively limited training set and the wide range of rate
constants considered. It is evident that both the MLREM and
BRANNLP have made meaningful predictions of the expected
rate constants for ILs which were not included in the original
study. It is apparent that neither the MLREM nor the BRANNLP
model performed significantly better than the other. While there
were a few outliers, the majority of predictions were well within an
order of magnitude, which is good for organic reactions.
The difficulty in predicting rate constants lies in the depen-
dence on multiple variables, and for this paper these are the
reaction temperature, the nature of the ionic liquid and
the proportion of the ionic liquid in the reaction mixture. While
the use of systematic studies enables some structure–property
relationships to be determined, they are not able to extract the
complex multivariate trends that can be obtained using
machine learning methods. Here we have addressed this lim-
itation in the predictive tools available, and shown that given a
reasonable set of initial data that meaningful predictions can
be made, noting specific issues with certain ion types that may
be a function of the descriptors used and the training data
available. A key advantage of the approach used in this paper is
that it involved experimental data and an assumption free
position for the selection of descriptors. This approach meant
that the models developed were purely based on the experi-
mental data, with no intervention in the selection of descrip-
tors, and no assumptions required for computational models.
Due to the multitude of possible cations and anions which
can be present in ILs, there is a very broad compositional space
which needs to be meaningfully represented. Here our
approach has been to use DRAGON descriptors to describe
the chemical structures of the cations and anions, where a set
of 33 descriptors was able to uniquely characterise all the
structures. A key advantage of this approach is that it can be
easily extended to any set of ionic liquids through the inclusion
of more descriptors. In addition, the methodology is not
dependent on any physical properties of the ILs, such as
viscosity and melting point, though these could be included
as inputs.
It should be noted that the work described is based on a
reaction that is extremely well-described in a range of ionic
liquids; as such, there is systematic data covering different
conditions (temperature, solvent composition) and different
cation and anion types. We would like to emphasise that high
quality models require consistent sets of data, with data cover-
ing the compositional space. The cases where the model
presented has (relatively) limited predictability correspond to
those systems with (relatively) less data in the training set.
Importantly, while the reaction itself is straightforward
(a bimolecular substitution involving a neutral amine nucleo-
phile), the understanding gained from this model might be
readily extended to series where less information is available
but the reaction is known to behave similarly in ionic
liquids.92–94 That is, there is the potential for broader applic-
ability, even into systems where less data is available.
Phys. Chem. Chem. Phys., 2021, 23, 2742--2752 | 2749

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Conclusions
In this study we have developed multiple linear regression
models (MLREM) and neural networks (BRANNLP) for the rate
constant, k2, of the reaction between benzyl bromide and
pyridine. The reaction has been conducted in mixtures of
ionic liquid and acetonitrile at different temperatures, with
different ionic liquids, and in different proportions of the two
co-solvents. An original set of 160 rate constant data from 36
ILs was used as the inputs. Structure–property relationships
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were obtained through using the MLREM model, and both
MLREM and BRANNLP showed good agreement for training
and test sets. Additionally, predictive models were developed
using the full data set, and used to obtain rate constant
predictions for 96 new ILs along with the previous 36 ILs,
covering all possible cation and anion combinations of the
original ions used. A set of 17 ionic liquids, 11 not included in
the initial training set, were selected to ensure that they covered
the range of ions used in the training set, and prepared where
necessary. The rate constant for the reaction was determined in
mixtures containing them – at a particular temperature and at a
particular solvent composition with acetonitrile. Overall there
was good agreement for most of these experimental data with
the predictions from both MLREM and BRANNLP analyses,
noting the limitations in describing ionic liquids containing
some components. This work has shown that the use of
machine learning is highly useful for predicting the rate con-
stants of organic reactions in ILs, given sufficient experimental
data to build the models.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
KSSM and JBH acknowledge financial support from the Aus-
tralian Research Council Discovery Project Funding Scheme
(Project DP180103682). RFBR is grateful to the School of Chem-
istry, University of New South Wales for a Summer Vacation
Research Scholarship. All data is available at the following
Figshare repository: 10.25439/rmt.12665651.
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