Iridium-catalysed ortho-directed deuterium labelling of aromatic esters - An experimental and theoretical study on directing group chemoselectivity

Article abstract of DOI:10.3390/molecules200711676

Herein we report a combined experimental and theoretical study on the deuterium labelling of benzoate ester derivatives, utilizing our developed iridium N-heterocyclic carbene/phosphine catalysts. A range of benzoate esters were screened, including derivatives with electron-donating and -withdrawing groups in the para- position. The substrate scope, in terms of the alkoxy group, was studied and the nature of the catalyst counter-ion was shown to have a profound effect on the efficiency of isotope exchange. Finally, the observed chemoselectivity was rationalized by rate studies and theoretical calculations, and this insight was applied to the selective labelling of benzoate esters bearing a second directing group.

Full text of DOI:10.3390/molecules200711676

Molecules 2015, 20, 11676-11698; doi:10.3390/molecules200711676
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Iridium-Catalysed ortho-Directed Deuterium Labelling of
Aromatic Esters—An Experimental and Theoretical Study on
Directing Group Chemoselectivity
Jennifer Devlin †, William. J. Kerr *, David M. Lindsay, Timothy J. D. McCabe 1,†, Marc Reid †,‡
and Tell Tuttle
Department of Pure & Applied Chemistry, University of Strathclyde, WestCHEM,
295 Cathedral Street, Glasgow G1 1XL, UK; E-Mails: jennifer.devlin.2013@uni.strath.ac.uk (J.D.);
david.lindsay@strath.ac.uk (D.M.L.); timothy.mccabe@strath.ac.uk (T.J.D.M.);
marc.reid@ed.ac.uk (M.R.); tell.tuttle@strath.ac.uk (T.T.)
†
These authors contributed equally to this work.
‡
Current address: School of Chemistry, University of Edinburgh, EastCHEM, David Brewster Road,
Edinburgh EH9 3FJ, UK.
* Author to whom correspondence should be addressed; E-Mail: w.kerr@strath.ac.uk;
Tel.: +44-141-548-2959.
Academic Editor: Michael Findlater
Received: 2 June 2015 / Accepted: 19 June 2015 / Published: 25 June 2015
Abstract: Herein we report a combined experimental and theoretical study on the deuterium
labelling of benzoate ester derivatives, utilizing our developed iridium N-heterocyclic
carbene/phosphine catalysts. A range of benzoate esters were screened, including derivatives
with electron-donating and -withdrawing groups in the para- position. The substrate scope,
in terms of the alkoxy group, was studied and the nature of the catalyst counter-ion was
shown to have a profound effect on the efficiency of isotope exchange. Finally, the observed
chemoselectivity was rationalized by rate studies and theoretical calculations, and this insight
was applied to the selective labelling of benzoate esters bearing a second directing group.
Keywords: hydrogen isotope exchange; deuterium; iridium; esters; C–H activation; DFT

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1. Introduction
The ability to incorporate an isotopic label into a biologically-active molecule is of profound
importance in the drug discovery process. Such a radioactive “tag” or “label” can be used to provide
vital information on a compound’s absorption, distribution, metabolism, excretion, and toxicological
(ADMET) properties. As a result of these uses, isotopic labelling is the gold standard method by which
early stage drug discovery processes can be optimised.
Research into deuterium (2H or D) and tritium (3H or T) labelling is more substantial than for other
isotopes, and has been developed on a number of fronts over the past 60 years [1–10]. Further to this, key
developments in synthetic strategies and analytical techniques for tritium labelling over the past three
decades now makes this the preferred technique for many ADMET studies [5]. In one particularly
active branch of such labelling research, hydrogen isotope exchange (HIE) is employed to deliver either
deuterium or radioactive tritium to pharmaceutical drug candidates in one synthetic step. As well as
circumventing the requirement for isotopically-enriched starting materials in preparing tritiated drug
candidates [1,5], HIE can also provide analogous deuterated compounds for use as internal standards for
mass spectrometry [11,12], for kinetic isotope studies [13,14], and for the alteration of reaction pathways
in total synthesis [15].
Over recent years, research in our laboratory has focused on the development of iridium(I)
N-heterocyclic carbene (NHC)-ligated precatalysts of the type 1, and their application in HIE via
ortho-directed C–H activation protocols (2→4 via 3, Scheme 1) [6,16–22]. Despite the growing list of
compatible directing groups, we [23] and others [24–27] have found these developed C–H activation
methods less applicable in the labelling of aromatic esters under ambient conditions. Herein, we report
the extension of our methodology to encompass the labelling of weakly coordinating benzoate ester
derivatives under mild conditions.
Scheme 1. General method for Ir-catalysed ortho-HIE via a C–H activation pathway.
2. Results and Discussion
2.1. Catalyst Screening and Comparisons with Crabtree’s Catalyst
Until recently, Crabtree’s catalyst, [(COD)Ir(PCy3)(py)]PF6, 5, was the most widely applied
iridium-based HIE catalyst for labelling applications within an industrial setting [24,28]. As such, any

