The synthesis of highly active iridium(i) complexes and their application in catalytic hydrogen isotope exchange

Article abstract of DOI:10.1002/adsc.201400730

A series of robust iridium(I) complexes bearing a sterically encumbered N-heterocyclic carbene ligand, alongside a phosphine ligand, has been synthesised and investigated in hydrogen isotope exchange processes. These complexes have allowed isotope incorpo

Full text of DOI:10.1002/adsc.201400730

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DOI: 10.1002/adsc.201400730
The Synthesis of Highly Active Iridium(I) Complexes and their
Application in Catalytic Hydrogen Isotope Exchange
Jack A. Brown,a Alison R. Cochrane,a Stephanie Irvine,a William J. Kerr,a,*
Bhaskar Mondal,a John A. Parkinson,a Laura C. Paterson,a Marc Reid,a
Tell Tuttle,a Shalini Andersson,b and Gçran N. Nilssonb
a
Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow
G11XL, Scotland, U.K.
Fax : (+44)-141-548-4822; phone: (+44)-141-548-2959; e-mail: w.kerr@strath.ac.uk
Medicinal Chemistry, AstraZeneca, R&D Mçlndal, SE-431 83 Mçlndal, Sweden
b
Received: July 25, 2014; Published online: October 2, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400730.
Abstract: A series of robust iridium(I) complexes preparative approaches. Furthermore, a number of
bearing a sterically encumbered N-heterocyclic car- industrially-relevant drug molecules has also been la-
bene ligand, alongside a phosphine ligand, has been belled, including the sulfonamide containing drug,
synthesised and investigated in hydrogen isotope ex- Celecoxib. Alongside detailed NMR experiments, in-
change processes. These complexes have allowed iso- itial mechanistic investigations have also been per-
tope incorporation over a range of substrates with formed, providing insight into both substrate binding
the use of practically convenient deuterium and triti- energies, and, more importantly, relative energies of
um gas. Moreover, these active catalysts are capable key steps in the mechanistic cycle as part of the over-
of isotope incorporation to particularly high levels, all exchange process.
whilst employing low catalyst loadings and in short
reaction times. In addition to this, these new catalyst
species have shown flexible levels of chemoselectivi- Keywords: catalysis; deuterium; hydrogen isotope
ty, which can be altered by simple manipulation of exchange; iridium; tritium
Introduction
Despite colossal financial commitment to drug discov-
ery, the pharmaceutical industry is burdened by un-
sustainable attrition rates associated with new chemi-
cal entities. Accordingly, positioning metabolism and
pharmacokinetic studies earlier in such discovery pro-
grammes is crucial in assessing the overall properties
of a drug candidate and as aligned to reducing the
Scheme 1. Ideal hydrogen isotope exchange process.
Whilst various transition metal species have demon-
present levels of attrition of over 90%.[1] One key strated activity within the field of HIE,[3–6] for
methodology applied extensively within this area is a number of years [IrACHTUNRGTENNUG(COD)CAHTUNGTRENN(GUN PCy3)(py)]PF6, Crab-
isotopic labelling, which allows the biological fate of treeꢀs catalyst,[7] was regarded as the industry standard
a potential drug molecule to be carefully monitored.[2] to facilitate such a process. This iridium-based com-
In particular, transition metal-catalysed hydrogen iso- plex demonstrates appreciable activity in the labelling
tope exchange (HIE) offers a simple and direct tech- of a range of substrates, however, it is often found
nique, which potentially allows the regioselective la- that (super-)stoichiometric quantities of the catalyst
belling of fully functionalised molecules (Scheme 1), and lengthy reaction times are required to deliver the
eliminating the need for any additional synthetic pro- observed levels of isotope incorporation.[8] In addi-
cesses or prolonged preparative pathways associated tion, tritiation reactions promoted by Crabtreeꢀs cata-
with the installation of an isotopic label.
lyst frequently produce considerable quantities of ra-
dioactive waste, which is a clear drawback with
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Jack A. Brown et al.
