Iodine(III)-Mediated Electrochemical Trifluoroethoxylactonisation: Rational Reaction Optimisation and Prediction of Mediator Activity

Article abstract of DOI:10.1002/chem.201804152

A new electrochemical iodine(III)-mediated cyclisation reaction for the synthesis of 4-(2,2,2-trifluoroethoxy)isochroman-1-ones is presented. Based on this reaction design of experiments and multivariate linear regression analysis were used to demonstrate

Full text of DOI:10.1002/chem.201804152

A Journal of
Accepted Article
Title: Iodine(III)-mediated Electrochemical Trifluoroethoxylactonisation
- Rational Reaction Optimisation and Prediction of Mediator
Activity
Authors: Robert Möckel, Emre Babaoglu, and Gerhard Hilt
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10.1002/chem.201804152
Chemistry - A European Journal
Electrosynthesis
Iodine(III)-mediated Electrochemical Trifluoroethoxylactonisation -
Rational Reaction Optimisation and Prediction of Mediator Activity
*
*
Robert Möckel , Emre Babaoglu and Gerhard Hilt
Organic electrochemistry has recently drawn a lot of attention due
to an increased demand for more environmental friendly reactions i.e.
the substitution of oxidants and reductants by electricity.1
Electrochemical batch reactions are also easy to implement into flow
conditions which is an appealing point with regard to industrial
applications.2 Although an electrochemical approach often simplifies
reactions as oxidants or reductants are avoided and often no inert
conditions are required, it brings new challenges especially when it
comes to reaction optimisation. In this regard, new reaction
parameters, such as electrode material, cell design (e.g. divided,
undivided, pseudo-divided), supporting electrolytes and, most
importantly, frequently employed mediators are noteworthy.
Furthermore, the fact that special cells and power supplies have to be
used limits the number of experiments that can be done in parallel
which aggravates the optimisation process.3
In order to prove the concept, we chose the field of
hypercoordinate iodine(III)-chemistry. The choice for an iodine(III)-
mediated reaction was governed by several reasons; most
importantly, the fascinating reactivity of those compounds that show
reactivity patterns comparable to that of transition metals.9 Although
iodine(III) mediated reactions depend on a stoichometric use of
oxidants, only a rare number of examples of their application as in-
cell mediators in electrochemical reactions has been reported. In
addition, these examples cover exclusively simple oxidative
fluorination reactions at highly activated substrates (thioacetales, 1,3-
dicarbonyls).10 More challenging reactions at unactivated substrates
with more complicated reaction mechanisms or efforts towards
iodine(III) mediated enantioselective electrochemical reactions have
not been reported yet.10d
As optimisation is a fundamental problem, not only for chemical
method development, a range of statistical tools are available in order
to accelerate, hedge and simplify optimisation processes. One tool
which is well-known but nonetheless seldom used in academic
research, is design of experiments (DOE). It deals with the challenge
of distributing measuring points as efficiently as possible within their
experimental space in order to reduce the number of necessary
experiments with at the same time higher statistical significance.4
Another method which found increasing use in recent years is
multivariate linear regression analysis (MLR). This tool deals with
the prediction of one or even more variables from multiple descriptor
variables. In chemistry it is often combined with theoretical methods
like DFT calculations in order to predict outcome variables like yield
or enantiomeric excess from computationally accessible predictors.5
Even though those methods have been used (extensively in case
of MLR) for the optimisation of general chemical reactions their
application in electrochemistry is rare.5 Two examples for
multivariate modelling of electrochemical reactions have been
reported by Sigman regarding reaction yield prediction of a TEMPO-
mediated oxidation6 and for the prediction of the stability of
anolytes.7 The only example for the usage of DOE in an
electrochemical reaction has, to our knowledge, been reported
recently by us in which we used DOE for the optimisation of an
electrochemical iododesilylation reaction.8
Ar*I(OAc)2
pervious work
or
O
Ar*I + m-CPBA + Py*HF
O
O
O
R
Fujita X = OAc
R
2
1
X
yield: 57-84%, up to 97% ee
Jacobsen X = F
yield: 22-70%, up to 95% ee
this work
O
O
O
ArI
O
O
electrolysis, TFE
R
R
F3C
1
2
Scheme 1. Previous work on iodine(III)-mediated lactonisation by
Fujita11 and Jacobsen.12
A substrate class that has been used before in iodine(III)-mediated
lactonisation reactions are vinyl benzoic esters (Scheme 1). Fujita
reported a lactonisation using tosylate and acetate as nucleophiles
together with stoichiometric amounts of the respective iodine(III)
reagent.11 Jacobsen could improve a similar reaction with fluorine as
nucleophile by using meta-chloroperbenzoic acid as oxidant and
thereby facilitating a sub-stoichiometrically use of the iodine
mediator.12 We wanted to expand this type of reactions by using
electrochemical conditions in order to circumvent the use of
stoichiometric amounts of oxidant or iodine(III) reagent and
furthermore by using a different introduced nucleophile. We chose
trifluoroethoxylate as it is a challenging anion due to its low
nucleophilicity and furthermore due to its potential application in
pharmacologically active compounds.13
On the basis of the promising results we made with DOE in this
reaction, we were interested whether we could expand the use of DOE
and furthermore combine it with multivariate modelling to be able to
optimise the used mediator in a virtual screening.