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studies which evaluate our developed catalysts in the labelling of aromatic esters should also
compare them against the ability of 5 to mediate the same catalytic labelling reactions under identical
conditions [19,29]. To this end, and to initiate this research programme, the labelling of a series of
para-substituted ethyl benzoate derivatives 6 was examined, using our standard labelling protocol
(5 mol % [Ir], 1 atm D2, 1 h) with Crabtree’s catalyst 5 (Scheme 2, blue bars) and our developed
catalyst systems 1b and 1a (Scheme 2, red and green bars, respectively). With the exception of the
p-chloro and p-methoxy esters (6d and 6e), Crabtree’s catalyst 5, proved relatively ineffective in the
deuteration of these ester substrates, with incorporations as low as 10% being observed with the
electron-withdrawing p-CF3 ester 6c. On assessing the larger and more electron-rich variant of our
catalyst series, 1b, a significant improvement in labelling esters 6c (X = CF3) and 6d (X = Cl) was
observed, whereas the other esters 6a, 6b and 6e were labelled less efficiently relative to Crabtree’s
catalyst. Only on employing our more Lewis acidic catalyst, 1a, did we observe the most efficient and
encouraging improvement in ester labelling across all examples tested, with the exception of the parent
ethyl benzoate 6a. We hypothesize that the more flexible Lewis acidity of 1a vs. 5 or 1b partially
diminishes the importance of the ester coordination event and negative Hammett σp values,[30] and
simultaneously enhances the effect of positive σm in relation to a more facile C–H activation event. For
example, compare the order of substrate reactivity for catalyst 5 (OMe > Cl > Me > H > CF3) vs. 1a
(OMe–Cl > CF3 > Me > H). In the absence of more detailed reaction monitoring, we acknowledge that
the observed results cannot be directly related to the kinetically-derived Hammett values. Nonetheless,
the hypothesis remains feasible.
96
100
90
80
70
60
50
40
30
20
10
0
95
89
80
77
68
62
56
55
catalyst 5
catalyst 1b
catalyst 1a
% D
39
23
20
19
10
10
6a
6b
6c
6d
6e
Scheme 2. Comparative labelling of ethyl benzoates 6 using catalysts 5, 1b, and 1a.

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2.2. Applicable Substrate Scope with Catalyst 1a
2.2.1. Para-Substituted Methyl Benzoates
Using the most efficient of the three catalysts tested, catalyst 1a, we investigated the possibility of
labelling methyl esters under the same conditions employed for the ethyl analogues 6 (Table 1). While
methyl esters 8d and 8e were labelled with high levels of deuterium incorporation, the other methyl
esters in the series proved more capricious. Specifically, substrates 8a, 8b and 8c were repeated multiple
times, with individual deuterium incorporations ranging from 27% to 52% (see Experimental Section
for full details).
Table 1. Labelling of methyl benzoates 8 using catalyst 1a.
Entry
X
H
Substrate %D a
1
2
3
4
5
8a
8b
8c
8d
8e
52
42
32
93
89
CH3
CF3
Cl
OMe
a %D incorporation is the average of two runs and was determined by 1H-NMR spectroscopy.
2.2.2. Scope of O-Alkyl Substitution with Electron-Rich Benzoate Esters
Beyond methyl and ethyl benzoates, we also examined the applicability of larger O-alkyl ester
substituents using our labelling method (Table 2). We pursued this line of enquiry for p-methoxybenzoate
derivatives only, in order to minimise potential substrate coordination issues associated with the aryl
substituent. Whilst the n-propyl, 2,2,2-trifluoroethyl, and tert-butyl benzoate derivatives 10a, 10b and
10c unfortunately proved to be less applicable, iso-propyl and benzyl esters 10d and 10e could be
labelled with appreciable levels of deuterium incorporation.
Table 2. Labelling of electron-rich benzoate esters using catalyst 1a.
Entry
R
n-Pr
Substrate
10a
%D a
28
1
2
3
4
5
CH2CF3
t-Bu
i-Pr
10b
8
10c
10
10d
73
Bn
10e
62
a %D incorporation is the average of two runs and was determined by 1H-NMR spectroscopy.

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2.3. Reaction Optimisation for Efficient Labelling of Challenging Benzoate Ester Substrates
2.3.1. Temperature Effects
Due to the application of this hydrogen isotope exchange method in related tritiation chemistries [6],
significant effort is usually made to maintain ambient reaction conditions during the optimization of
ortho-deuteration processes. Having stated this, the use of slightly raised reaction temperatures need
not be completely discounted from such investigations. We therefore revisited the labelling of the most
challenging methyl and ethyl benzoate derivatives, using a moderately increased reaction temperature
of 40 °C (Scheme 3). Pleasingly, dramatic improvements in deuterium incorporation were observed
across all substrates examined, 6a–c and 8a–c, whilst the short reaction times were maintained (see
Experimental Section 3.4).
96
96
100
90
80
70
60
50
40
30
20
10
0
93
90
86
77
76
68
52
25 °C
40 °C
%D
42
32
23
6a
6b
6c
8a
8b
8c
Scheme 3. Temperature effects on deuterium labelling of previously problematic benzoate esters.
2.3.2. Catalyst Counterion Effects
We recently reported the improved activity and broad-spectrum solubility resulting from replacement
of the PF6 counterion in catalyst 1a with tetrakis[bis-3,5-trifluoromethylphenyl]borate, BArF, to give
complex 1d [18]. Applying improved catalyst 1d to the labelling of larger ester derivatives 10a–e under
otherwise identical conditions, significant and more usable levels of deuterium incorporation were
observed across all examples (Scheme 4). Importantly, this counter-ion switch demonstrates an alternative
means by which ester labelling efficiency can be improved, should ambient temperature conditions
be required.