Table 1. Preparation of iridium complexes.[a]
regard to both cost and environmental concerns.[2c,9]
In view of the issues associated with Crabtreeꢀs cata-
lyst, it is evident that alternative metal-based com-
plexes for use in hydrogen isotope exchange would be
beneficial to pharmaceutical partners with, in particu-
lar, the desired catalysts being capable of labelling an
assortment of substrates to high levels of incorpora-
tion under mild reaction conditions and with lowered
catalyst loadings. Following the work of Nolan[10] and
Buriak[11] in the field of olefin hydrogenation, we felt
that in order to enhance catalytic activity in HIE pro-
cesses, relative to Crabtreeꢀs catalyst, greater steric
demand around the metal centre, coupled with bal-
anced electronic parameters, was required.[12] In this
regard, we have reported on the preparation and ap-
plication of a series of new iridium complexes bearing
a bulky N-heterocyclic carbene (NHC), 1,3-bis(2,4,6-
trimethylphenyl)imidazol-2-ylidene (IMes), alongside
an appreciably encumbered phosphine, and which
have appreciable potential as highly active catalysts
Entry
PR3
Complex
Yield[b]
1
2
3
4
5
PPh3
PBn3
PMe2Ph
PMePh2
PACTHNUTRGNEN(UG O-i-Pr)3
5a
5b
5c
5d
5e
62
59
71
69
75
[a]
Reaction conditions: (a) NaOEt, PhH, room temperature,
10 min. (b) 4, PhH, room temperature, 5 h. (c) AgPF6,
THF, room temperature, 30 min. (d) PR3, THF, room
temperature, 2 h.
[b]
Isolated yields.
for HIE with deuterium.[13] Additionally, we have exchange across a wide range of substrates (6a–i) in-
shown that these robust and practically accessible iri- cluding ketones, amides, and heterocyclic functionali-
dium species can be applied within the selective re- ties (Table 2). In general, compounds 7a–g, which are
duction of alkenes (and alkynes)[14] and in the Z-selec- labelled via a 5-membered metallocyclic intermediate
tive dimerization of terminal alkynes.[15]
(5-mmi), were delivered with high deuterium incorpo-
Herein, we report the activity and selectivity spec- rations in a regioselective and reproducible manner.
trum of this class of iridium complex in the area of Furthermore, the isotopic labelling of weakly coordi-
deuterium and, importantly, tritium labelling, as well nating nitrobenzene, 6g, proceeded without incident
as our initial investigations into the overall mecha- and with no reduction of the nitro moiety, as has been
nism of the hydrogen isotope exchange process with detected with previously employed catalysts.[5f,8b] It is
these emerging catalyst species.
important to highlight that the levels of isotope ex-
change in benzamide, 6c, were somewhat more varia-
ble, ranging from 32% in the presence of complex 5a,
to 90% in reactions catalysed by complex 5d. Indeed,
this substrate is notoriously difficult to label effective-
Results and Discussion
First of all, and importantly in a practical sense, ly, with 110 mol% of Crabtreeꢀs catalyst being previ-
a robust and readily utilisable route to our novel Ir(I) ously required to deliver the isotopically-enriched
complexes bearing a sterically encumbered NHC in product with only a moderate 65% D incorpora-
conjunction with a bulky tertiary phosphine ligand tion.[8b] The examination of additional substrates re-
was achieved according to a variation of a procedure vealed the ability of our novel Ir(I) complexes to also
delineated by Herrmann.[16] The use of sodium ethox- facilitate isotope exchange in C H units positioned
ꢀ
ide in the relatively weakly coordinating solvent, ben- five bonds away from the required coordinating func-
zene, was crucial to allow the in situ generation and tionality i.e., via a 6-membered metallocyclic inter-
introduction of the NHC ligand, avoiding the necessi- mediate (6-mmi). This process is believed to be ener-
ty to pre-form and isolate the free carbene species getically more demanding and, as such, often leads to
under glove-box conditions. Following this modified lower levels of deuteration. In our hands, the simplest
synthetic route, five novel Ir(I) complexes were deliv- substrate of this class, acetanilide, 6h, was labelled up
ered in good yields (Table 1). These bright red cata- to an excellent 95% D loading. Furthermore, deuteri-
lysts are air- and moisture-stable crystalline solids, um incorporation in benzanilide, 6i, occurred with
and have been characterised by NMR and mass spec- high degrees of exchange observed in positions la-
tral techniques. In addition, the structures of complex belled via both a 5-mmi and a 6-mmi.