[*]
M. Sc. R. Möckel, M. Sc. E. Babaoglu, Prof. Dr. G. Hilt
Institut für Chemie, Universität Oldenburg,
Carl-von-Ossietzky-Straße 9-11, 26129 Oldenburg, Germany
email: gerhard.hilt@uni-oldenburg.de
robert.moeckel@uni-oldenburg.de
M. Sc. R. Möckel, M. Sc. E. Babaoglu
Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein-Straße 4, 35043 Marburg, Germany
1
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10.1002/chem.201804152
Chemistry - A European Journal
Having these optimised reaction conditions in hand, the next
variable to optimise was the mediator. By screening a set of
commercially available aryl iodides and subsequent multilinear
regression with theoretically obtained values, a model for the
prediction of the yield was to be generated. The second step should
be a virtual screening of potentially chiral mediators to reduce the
effort invested in the synthesis of those synthetically challenging
mediators dramatically. An often-occurring problem when screening
new systems is an asymmetrical distribution of the predictor and
connected with this of the target values. To minimize this problem,
we generated a descriptor set for a large set of 46 mediators. Only
commercially available mediators were considered to ensure an as
efficient and rapid screening as possible. From this set we selected 18
mediators as fitting and 6 mediators as validation set using a D-
optimal design ensuring an even distribution of the predictors and
thereby hopefully a uniform yield distribution. The selected
mediators are spanning a broad range of electron rich as well as
electron poor arenes with ortho-, meta- and para-substitution (see
Figure 2) confirming the DOE approach. Each mediator was used in
triplicate to ensure good reproducibility applying the optimised
reaction conditions (the reaction temperature was set to 25 °C in ease
of preparational simple conditions).
Design of Experiment (DOE)
We started the optimisation process using a D-optimal screening
design consisting of 19 reactions (covering only linear terms and, in
case of concentrations, their corresponding acids/electrolytes cross
terms) in order to probe as many variables as possible with the lowest
possible number of experiments. Investigated factors were: the
mediator loading (iodobenzene was chosen as mediator to avoid
possible substituent effects on the reaction), an additional acid, as
preceding test reactions showed an impact on the yield (acetic acid,
trifluoroacetic acid and methanesulfonic acid) and the supporting
electrolyte
(tetrabutylammonium
tetrafluoroborate,
lithium
perchlorate and lithium hexafluorophosphate), their respective
concentrations, the electrodes (graphite and platinum), temperature (6
to 35 °C), the current density (2.5 to 7.5 mA/cm2) and the applied
charge (1.8 to 2.4 F/mol). The styrene derivative 1a was chosen as
screening substrate in order to be able to follow reaction progress and
determining yields using 19F NMR spectroscopy.
PhI (25 mol%)
O
TFA 0.9 M
O
F
LiClO4 0.8 M
O
F
O
TFE, Pt electrodes, 6 °C
2.0 F/mol, 7.5 mA/cm2
yield
CH2Br 56%
CO2Me 22%
yield
O
CF3
1a
2a
Ro =
Ro = OCF3 67%
I
DOE: 78% (initial: 27%), 25 reactions
Ro
OCF2H 52%
80
60
40
20
0
Br
I
OMe
61%
61%
22%
Ph
CF3
CH2CN 37%
H
10%
69%
71%
yield
I
Rm
=
I
(CO Me) 41%
2
2
(CF3)2
50%
53%
25%
66%
64%
60%
Me2
OMe
CF3
Me
Rm
Rm
22%
23%
0
20
40
60
80
yield predicted / %
RMSE=2,3969 R^2 =1,00 p-values<.0001
F
I
I
Figure 1. DOE optimised reaction conditions and plot of measured vs.
predicted yields. Reactions were performed on a 0.5 mmol scale.