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100
90
80
70
60
50
40
30
20
10
0
94
89
89
72
61
PF₆
%D
41
BArF
28
24
10
8
10a
10b
10c
10d
10e
Scheme 4. Exploiting anion effects for improved ester labelling.
2.4. Exploring Chemoselectivity Issues in Ester Labelling
2.4.1. Experimental Observations
From the outset of our studies, it was clear that the main challenge in labelling aromatic esters would
be the weak coordinating ability of this functional group. To understand this issue in more detail, we
conducted a series of intramolecular competition studies where multiple potential directing groups
can compete for coordination (and subsequent C–H activation) at the iridium centre. To this end, we first
investigated the labelling of ethyl p-nitrobenzoate, 12, under the optimised ambient reaction conditions.
Interestingly, we observed an approximate 1.4:1 selectivity for labelling via the nitro rather than the ester
directing group (Scheme 5). This chemoselectivity was eroded entirely on changing the ester to a
tertiary amide in 13 (1:1 nitro:amide), and reversed by replacing the ester with a ketone in 14 (3:1 in
favour of the ketone).
Scheme 5. Variation in labelling regioselectivity based on directing group chemoselectivity.

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Focusing on the extreme substrate cases, with substrates 12 and 14, 1 mol % of catalyst 1a was
employed to allow reaction rates and labelling selectivities to be monitored over time (Scheme 6). In the
case of substrate 12, and the labelling of the positions ortho- to the ester vs. the nitro, the difference in
reaction rate, and thus product selectivity, remains largely constant throughout the course of the
reaction. Conversely, with substrate 14, the relative rate of labelling ortho- to ketone vs. nitro is higher
at lower conversions, and decreases rapidly over time.
80
70
60
50
40
30
20
10
0
8
7
6
5
4
3
2
1
0
Nitro
Ester
Selectivity
0
0.5
1
1.5
2
2.5
3
Time (h)
100
90
80
70
60
50
40
30
20
10
0
8
7
6
5
4
3
2
1
0
Nitro
Ketone
Selectivity
0
0.5
1
1.5
2
2.5
3
Time (h)
Scheme 6. Rate and product selectivity studies for 12 (top) and 14 (bottom).

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2.4.2. Theoretical Analysis
In previous C–H activation studies, we rationalised observed directing group chemoselectivity using
density functional theory (DFT) calculations (see Supplementary Materials for details) to model the
relative energies of the binding conformers and subsequent C–H activation pathways [20]. We have now
extended this approach to the analysis of the labelling reactions of 12 and 14 (Scheme 7). In agreement
with previous findings, we qualitatively predicted that the most stable binding isomer should also be
the most reactive. If Curtin-Hammett kinetics are assumed [31], the calculated ΔΔG‡ (and thus product
selectivity) from equilibrium and activation parameters is predicted to be higher for the ketone in 14 vs.
the nitro group in 12 (5.5 vs. 1.4 kcal/mol, respectively). However, the current model does not account
for the barrier to interconversion of binding conformations (ketone to nitro, ester to nitro, and vice versa
for each case). Considering these points in the context of the experimentally-determined product selectivity
vs. time (vide supra), only substrate 12 (showing little variation in selectivity over time) appears to show
rapid equilibrium between the binding isomers. Conversely, the labelling of 14 via the ketone may
be interpreted as being faster than the rate of interconversion between binding conformers as well as
possessing a lower barrier to C–H activation.
Scheme 7. Density functional theory (DFT) analyses on the C–H activation step in labelling
substrates 12 and 14 with 1a.

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2.4.3. Practical Exploitation of Directing Group Chemoselectivity
The fundamental analysis of intramolecular directing group chemoselectivity served to show that
observed labelling patterns are, in part, dependent on the relative catalyst binding affinities of each
directing group. With this new understanding in hand, we questioned if it would be possible to control
the direction of labelling using the inherent reactivity of a given multi-functional substrate. Pleasingly,
using substrate 14 as a proof-of-concept substrate, minimal optimisation was required to show that
judicious choice of catalyst loading and reaction temperature allowed control of the labelling pattern
(Scheme 8). Specifically, labelling ortho- to the ketone group could be achieved with a 5 mol % catalyst
loading of 1a at room temperature to give 18, whereas the globally-labelled product 19 could be obtained
by employing 5 mol % of 1a at 40 °C. In turn, the previously elusive nitro-selective product, 20, was
accessed by a retro-labelling strategy (employing H2 in place of D2) conducted on the globally-labelled
product 19.
Scheme 8. Condition-dependent flexible access to alternatively deuterated forms of 18.
3. Experimental Section
3.1. General Considerations
All reagents were obtained from commercial suppliers (Sigma-Aldrich, Gillingham, UK; Alfa Aesar,
Heysham, UK; or Strem, Newton, UK) and used without further purification, unless otherwise stated.
Dichloromethane was obtained from a PureSolv SPS-400-5 Solvent Purification System (Innovative
Technology, Inc., Galway, Ireland), and deoxygenated by bubbling argon through for a minimum of ten
minutes. Thin layer chromatography was carried out using Camlab silica plates coated with fluorescent
indicator UV254 (Sigma-Aldrich), and were visualized using a Mineralight UVGL-25 lamp (Fisher
Scientific UK Ltd., Loughborough, UK) or developed using vanillin solution. Catalysts 1a [20], 1b [16],
and 1d [18] were prepared according to literature procedures. Esters 6c [32], 10a [33], 10b [34], 10c [35],
10d [36], 10e [37], and 13 [38] were prepared according to the corresponding literature procedures.
1H-NMR spectra were recorded on a Bruker DPX 400 spectrometer (Bruker, Coventry, UK) at 400 MHz.
Chemical shifts are reported in ppm and coupling constants are reported in Hz. All coupling constants
are 3JH–H unless otherwise stated.