5a–c have been confirmed by X-ray crystallogra-
To further explore the capabilities of our com-
plexes, a series of rate and activity studies was per-
phy.[13a]
Under the standard reaction conditions developed formed. A loading study revealed that excellent deu-
within our laboratory, employing a catalyst loading of terium incorporation is maintained in the presence of
5 mol% in DCM under 1 atmosphere of D2 gas for catalyst quantities as low as 0.5 mol% (Scheme 2).
16 h, complexes 5a–e facilitated high levels of H/D Furthermore, whereas catalyst 5a mediated the 97%
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The Synthesis of Highly Active Iridium(I) Complexes and their Application
Table 2. HIE studies with complexes 5a–e.[a,b]
(Table 2), benzanilide substrates offer two potential
sites of labelling, through either a 5- or 6-mmi. It was
therefore proposed that the emerging catalysts had
the potential to exert regioselective deuteration in
substrates of this type. Such discrimination of H/D ex-
change in one position over another would be of par-
ticular benefit to pharmaceutical partners, allowing
specific drug metabolites to be traced preferentially
during in vivo distribution studies. In an attempt to
establish such selective HIE, the labelling of benzani-
lide 6j was studied. As illustrated in Scheme 3, the
use of 5 mol% of complex 5c delivered appreciably
high levels of isotope incorporation in both positions
a and b. In contrast, reducing the amount of catalyst
present in the reaction system to 0.5 mol% resulted in
a significant decline in the degree of labelling ob-
served in position b, via a 6-mmi, while the elevated
level of exchange in position a, proceeding via the
more favourable 5-mmi, was maintained. A similar
result was obtained with the benzanilide derivative
6k, which is capable of labelling through both a 5-
and a 6-mmi at three possible sites in the molecule.
At a 5 mol% catalyst loading, complex 5c showed ex-
cellent levels of incorporation into positions a and
b (both via a 5-mmi), while position c (via a 6-mmi)
showed more moderate D uptake. Pleasingly, when
the catalyst loading was reduced to 0.5 mol%, not
only did we again observe exclusive labelling via the
5-mmi over the 6-mmi, there was also selectivity
noted between positions a and b. The preferential la-
belling at position a suggests more effective iridium
metal centre coordination with the more available
oxygen lone pairs within the amide carbonyl group
over the oxygen atoms of the nitro unit.
[a]
5 mol% of Ir catalyst employed over 16 h.
Average incorporation into the positions shown over two
[b]
separate reaction runs; the percentage given refers to the
level of D incorporation over the total number of posi-
tions shown, for example, 97% for the two possible posi-
tions in 7a indicates 1.94 D incorporation.
Based on these findings, it was envisaged that our
overall protocols could be manipulated to achieve se-
lective labelling into a position labelled via a 6-mmi
(Scheme 4). This was accomplished by employing the
heavily labelled compound 7j (a: 96%; b; 93%) as
substrate with H2 to allow H exchange at position a,
leaving the deuterium in place at position b. As
Scheme 2. Catalyst loading and labelling time study.
deuteration of 6a within 120 min, more electron-rich
catalysts, 5b and 5c, delivered more rapid labelling
(60 and 90 min, respectively). Presumably, the more
ꢀ
electron-rich catalysts better facilitate the C H acti-
vation process central to the H/D exchange reac-
tion.[17]
The excellent levels of efficiency displayed by these
complexes prompted us to examine their catalytic ac-
tivity further. As demonstrated in the labelling of 6i Scheme 3. Labelling selectivity for a 5-mmi over a 6-mmi.
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Table 4. Catalyst turnover.
Scheme 4. Selective removal of the D label via the 5-mmi.