Yields were determined by 19F NMR analysis using C6F6 as internal
standard (for detailed information see SI).
yield
18%
64%
Rp =
I
OMe
CF3
I
Rp
F
F
F
F
F
By this means, we could exclude the current density and the
applied charge as impact factors. In case of the categorical factors, we
constricted the design to the top scorers meaning lithium perchlorate
as electrolyte and trifluoroacetic acid as supporting acid. The
remaining design was expanded by only six reactions in order to cover
quadratic terms as well as the cross interactions of the acid and the
electrolyte concentration. The resulting model consists of nine factors
with a very good R2 of >0.99, p-values < 0.01 and a very good lack
of fit of 0.31. The most important factor was found to be the applied
electrolyte together with its respective concentration. The single
quadratic term which is relevant is the acid concentration. The
thereby derived optimal conditions are shown in Figure 1. Not
surprisingly, the mediator loading showed an equally small positive
effect but was set to 25 Mol-% in all following investigations to have
catalytic conditions. Using those optimised conditions, we were able
to increase the yield dramatically from 27 to 78% carrying out only
25 reactions.
65%
40%
F
F
Figure 2. Screened iodoarene mediators for MLR. All reactions were
carried out three times (for determination of the standard deviation)
on a 0.5 mmol scale. Yields were determined by GC-FID analysis
using mesitylene as internal standard at room temperature.
For the generation of the descriptor set, we calculated three
distinctive structures: the iodobenzene derivative, its di-cation, and
the respective hypercoordinate iodine(III) structure with two
trifluoroacetoxy ligands.14 The calculated predictors were: the free
oxidation enthalpy ∆Gox, the free binding enthalpy of the trifluoro-
acetoxy ligands ∆Gbond,TFA and for each structure respectively the
NBO charge on the iodine, HOMO and LUMO energies. Furthermore,
an IR deformation vibration in III and in order to cover steric effects,
Multivariate linear regression (MLR)
2
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10.1002/chem.201804152
Chemistry - A European Journal
O-O distance
O
O
O
O
2+
I
I
F3C
CF3
ΔGBond
ΔGOx
I
CF3
I
O
R’
Lortho, B1ortho
B2ortho, B3ortho
B4ortho, B5ortho
,
R
R
,
x2
R
x1
B1I, B5I
B1I2+, B5I2+
B1TFA, B5TFA
3g
HOMO, LUMO, NBOI/I2+/TFA
various Sterimol parameters and finally the distance LO-O between the
two oxygens in structure III (for more information see Scheme 2 and
SI).
Figure 3. Normalised multivariate linear regression model for the
yield of aryl iodide mediators and structure of potentially chiral
mediator 3g (for structures of remaining test set see SI).
Scheme 2. Calculated molecular descriptors for multivariate linear
regression modelling. Respective Sterimol parameters B1 and B5 were
determined along x1-axis, B1ortho, B2ortho, B3ortho, B4ortho, B5ortho and Lortho
along the x2-axis. Distance LO-O was measured along the O-O bond axis.
IRTFA ring deformation vibration in x1 direction was measured in III. All
structures and electronic parameters (∆Gox: free oxidation enthalpy,
∆Gbond: binding free enthalpy, NBO, HOMO and LUMO values) were
determined on the M06-2X/def2-TZVPP-D3 level (for computational
details, see SI).
Substrate Scope
In a last step, the performance of iodobenzene as mediator under
the optimised reaction conditions should be evaluated. Once again,
we wanted to reduce the experimental expenditure by refraining from
testing a large range of substrates. Only a small number of substrates
were subjected to the reaction in order to check for electronic and
steric effects. Electronic effects were examined by modifying the
aromatic core. For electron-neutral or electron-deficient substrates no
distinct dependency could be observed (Figure 4).