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3.2. General Procedures
3.2.1. Deuteration of Substrates Using Iridium(I) Complexes 1a, 1b, 1d and 5
A three-necked round bottom flask was fitted with two stopcock side arms and a rubber septum,
and then flame-dried. To this flask was added the iridium(I) complex and substrate. The solvent, DCM
(2.5 mL, unless stated otherwise), was added, rinsing the inner walls of the flask, and the rubber septum
was replaced with a greased glass stopper. The solution was placed under an atmosphere of Ar and
stirred whilst being cooled to −78 °C in a dry ice/acetone bath. The flask was evacuated then refilled
with argon and this process repeated. Upon a third evacuation, an atmosphere of deuterium gas was
introduced to the flask. After sealing the flask, the cold bath was removed and the flask heated in an oil
bath to the desired temperature. The reaction mixture was stirred for the allotted reaction time before
removing the deuterium atmosphere and replacing with air. The resulting solution was washed with
DCM and transferred to a single-necked flask before removing the solvent under reduced pressure. The
catalyst was triturated from the remaining residue by addition of diethyl ether (3 × 5 mL). The solution
was filtered through a short plug of silica before the solvent was removed in vacuo to deliver the crude
product for analysis of the deuterium incorporation.
1
The level of deuterium incorporation in the substrate was determined by H-NMR spectroscopy.
The integrals were calibrated against a peak corresponding to a position not expected to be labelled.
Equation (1) was then used to calculate the extent of labelling:
residual integral
% Deuteration = 100 − [ꢀ
ꢁ × 100]
(1)
number of labelling sites
3.2.2. Deuteration of Substrates for Rate Studies
A three-necked round bottom flask fitted with one stopcock side arm and two rubber septa was
flame-dried. To this flask was added the iridium(I) complex, and substrate. The solvent, DCM (25 mL),
was added, rinsing the inner walls of the flask, and one rubber septum was replaced with a greased
glass stopper. The solution was placed under an atmosphere of argon and stirred whilst being cooled
to −78 °C in a dry ice/acetone bath. The flask was evacuated then refilled with argon and this process
repeated. Upon a third evacuation, an atmosphere of deuterium gas was introduced to the flask via a
balloon. The balloon was left in place for the duration of the reaction to ensure a continuous supply of
deuterium. The cold bath was removed and the flask heated in an oil bath to the desired temperature.
The reaction mixture was then stirred for the allotted reaction time. An aliquot (1 mL) of the reaction
mixture was removed at intervals throughout the reaction (10, 20, 30, 40, 50, 60 min, 2 h, and 18 h). Each
aliquot was transferred to a vial containing diethyl ether. After removal of solvent in vacuo, the residue
was analysed by 1H NMR spectroscopy. The integrals were calibrated against a peak corresponding to
a position not expected to be labelled. The extent of labelling was determined using Equation (1).

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3.3. Labelling Studies
3.3.1. Deuteration of Ethyl benzoate 6a with Complex 5
1H-NMR (400 MHz, CDCl3): δ 8.05 (d, J = 7.1 Hz, 2H, CH3), 7.54 (t, J = 7.3 Hz, 1H, CH1), 7.43 (t,
4
5
J = 7.9 Hz, 2H, CH2), 4.38 (q, J = 7.2 Hz, 2H, CH2 ), 1.39 (t, J = 7.1 Hz, 3H, CH3 ). Incorporation
expected at δ 8.05. Determined against integral at δ 1.39. Following General Procedure A, results are
reported as (a) amount of substrate; (b) amount of catalyst; (c) reaction time; (d) reaction temperature;
and (e) level of incorporation.
Run 1: (a) 6a, 0.032 g, 0.215 mmol; (b) 5, 8.04 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 17%.
Run 2: (a) 6a, 0.032 g, 0.215 mmol; (b) 5, 8.04 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 22%
3.3.2. Deuteration of Ethyl 4-methylbenzoate 6b with Complex 5
1H-NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.0 Hz, 2H, CH3), 7.21 (d, J = 7.9 Hz, 2H, CH2), 4.34
4
1
5
(q, J = 7.1 Hz, 2H, CH2 ), 2.38 (s, 3H, CH3 ) 1.36 (t, J = 7.1 Hz, 3H, CH3 ). Incorporation expected at
δ 7.91. Determined against integral at δ 2.38. Following General Procedure A, results are reported as
(a) amount of substrate; (b) amount of catalyst; (c) reaction time; (d) reaction temperature; and (e) level
of incorporation.
Run 1: (a) 6b, 0.035 g, 0.215 mmol; (b) 5, 8.04 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 36%.
Run 2: (a) 6b, 0.035 g, 0.215 mmol; (b) 5, 8.04 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 41%.
3.3.3. Deuteration of Ethyl 4-(trifluoromethyl)benzoate 6c with Complex 5
1H-NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.3 Hz, 2H, CH2) 7.67(d, J = 8.3 Hz, 2H, CH1) 4.38
(q, J = 7.2 Hz, 2H, CH23), 1.38 (t, J = 7.2 Hz, 3H, CH34). Incorporation expected at δ 8.12. Determined
against integral at δ 1.38. Following General Procedure A, results are reported as (a) amount of substrate;
(b) amount of catalyst; (c) reaction time; (d) reaction temperature; and (e) level of incorporation.
Run 1: (a) 6c, 0.044 g, 0.215 mmol; (b) 5, 8.04 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 8%
Run 2: (a) 6c, 0.044 g, 0.215 mmol; (b) 5, 8.04 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 11%