Entry
L1/L2 (catalyst)
% D
TON[a]
TOF[b]
1
2
IMes/PBn3 (5b)
Py/Ph3P (Crabtreeꢀs)
88
29
1056
348
176
58
shown in Scheme 4, employing 5 mol% of complex 5c
under an atmosphere of hydrogen resulted in the se-
lective removal of deuterium via the 5-mmi, while the
level of D at position b remained high. Accordingly,
this section of our study has shown that it is now pos-
sible to access both classes of selectively labelled
compounds, which illustrates a further distinct practi-
[a]
Measured as no. moles of substrate converted/no. moles
of catalyst employed.
Measured as no. moles of substrate converted/no. moles
of catalyst employed/hours.
[b]
cal advantage delivered by these novel iridium cata- 7m. In addition to the high level of D uptake ob-
lyst systems. To the best of our knowledge, this level tained in position b, the D incorporation at position
of labelling selectivity by this direct approach is un- a represents the first example of deuterium labelling
precedented in the literature.
adjacent to a primary sulfonamide moiety as facilitat-
To further illustrate the capabilities of these cata- ed by complexes of this type,[18] albeit at relatively
lysts, a number of available drug molecules was ap- moderate levels. Furthermore, Sanofi–Aventisꢀ anti-
plied in hydrogen isotope exchange reactions. The androgen Nilutamide, 7n, provides a further example
ability to label fully functionalised drug scaffolds is of preferential labelling via a 5-mmi over a 6-mmi.
central to the application of HIE catalysis, especially
Following the exploration of substrate scope, we
as aligned to the endeavours of pharmaceutical part- sought to gain further insight regarding the effective-
ners. Pleasingly, complexes 5a–c performed very well ness of our novel system via the analysis of catalyst
with a series of drug substrates at relatively low cata- turnover. As shown in Table 4, the deuteration of ace-
lyst loadings and over short reaction times (7l–o; tophenone using catalyst 5b delivered very good turn-
Table 3). Of particular note is the high level of D in- over within a 6 h reaction period, using extremely low
corporation in the Pfizer COX-2 inhibitor, Celecoxib, levels of catalyst. Under the same conditions, Crab-
treeꢀs catalyst showed a vastly reduced efficiency; pre-
sumably due to its lower relative activity and instabili-
Table 3. HIE studies with marketed drug molecule sub-
strates.
ty over time.[12]
Mechanistic Investigations
Although the mechanism of iridium-catalysed HIE
was proposed by Heys in 1996,[5d] there exists only
limited evidence to support the perceived sequence of
events.[5o] Therefore, we were interested in embarking
upon focused mechanistic investigations to increase
the general comprehension of such catalysed hydro-
gen isotope exchange process. Furthermore, by em-
bedding our emerging iridium complex class within
this study, we envisaged that any enhanced under-
standing could provide beneficial foundations to be
used in the design of future catalyst systems.
Initially and to this end, an exchange reaction was
carried out in an NMR tube, using deuterated di-
chloromethane, to allow us to monitor two key fea-
[a]
tures in the proposed pathway: the initial removal of
5 mol% of Ir catalyst employed over 16 h.
[b]
the cyclooctadiene (COD) unit from the iridium com-
plex, and the resultant geometry of the major ligands
around the metal centre. Since the formation of iridi-
10 mol% of Ir catalyst employed over 1 h.
2.5 mol% of Ir catalyst employed over 1 h.
5 mol% of Ir catalyst employed over 1 h.
[c]
[d]
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The Synthesis of Highly Active Iridium(I) Complexes and their Application
um hydrides is thought to be central to the removal
of the COD ligand, the reverse exchange reaction
(Scheme 5) was carried out by employing fully deuter-
ated acetophenone 9 and exchanging with hydrogen
gas, in an attempt to observe any potential Ir-hydride
species. Complex 5a was chosen as this is the slowest
acting of this series of catalysts, with 10 mol% being
Scheme 5. Reverse exchange reaction monitored in an NMR
employed in order to fully observe intermediate com- tube.
Figure 1. 1H (top) and 31P (bottom) NMR spectra of complex 5a in CD2Cl2.