Having the theoretical as well as experimental data in hand,
multivariate linear regression analysis was applied. To cope with the
high number of descriptors we applied various techniques. To initially
reduce the number of relevant descriptors, we used principal
component analysis and the partial least squares method implemented
in JMP 13.16 Ensuing, the stepwise algorithm implemented in JMP 13
using five-fold internal cross validation, taking quadratic and two-
way cross interactions into account, was used (for further information
see SI). The final model consists of seven descriptors. It shows a high
predictive power with a RMSE of 5.59 in the validation set. The
model is dominated by two terms, the HOMOI and the HOMOI2+
energy. Less important are the B5I2+, LO-O, NBOI, and LUMOI.
Using cyclic voltammetry, some of those terms could be attributed to
two different factors that determine the performance of the mediator
(see SI). HOMOI and HOMOI2+ as the most important terms could
be connected to their oxidation potential which most likely reflects
their stability towards oxidative degradation processes. LUMOI, LO-
R2
O
59 %
58 %
54 %
57 %
45 %
traces
54 %
2a R = F
2b R = H
2c R = Cl
2d R = Br
2e R = Ph
2f R = OMe
2g R = CO2Me
O
O
R
O
R1
O
CF3
F3C
O
2h R1 = Me, R2 = H 54 %
2i R1 = H, R2 = Me 60 %
O
2j R = nProp
2k R = iProp
2l R = cHex
2m R = Bn
60 % dr = 64:36
43 % dr = 74:26
45 % dr = 90:10
32 % dr = 85:15
F
O
R
O
CF3
and NBOI correlate with the peak current ratios j, depicting the
O
reactivity of the mediator towards the substrate.
Figure 4. Results of the electrochemical lactonisation reaction using
25 mol% iodobenzene as mediator. All reactions were carried out on a
1.0 mmol scale using the reported optimised reaction conditions.
Diastereomer ratios were determined by GC/MS prior to
chromatographic purification. For further information see experimental
section.
As we found the optimal achiral mediator to be iodobenzene (it
possesses nearly ideal descriptor values, thus further virtual screening
is not promising) we drew our attention to chiral mediators. This field
is much more challenging as all tested chiral mediators, commonly
used in literature, decomposed under the reaction conditions (yields
are plotted in Figure 3 as test set, see SI for a complete list with their
respective structures). According to the model, this can be mainly
attributed to their low oxidation potential. That’s why we calculated
in a virtual screening a large set of chiral mediators in order to find a
new potentially chiral mediators that is stable under the reaction
conditions. One of the top scorers 3g which could be obtained by
directed optimisation of a literature known mediator, is shown in
Figure 3. It shows a promising yield of 56 % (compared to 71 % for
iodobenzene) and perfectly illustrates the time saving benefits in
synthesis due to a virtual screening. Current investigations on the
enantiomeric excess of this and other high yielding chiral mediators
are under way and will be reported soon.
The electron-rich substrate 2f decomposed and only product
traces could be found. Steric effects were studied at three positions:
at the aromatic core and at the two ortho-positions using the
respective methyl derivatives 2h and 2i but no significant effect could
be observed. The vinylic position was the third position to be
modified in order to check for effects on the yield and potential
diastereomers. Unfortunately, we observed a negative correlation. For
sterically demanding groups, such as cyclohexyl 2l, satisfying
diastereomer ratios of up to 90:10 could be observed but accompanied
with low yields. For sterically less demanding substrates like n-propyl
2j, good yields were obtained but the diastereomer ratio was lower.
3
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10.1002/chem.201804152
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To further reduce the synthetic effort in the determination of the
functional group tolerance, a compatibility test was carried out which
is based on the addition of additives containing one specific
functional group to a screening reaction in order to measure the
product and the additive yield and thereby determine the stability or
parameters of which three are categorical, we could reduce the
number of experiments needed for a statistically significant result
dramatically to 25 reactions. Using multivariate linear regression, we
could build up a model by which we can predict yields for
theoretically calculated mediators. This allowed us to do a virtual
screening yielding inter alia one potentially chiral mediator with a
promising yield of 56 % doubling the yield of literature known
mediators. As far as we know, this is the first reported example for
the combination of all those methods and we hope that it will be a
kick-off for other groups to use design of experiment in combination
with multivariate modelling in order to speed up the reaction and
mediator optimisation process with simultaneously higher
significance of the results.
influence on the reaction of the respective functional group.17
A
selection of results is shown in Table 1. In general, functional groups
that are labile towards oxidative conditions or groups that show
intrinsic reactivity towards iodine(III)-species show low additive
and/or product yields.18 This is the case for alkenes, alkynes or some
heterocycles like furanes or indoles. Nevertheless, a broad range of
functional groups is stable. Noteworthy are electron-deficient
heterocycles such as chinoline or pyridine, Boc-protected amides but
oxidative labile groups like aliphatic amines or aldehydes are stable
as well (for complete list, see SI).