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3.3.4. Deuteration of Ethyl 4-chlorobenzoate 6d with Complex 5
1H-NMR (400 MHz, CDCl3): δ 7.95 (d, J = 8.8 Hz, 2H, CH2) 7.38 (d, J = 8.8 Hz, 2H, CH1) 4.34
3
4
(q, J = 7.3 Hz, 2H, CH2 ), 1.36 (t, J = 7.3 Hz, CH3 ). Incorporation expected at δ 7.95. Determined
against integral at δ 1.36. Following General Procedure A, results are reported as (a) amount of substrate;
(b) amount of catalyst; (c) reaction time; (d) reaction temperature; and (e) level of incorporation.
Run 1: (a) 6d, 0.039 g, 0.215 mmol; (b) 5, 8.04 mg; 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 50%
Run 2: (a) 6d, 0.039 g, 0.215 mmol; (b) 5, 8.04 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 59%
3.3.5. Deuteration of Ethyl 4-methoxybenzoate 6e with Complex 5
1H-NMR (400 MHz, CDCl3): δ 7.98 (d, J = 9.1 Hz, 2H, CH3), 6.89 (d, J = 9.0 Hz, 2H, CH2), 4.30
4
1
5
(q, J = 7.0 Hz, 2H, CH2 ), 3.83 (s, 3H, CH3 ), 1.35 (t, 7.1Hz, 3H, CH3 ). Incorporation expected at δ
7.98. Determined against integral at δ 3.83. Following General Procedure A, results are reported as (a)
amount of substrate; (b) amount of catalyst; (c) reaction time; (d) reaction temperature; and (e) level
of incorporation.
Run 1: (a) 6e, 0.038 g, 0.215 mmol; (b) 5, 8.04 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 89%
Run 2: (a) 6e, 0.038 g, 0.215 mmol; (b) 5, 8.04 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 71%
3.3.6. Deuteration of Esters 6a–e Using Catalysts 1b and 1a
For the results relating to catalysts 1b and 1a in Scheme 2, please refer to the spectroscopic data from
Sections 3.3.1–3.3.5 for the analysis of the deuterated esters 6a–e. As catalyst type and amount used are
the only variables changed, General Procedure A was followed with the results tabulated in Table 3.
3.3.7. Deuteration of Methyl Benzoate 8a with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 8.04 (d, J = 7.0 Hz, 2H, CH3), 7.56 (t, J = 7.4 Hz, 1H, CH1), 7.44
4
(t, J = 7.9 Hz, 2H, CH2), 3.92 (s, 3H, CH3 ). Incorporation expected at δ 8.04. Determined against
integral at δ 3.92. Following General Procedure A, results are reported as (a) amount of substrate; (b)
amount of catalyst; (c) reaction time; (d) reaction temperature; and (e) level of incorporation.

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Run 1: (a) 8a, 0.032 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 52%
Run 2: (a) 8a, 0.032 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 51%
Table 3. Deuteration of Esters 6a–e.
Entry
Substrate
Catalyst
%D (run 1)
%D (run 2)
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6a
6b
6c
6d
6e
10
15
62
85
65
6
53
74
95
96
10
23
50
93
59
40
83
79
95
96
1b (10.5 mg)
1a (10.1 mg)
10
3.3.8. Deuteration of Methyl 4-methylbenzoate 8b with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.0 Hz, 2H, CH3), 7.21 (d, J = 8.0 Hz, 2H, CH2), 3.89
4
1
(s, 3H, CH3 ), 2.39 (s, 3H, CH3 ). Incorporation expected at δ 7.99. Determined against integral at δ
2.39. Following General Procedure A, results are reported as (a) amount of substrate; (b) amount of
catalyst; (c) reaction time; (d) reaction temperature; and (e) level of incorporation.
Run 1: (a) 8b, 0.035 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h, d) 25 °C; and (e) 35%
Run 2: (a) 8b, 0.035 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 48%
3.3.9. Deuteration of Methyl 4-(trifluoromethyl)benzoate 8c with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.8 Hz, 2H, CH2), 7.70 (d, J = 8.8 Hz, 2H, CH1), 3.94
3
(s, 3H, CH3 ). Incorporation expected at δ 8.14. Determined against integral at δ 3.94. Following
General Procedure A, results are reported as (a) amount of substrate; (b) amount of catalyst; (c)
reaction time; (d) reaction temperature; and (e) level of incorporation.
Run 1: (a) 8c, 0.044 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 27%
Run 2: (a) 8c, 0.044 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 36%

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3.3.10. Deuteration of Methyl 4-chlorobenzoate 8d with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.9 Hz, 2H, CH2), 7.36 (d, J = 8.9 Hz, 2H, CH1), 3.90
3
(s, 3H, CH3 ). Incorporation expected at δ 7.93. Determined against integral at δ 3.90. Following
General Procedure A, results are reported as (a) amount of substrate; (b) amount of catalyst; (c)
reaction time; (d) reaction temperature; and (e) level of incorporation.
Run 1: (a) 8d, 0.039 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 91%
Run 2: (a) 8d, 0.039 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 94%
3.3.11. Deuteration of Methyl 4-methoxybenzoate 8e with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 7.96 (d, J = 9.0 Hz, 2H, CH3), 6.89 (d, J = 9.0 Hz, 2H, CH2), 3.85
4
1
(s, 3H, CH3 ), 3.82 (s, 3H, CH3 ). Incorporation expected at δ 7.96. Determined against integral at
δ 3.82. Following General Procedure A, results are reported as (a) amount of substrate; (b) amount of
catalyst; (c) reaction time; (d) reaction temperature; and (e) level of incorporation.
Run 1: (a) 8e, 0.038 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 87%
Run 2: (a) 8e, 0.038 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 90%
3.3.12. Deuteration of n-Propyl 4-methoxybenzoate 10a with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 8.00 (d, J = 9.2 Hz, 2H, CH3), 6.92 (d, J = 9.2 Hz, 2H, CH2), 4.25
1
5
6
(t, J = 6.8 Hz, 2H, CH4), 3.86 (s, 3H, CH3 ), 1.82–1.73 (m, 2H, CH2 ), 1.02 (t, J = 7.3 Hz, 3H, CH3 ).
Incorporation expected at δ 8.00. Determined against integral at δ 3.86. Following General Procedure A,
results are reported as (a) amount of substrate; (b) amount of catalyst; (c) reaction time; (d) reaction
temperature; and (e) level of incorporation.
Run 1: (a) 10a, 0.042 g, 0.215 mmol; (b) 1a, 10.9 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 28%
Run 2: (a) 10a, 0.038 g, 0.215 mmol; (b) 1a, 10.9 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 27%