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plexes and reaction progression by NMR analysis (see reaction solvent. Following the initial addition of hy-
1
the Supporting Information for full details).
drogen gas, several peaks emerged in the H NMR
Prior to the monitoring of the reaction, it was nec- spectrum in the region of ꢀ13–0 ppm, indicating the
essary to gather data on the parent complex, to allow presence of the expected iridium hydrides. The reac-
the detection of any changes that occur as the overall tion was then further monitored to assess the reduc-
process progresses. Accordingly, 1H and 31P NMR tion and removal of the COD ligand, as shown by the
spectra of complex 5a were obtained in CD2Cl2. The disappearance of the multiplet peaks at 4.39–4.36 and
1
most relevant H spectrum peaks at the beginning of 3.35–3.33 ppm; importantly, following this further
the reaction were the multiplets at 4.39–4.36 and analysis the peaks corresponding to the iridium hy-
3.35–3.33 ppm, as shown in Figure 1. These peaks cor- drides had also disappeared, suggesting that these hy-
respond to the olefinic protons of the COD ligand, drides play a key role in the removal of the COD
and are expected to lose intensity and disappear at ligand. Furthermore, in the absence of the COD
the beginning of the reaction as the COD is reduced. ligand, 31P NMR analysis showed that the original
With regard to the 31P NMR, the peak present at phosphine signal (16.35 ppm) had been replaced with
16.35 ppm corresponds to the phosphine ligand bound a new peak at 20.80 ppm, indicating that the parent
to the metal centre.
complex had been fully converted to an alternative
Figure 2 shows a 2D 31P/13C HMQC experiment of phosphorus-containing iridium species within the re-
2
the same parent complex 5a. This allowed the JP, C action manifold.
coupling constant between the bound phosphorus
To further investigate the new COD-free iridium
atom and the carbon of the carbene ligand to be es- intermediate, a second 2D HMQC 13C/31P correlation
tablished. It was envisaged that by carrying out this spectrum was obtained. As illustrated in Figure 3, the
correlation experiment as the reaction proceeds, the carbene carbon signal at 177 ppm had been replaced
2
observed magnitude of this JP, C coupling constant by a new signal at ~160 ppm. This change in chemical
would provide some indication of the geometry of the shift was accompanied by a correlation to the phos-
two major ligands. As presented in Figure 2, a distinct phine signal at 20.80 ppm, and with an appreciably
2
correlation was observed between the bound phos- elevated JP, C coupling constant of 118 Hz. Indeed,
2
phine at 16.35 ppm and the carbene carbon at such large JP, C coupling constants in similar iridium
2
177 ppm. The JP, C coupling constant was measured at complexes, bearing phosphine and NHC ligands, have
8.6 Hz, in accord with these two ligands adopting some literature precedent. For example, iridium(I)
a cis-arrangement in the parent complex. In turn, we complex 11, depicted in Figure 4, has been shown to
were confident that the geometry of the ligands in have the triphenylphosphine and bis-benzyl NHC li-
any reaction intermediates could then be deduced by gands in a relative trans-arrangement.[19a] The data for
comparing the coupling constants obtained through- this compound reveal the carbene carbon of the NHC
2
out the reaction. Consequently, the reaction to have a chemical shift of 177.6 ppm and a JP, C cou-
(Scheme 5) was performed in an NMR tube using d5- pling constant of 116 Hz. In an analogous manner,
acetophenone 9 and hydrogen gas, with CD2Cl2 as the iridiumACHTUNTRGNEUNG(III) complex 12 has the triisopropylphosphine
Figure 2. 2D 31P/13C HMQC experiment of the parent com-
plex.
Figure 3. 2D 31P/13C HMQC spectrum of intermediate Ir
complex.
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The Synthesis of Highly Active Iridium(I) Complexes and their Application
Figure 4. Known Ir complexes with phosphine/NHC ligands
in a trans-arrangement.