Experimental Section
Table 1. Functional group tolerance test using 25 mol% iodobenzene
as mediator with screening substrate 1a.
In an H-type cell, both chambers were loaded with 10 mL of an 0.9 M
trifluoroacetic acid solution in trifluoroethanol and lithium perchlorate
(851 mg, 0.8M). Iodobenzene (0.125 mmol, 25 Mol-%) and the
respective vinyl benzoate (1.00 eq., 0.5 mmol) were added to the
anode compartment. The cell was equipped with platinum electrodes
and the solutions were stirred until all solids were dissolved. The
reaction was electrolysed under constant current density (7.5 mA/cm2)
at RT until complete conversion (GC/MS monitoring) could be detected
(normally 2 F/mol). The anode compartment solution was taken up with
a syringe and filtered through a pad of neutral aluminium oxide which
was rinsed thoroughly with ethyl acetate. The solvent was evaporated
under reduced pressure. The crude product was purified by column
chromatography using neutral aluminium oxide as stationary phase.
Additive
Yield Starting
material / %
Yield
Product
Yield
Additive
-
0%
0%
0%
0%
0%
0%
0%
2%
0%
0%
86%
19%
0%
0%
0%
0%
9%
0%
0%
2%
0%
10%
0%
0%
71%
75%
58%
68%
53%
53%
67%
43%
40%
33%
0%
-
1-Dodecylamine
Benzaldehyde
Butanol
100%
77%
100%
69%
64%
75%
0%
1-N-Boc-2-piperidone
2,6-Lutidine
2-Chlorochinoline
2-Butylfuran
1-Dodecyne
7%
1-Octene
0%
Acknowledgements
2-Methylanisole
N-Methyl indole
Sulfolane
Benzothiazole
1-Chlorooctane
Chlorobenzene
Carbazole
Dibutyl ether
Heptyl cyanide
2-Butylfuran
Nitrobenzene
4-(TMS)toluene
Valerophenone
Methyl benzoate
0%
10%
68%
45%
71%
67%
51%
49%
55%
43%
64%
19%
59%
69%
34%
90%
94%
92%
87%
42%
100%
100%
0%
100%
0%
82%
88%
We thank the Hochschulrechenzentrum Marburg and Oldenburg
for providing computer time and for the excellent service. We thank
Alexander Nödling and Reinhart Möckel for helpful discussions and
Marc Schmidtmann for help with crystal structure analysis.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: hypercoordinate iodine · iodine(III) · electrochemistry ·
iodoarenes · design of experiments · compatibility test · multivariate
linear regression
All reactions were carried out on a 0.5 mmol scale using the reported
optimised reaction conditions. Additive yields were determined by GC-
FID analysis using mesitylene as the internal standard. For more
examples see SI.
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Chemistry - A European Journal
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10.1002/chem.201804152
Chemistry - A European Journal
Entry for the Table of Contents
Electrosynthesis
R. Möckel, E. Babaoglu, G. Hilt______
Page – Page
Iodine(III)-mediated Electrochemical
Trifluoroethoxylactonisation - Rational
Reaction Optimisation and Prediction of
Mediator Activity
-
+
DoE
MLR
virtual
screening
Computer says yes ˗ A new electrochemical iodine(III)-mediated cyclisation
reaction for the synthesis of 4-(2,2,2-trifluoroethoxy)isochroman-1-ones is
presented. Based on this reaction we used design of experiment and multivariate
linear regression analysis to demonstrate their first application in an electrochemical
reaction. The broad applicability of this reaction conditions could be shown by a
range of substrates and an extensive compatibility test.
6
This article is protected by copyright. All rights reserved.

10.1002/chem.201804152
Chemistry - A European Journal
7
This article is protected by copyright. All rights reserved.