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3.3.13. Deuteration of 2,2,2-Trifluoroethyl 4-methoxybenzoate 10b with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 8.06 (d, J = 9.3 Hz, 2H, CH3), 6.97 (d, J = 9.3 Hz, 2H, CH2), 4.69
4
1
(q, 3JH-F = 8.5 Hz, 2H, CH2 ), 3.90 (s, 3H, CH3 ). Incorporation expected at δ 8.06. Determined against
integral at δ 3.90. Following General Procedure A, results are reported as (a) amount of substrate; (b)
amount of catalyst; (c) reaction time; (d) reaction temperature; and (e) level of incorporation.
Run 1: (a) 10b, 0.050 g, 0.215 mmol; (b) 1a, 10.9 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 9%
Run 2: (a) 10b, 0.050 g, 0.215 mmol; (b) 1a, 10.9 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 7%
3.3.14. Deuteration of t-Butyl 4-methoxybenzoate 10c with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.7 Hz, 2H, CH3), 6.89 (d, J = 8.9 Hz, 2H, CH2), 3.85
1
4
(s, 3H, CH3 ), 1.58 (s, 9H, CH3 ). Incorporation expected at δ 7.94. Determined against integral at
δ 3.85. Following General Procedure A, results are reported as (a) amount of substrate, (b) amount of
catalyst, (c) reaction time, (d) reaction temperature, and (e) level of incorporation.
Run 1: (a) 10c, 0.045 g, 0.215 mmol; (b) 1a, 10.9 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 10%
Run 2: (a) 10c, 0.045 g, 0.215 mmol; (b) 1a, 10.9 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 9%
3.3.15. Deuteration of Iso-propyl 4-methoxybenzoate 10d with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 7.97 (d, J = 9.0 Hz, 2H, CH3), 6.89 (d, J = 9.0 Hz, 2H, CH2), 5.20
1
5
(septet, J = 6.3 Hz, 1H, CH4), 3.84 (s, 3H, CH3 ), 1.33 (d, J = 6.5 Hz, 6H, CH3 ). Incorporation
expected at δ 7.97. Determined against integral at δ 3.84. Following General Procedure A, results are
reported as (a) amount of substrate; (b) amount of catalyst; (c) reaction time; (d) reaction temperature;
and (e) level of incorporation.
Run 1: (a) 10d, 0.042 g, 0.215 mmol; (b) 1a, 10.9 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 79%
Run 2: (a) 10d, 0.042 g, 0.215 mmol; (b) 1a, 10.9 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 66%

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3.3.16. Deuteration of Benzyl 4-methoxybenzoate 10e with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 8.04 (d, J = 9.0 Hz, 2H, CH3), 7.45–7.43 (m, 2H, CH5), 7.40–7.37
4
(m, 2H, CH6), 7.35–7.32 (m, 1H, CH7), 6.92 (d, J = 9.0 Hz, 2H, CH2), 5.34 (s, 2H, CH2 ), 3.90 (s, 3H,
1
CH3 ). Incorporation expected at δ 8.04. Determined against integral at δ 3.90. Following General
Procedure A, results are reported as (a) amount of substrate; (b) amount of catalyst; (c) reaction time;
(d) reaction temperature; and (e) level of incorporation.
Run 1: (a) 10e, 0.052 g, 0.215 mmol; (b) 1a, 10.9 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 73%
Run 2: (a) 10e, 0.052 g, 0.215 mmol; (b) 1a, 10.9 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 51%
3.4. Temperature Effects
For the results relating to Scheme 3, readers are directed to the spectroscopic data in the relevant
parts of Section 3.3 for the analysis of the corresponding deuterated esters 6a–c and 8a–c. As catalyst
type and amount used are the only variables changed, the remaining results are tabulated below. In all
cases, 0.215 mmol of substrate was employed with 10.1 mg of catalyst 1a (0.01 mmol, 5 mol %) and
the reactions run at 40 °C, otherwise following General Procedure A, and the results shown below in
Table 4.
Table 4. Deuteration of Esters 6a–c and 8a–c at 40 °C.
Entry
Substrate
%D (run 1)
%D (run 2)
1
2
3
4
5
6
6a
6b
6c
8a
8b
8c
85
89
95
75
96
92
86
91
96
76
95
93
3.5. Catalyst Counterion Effects
3.5.1. Deuteration of n-Propyl 4-methoxybenzoate 10a with Complex 1d
Following General Procedure A, results are reported as (a) amount of substrate; (b) amount of
catalyst; (c) reaction time; (d) reaction temperature; and (e) level of incorporation.
(a) 10a, 0.042 g, 0.215 mmol; (b) 1d, 18.6 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 89%
3.5.2. Deuteration of 2,2,2-Trifluoroethyl 4-methoxybenzoate 10b with Complex 1d
Following General Procedure A, results are reported as (a) amount of substrate; (b) amount of
catalyst; (c) reaction time; (d) reaction temperature; and (e) level of incorporation.