Figure 6. Optimised structures of 13 and its isomers at DFT
level.
and IMes ligands in a trans-configuration, with a simi-
2
lar JP, C coupling constant value of 108 Hz.[19b] Howev- that the phosphine and NHC adopt a trans-orienta-
er, the chemical shift of the carbene carbon in this tion within the activated Ir species.
latter complex is significantly more upfield than that
Our DFT calculations were further expanded to
of complex 11, with a value of 165 ppm. From the evi- focus on the possible reaction pathway by which hy-
dence obtained regarding the activated catalytic spe- drogen isotope exchange proceeds. These more de-
cies in our HIE reaction, and from comparison with tailed investigations allowed the construction of the
available literature data,[19] it is proposed that the in- potential energy surface (PES) associated with the
termediate within this manifold has the phosphine proposed catalytic cycle. Using that suggested by
and NHC ligands in a trans geometry; furthermore, Heys as a basis,[5d] a mechanistic pathway employing
the 13C NMR chemical shift of the carbene carbon is our Ir(I) complexes in conjunction with acetophe-
consistent with this new catalytic intermediate pos- none, 6a, was determined (Scheme 6). It is proposed
sessing an iridium
G
that, following exposure to deuterium gas, complex 5a
To further support the above experimental evi- loses the COD ligand as d4-cyclooctane. The resulting
dence that the phosphine and NHC ligands align coordinately unsaturated Ir species is stabilised by co-
themselves in a trans-configuration, density functional ordination of the substrate, for example, 6a, delivering
theory (DFT) studies (see the Supporting Information
for full details on the level of theory used) were em-
ployed to calculate the relative energies of the pro-
posed cis- and trans-isomers of the intermediate iridi-
um species. Using Heysꢀ mechanism as a guide,[5d] the
most sterically hindered species along the catalytic
cycle is envisaged to be that formed subsequent to ox-
idative insertion with the substrate, for example, 13
with acetophenone (Figure 5). Therefore, the energet-
ic ordering of the possible isomers of 13 was investi-
gated to determine the probable active configuration
within the HIE manifold.
Potential orientations of the D2, hydride, and sub-
strate ligands were investigated; however, all alterna-
tive configurations converged to one of the three iso-
mers shown in Figure 6. In addition to the trans-
isomer 13, two cis-isomers were also optimised to
local minima on the potential energy surface (14 and
15, Figure 6). The relative energies of the three iso-
mers indicate that 14 and 15 are destabilised by 8.83
and 10.12 kcalmolꢀ1, respectively, relative to 13.
These findings support the experimental evidence
Figure 5. Oxidative addition intermediate in the catalytic
cycle.
Scheme 6. Proposed HIE catalytic cycle.
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16. Following oxidative addition to give 13, fluxionali- PMe3 (Table 5), the axial phosphine substituent has
ty of the dihydrogen hydride (13!17) allows isotopic a detectable impact on the energy of the oxidative ad-
hydrogen to orient in the position cis to the Ir C dition step, with a difference of 1.43 kcalmolꢀ1 calcu-
ꢀ
bond, resulting, ultimately, in reductive elimination lated for TS
A
(17!18) and isotope incorporation into the ortho-po- and the smaller PMe3.
sition of the substrate aryl ring, 7a’. In relation to
With regard to the key steps in our proposed cata-
modifications to Heysꢀ original mechanistic scheme, lytic cycle and considering the PPh3 system, the oxida-
ꢀ
we now believe that the initial activated iridium spe- tive addition of the iridium into the aryl C H bond,
cies is stabilised by association of the substrate form- requires a moderate activation enthalpy of 16.70 kcal
ing complex 16 in which the ortho aryl C H is agosti- molꢀ1 (Table 5, Figure 7). Furthermore, the conver-
ꢀ
cally coordinated to the iridium centre. Furthermore sion of 16 to 13 is endothermic by 3.66 kcalmolꢀ1 with
and in a more general sense, a series of 31P NMR respect to 16. The subsequent H/D exchange step
magnetization transfer experiments, analogous to the (13!17) is calculated to be rapid, with an activation
work of Grubbsꢀ within the field of ruthenium-cata- barrier of 2.25 kcalmolꢀ1. In contrast to oxidative in-
lysed olefin metathesis,[20] indicates that the phosphine sertion, reductive elimination is favoured enthalpical-
ligand does not dissociate from the iridium metal ly, presumably due to the decrease in steric strain
centre throughout the catalytic cycle (see the Sup- within the vicinity of the metal centre. Accordingly
porting Information for experimental details).