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(a) 10b, 0.050 g, 0.215 mmol; (b) 1d, 18.6 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 24%
3.5.3. Deuteration of t-Butyl 4-methoxybenzoate 10c with Complex 1d
Following General Procedure A, results are reported as (a) amount of substrate; (b) amount of
catalyst; (c) reaction time; (d) reaction temperature; and (e) level of incorporation.
(a) 10c, 0.045 g, 0.215 mmol; (b) 1d, 18.6 mg, 0.01 mmol; (c) 1 h, (d) 25 °C; and (e) 41%
3.5.4. Deuteration of iso-Propyl 4-methoxybenzoate 10d with Complex 1d
Following General Procedure A, results are reported as (a) amount of substrate; (b) amount of
catalyst; (c) reaction time; (d) reaction temperature; and (e) level of incorporation.
(a) 10d, 0.042 g 0.215 mmol; (b) 1d, 18.6 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 94%.
3.5.5. Deuteration of Benzyl 4-methoxybenzoate 10e with Complex 1d
Following General Procedure A, results are reported as (a) amount of substrate; (b) amount of
catalyst; (c) reaction time; (d) reaction temperature; and (e) level of incorporation.
(a) 10e, 0.052 g, 0.215 mmol; (b) 1d, 18.6 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 89%.
3.6. Chemoselectivity Studies
3.6.1. Deuteration of Ethyl 4-nitrobenzoate 12 with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 8.27 (d, J = 9.0 Hz, 2H, CH1), 8.19 (d, J = 8.3 Hz, 2H, CH2), 4.42
3
4
(q, J = 7.5 Hz, 2H, CH2 ), 1.41 (t, J = 7.5 Hz, 3H, CH3 ). Incorporation expected at δ 8.27 and 8.19.
Determined against integral at δ 1.41. Following General Procedure A, results are reported as (a)
amount of substrate; (b) amount of catalyst; (c) reaction time; (d) reaction temperature; and (e) level of
incorporation at position 1 and position 2.
Run 1: (a) 12, 0.042 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 1: 72%, 2: 49%
Run 2: (a) 12, 0.042 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 1: 72%, 2: 52%
3.6.2. Deuteration of N,N-Diethyl 4-nitrobenzamide 13 with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 8.28 (d, J = 8.9 Hz, 2H, CH1), 7.57 (d, J = 8.9 Hz, 2H, CH2),
3
4
3.17–3.53 (m, 4H, CH2 ), 1.25 (br s, 6H, CH3 ). Incorporation expected at δ 8.28 and 7.57. Determined

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against integral at δ 1.25. Following General Procedure A, results are reported as (a) amount of
substrate; (b) amount of catalyst; (c) reaction time; (d) reaction temperature; and (e) level of
incorporation at position 1 and position 2.
Run 1: (a) 13, 0.047 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 1: 89%, 2: 93%.
Run 2: (a) 13, 0.047 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h, d) 25 °C, and (e) 1: 94%, 2: 93%.
3.6.3. Deuteration of 4-Nitroacetophenone 14 with Complex 1a
O
2
3
1
O2N
14
1H-NMR (400 MHz, CDCl3): δ 8.32 (d, J = 8.9 Hz, 2H, CH1), 8.11 (d, J = 8.9 Hz, 2H, CH2), 2.69
3
(s, 1H, CH3 ). Incorporation expected at δ 8.32 and 8.11. Determined against integral at δ 2.69.
Following General Procedure A, results are reported as (a) amount of substrate; (b) amount of catalyst;
(c) reaction time; (d) reaction temperature; and (e) level of incorporation at position 1 and position 2.
Run 1: (a) 14, 0.0467 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 1: 28%, 2: 97%
Run 2: (a) 14, 0.0467 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 25 °C; and (e) 1: 33%, 2: 85%
3.7. Rate Studies
3.7.1. Deuteration of Ethyl 4-nitrobenzoate 12 with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 8.27 (d, J = 9.0 Hz, 2H, CH1), 8.19 (d, J = 8.3 Hz, 2H, CH2). 4.42
3
4
(q, J = 7.5 Hz, 2H, CH2 ), 1.41 (t, J = 7.5 Hz, 3H, CH3 ). Incorporation expected at 1: δ 8.27 and 2: δ
8.19. Determined against integral at δ 1.41. Following General Procedure B, results are reported as (a)
amount of substrate; (b) amount of catalyst; (c) reaction time; (d) reaction temperature; and (e) level of
incorporation at position 1 and 2 at each time interval.
Labelling at Position 1: (a) 12, 0.399 g, 2.15 mmol; (b) 1a, 2.17 mg, 0.0215 mmol; (c) 18 h; (d) 25 °C;
and (e) 21% (10 min), 37% (20 min), 47% (30 min), 56% (40 min), 61% (50 min), 64% (1 h), 73% (2 h),
and 76% (18 h).
Labelling at Position 2: (a) 12, 0.399 g, 2.15 mmol; (b) 1a, 2.17 mg, 0.0215 mmol; (c) 18 h; (d) 25 °C;
and (e) 2: 14% (10 min), 24% (20 min), 33% (30 min), 37% (40 min), 41% (50 min), 43% (1 h), 52%
(2 h), and 56% (18 h).

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3.7.2. Deuteration of 4-Nitroacetophenone 14 with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 8.32 (d, J = 8.9 Hz, 2H, CH1), 8.11 (d, J = 8.9 Hz, 2H, CH2), 2.69
3
(s, 1H, CH3 ). Incorporation expected at δ 8.32 and 8.11. Determined against integral at δ 2.69.
Following General Procedure B, results are reported as (a) amount of substrate; (b) amount of catalyst;
(c) reaction time; (d) reaction temperature; and (e) level of incorporation at position 1 and 2 at each
time interval.
Labelling at Position 1: (a) 14, 0.355 g, 2.15 mmol; (b) 1a, 2.12 mg, 0.021 mmol; (c) 18 h; (d) 25 °C;
and (e) 8% (10 min), 13% (20 min), 19% (30 min), 26%(40 min), 29% (50 min), 33% (1 h), 65% (2 h),
69% (18 h).
Labelling at Position 2: (a) 14, 0.0467 g, 2.15 mmol; (b) 1a, 2.12 mg, 0.01 mmol; (c) 18 h; (d) 25 °C;
and (e) 54% (10 min), 75% (20 min), 82% (30 min), 84% (40 min), 85% (50 min), 85% (1 h), 91%
(2 h), 95% (18 h).
3.8. Practical Exploitation of Directing Group Chemoselectivity
3.8.1. Deuteration of 4-Nitroacetophenone 14 with Complex 1a
1H-NMR (400 MHz, CDCl3): δ 8.32 (d, J = 8.9 Hz, 2H, CH1), 8.11 (d, J = 8.9 Hz, 2H, CH2), 2.69
3
(s, 1H, CH3 ). Incorporation expected at δ 8.32 and 8.11. Determined against integral at δ 2.69. See the
details within Section 3.6.3.
3.8.2. Deuteration of 4-Nitroacetophenone 14 with Complex 1a
Following General Procedure A, results are reported as (a) amount of substrate; (b) amount of catalyst;
(c) reaction time, (d) reaction temperature, and (e) level of incorporation at position 1 and position 2.
(a) 14, 0.035 g, 0.215 mmol; (b) 1a, 10.1 mg, 0.01 mmol; (c) 1 h; (d) 40 °C; and (e) 1: 97%, 2: 97%
3.8.3. Hydrogenation of 4-Nitroacetophenone-d4 19 with Complex 1a
Following General Procedure A (deuterium gas was replaced with hydrogen gas), results are
reported as (a) amount of substrate; (b) amount of catalyst; (c) reaction time; (d) reaction temperature;
and (e) level of incorporation of deuterium at position 1 and position 2.
(a) 19, 0.0363 g, 0.215 mmol; (b) 1a, 2.1 mg, 0.0021 mmol; (c) 1 h; (d) 25 °C; and (e) 1: 90%, 2: 12%.

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4. Computational Details
DFT [39] was employed to calculate the gas-phase electronic structures and energies for all species
involved in H/D exchange reactions. All structures have been optimised with the hybrid meta-GGA
exchange correlation functional M06 [40]. The M06 density functional was used in conjunction with
the 6-31G(d) basis set for main group non-metal atoms and the Stuttgart RSC [41] effective core
potential along with the associated basis set for Ir. The participating transition states (TS) are located at
the same level of theory. Harmonic vibrational frequencies are calculated at the same level of theory to
characterize respective minima (reactants, intermediates, and products with no imaginary frequency)
and first order saddle points (TSs with one imaginary frequency). The validity of using the 6-31G(d)
basis set has previously been checked by comparative single point energy calculations employing the
def2-TZVP basis set for all atoms on similar H/D exchange systems [20]. All calculations using the
M06 functional have been performed using Gaussian 09 quantum chemistry program package (version
A.02). Calculations were first carried out in the gas phase before reoptimising each structure at the same
level of theory, implementing the Polarizable Continuum Model (PCM) for DCM as the solvent [42].
All coordinates provided are listed in Cartesian format, with charge and multiplicity of each system
given at the top of the coordinate list (i.e., 0 1 = neutral singlet; 1 1 = 1 + charged singlet).
5. Conclusions
In summary, we have divulged novel iridium-catalysed methods for the ortho-deuteration of benzoate
esters by the application of complexes emerging from our laboratory, possessing a bulky NHC/phosphine
combination. Inherent variability in reproducibly labelling ester substrates to useable levels of
D-incorporation was solved by two methods: (i) a mild increase in reaction temperature; and (ii) a switch
in the catalyst anion from PF6 to BArF; this delivered good to excellent levels of deuterium incorporation
adjacent to ester directing groups. Kinetic studies on intramolecular directing group chemoselectivity
revealed that selectivity vs. time is substrate dependent, showing the possibility that different levels of
binding conformer equilibria are possible. Supporting DFT analyses of the systems studied experimentally
support previous findings that suggested the most stable binding conformer is also the most reactive.
We have demonstrated that such knowledge can be exploited experimentally and, as such, we have
shown that different modes of regioselective labelling is possible in a multifunctional substrate by
simple variation of the reaction conditions. Overall, we believe that these methods further enhance the
applicable substrate scope and wider utility of the iridium complexes at the centre of this study.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/07/11676/s1.
Acknowledgments
The authors would like to thank the Carnegie Trust for the Universities of Scotland (M.R.) for
funding. Mass spectrometry data were acquired at the EPSRC UK National Mass Spectrometry Facility
at Swansea University.

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Author Contributions
The project was devised by W.J.K. and M.R. Experimental results were obtained by J.D. and
T.J.D.M. Computational analysis was conducted by M.R. with consultation from T.T. The manuscript
was prepared by D.M.L., M.R., and W.J.K.
Conflicts of Interest
The authors declare no conflict of interest.
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