and based on this calculated PES, we can conclude
All of the intermediates and transition states in- that the rate-limiting step within such H/D exchange
volved in our proposed catalytic cycle, with the incor- processes appears to involve the oxidative addition or
ꢀ
poration of deuterium, have been fully optimised. reductive elimination of the ortho-C H bonds. In
Therefore, the enthalpy changes during the reaction a complementary experimental study, we strength-
progress have been monitored. Relative enthalpies of ened this argument by observing a primary kinetic
the stationary points on the PES and the barriers to isotope effect of approximately 3.7 (see the Support-
ꢀ
oxidative addition, H/D exchange, and reductive elim- ing Information for full details). This suggests that C
ination have also been calculated for each species H activation[21] is, indeed, rate-limiting.
shown in Scheme 6. In addition to the use of PPh3
Having established the relative reaction energetics
and in order to probe the possibility of performing in HIE reactions employing acetophenone, 6a, atten-
computational studies of more minimised cost, PMe3 tion turned to the reactivity of our catalysts with re-
was also investigated as the axial phosphine ligand spect to different target molecules. Such studies also
(Table 5). The decreased ligand size in the PMe3 sys- offered the potential to explain the selective labelling
tems does not alter the mechanism of the reaction, of substrates via a 5-mmi as opposed to a 6-mmi.
nor does it strongly affect the geometry of the ligands Three substrates were selected for investigation: ace-
around the equatorial plane, i.e., there is no large re- tophenone, 6a, 2-phenylpyridine, 6e, and acetanilide,
arrangement of the ligands and the changes in bond 6h (Figure 8).
lengths between the full (PPh3) systems and the trim-
In view of the similar energy values calculated for
med (PMe3) version are calculated to be in the region complexes bearing either PPh3 or PMe3 as the axial
of 0.02 ꢂ (see the Supporting Information for details). ligand, the remaining theoretical studies were per-
Comparing the calculated energetic parameters de- formed with the smaller tertiary phosphine ligand in
ꢀ
tected along the reaction path for both PPh3 and place. As our previous explorations had supported C
H activation as being rate-determining, the effects of
the alternative substrates were examined within this
portion of the catalytic process (Table 6). As revealed
Table 5. Relative energies (DE), enthalpies (DH), and Gibbs
by the activation enthalpy values the substrates label-
ling via a 5-mmi, acetophenone, 6a, and 2-phenylpyri-
dine, 6e, were found to be most active. The identifica-
tion of acetanilide, 6h, as the least active substrate
further supports our more general observations that
compounds which are labelled via a 6-mmi are less re-
active in our catalysed HIE reactions (vide supra).[5d]
Further theoretical calculations were performed to
determine the binding energies of the three substrates
under investigation (Table 7), since these had previ-
ously also been shown to influence labelling efficien-
cies.[22] The stabilisation energy, DHbind, resulting from
the complexation of the substrate to the iridium
metal, forming the species akin to 16, is calculated as
free energies (DG) for the catalytic cycle calculated at DFT
level (all are in kcalmolꢀ1).
DE[a]
DH[b]
DG[b]
PMe3
Species
PPh3
0.00
PMe3 PPh3
PMe3 PPh3
16
0.00 0.00
0.00 0.00
0.00
TS
ACHTUNGTRENNUNG(16-13) 17.21 18.14 16.70 18.13 18.65 18.35
13
TS
17
3.33
(13-17) 5.86
0.93
3.17
0.93
3.66
5.91
3.75
1.20
3.66
1.19
2.88
5.05
3.00
0.27
2.10
0.30
G
3.43
TS
ACHTUNGTRENNUNG
18
ꢀ0.42 ꢀ0.44 ꢀ0.45 ꢀ0.48 ꢀ0.41 ꢀ0.42
Energies are zero-point corrected.
All enthalpies and Gibbs free energies are at 298.15 K.
[a]
[b]
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The Synthesis of Highly Active Iridium(I) Complexes and their Application
Figure 7. The reaction PES employing Ph3P as the phosphine ligand.
values in Table 7, all complexes have a stabilising in-
teraction enthalpy with the substrates. It should be
noted that the values presented represent binding en-
thalpies, as opposed to free energies, and, as such, en-
tropic effects have not been accounted for. In all
cases, the entropic contribution will negatively affect
the stability of the complex relative to the separated
reactants.
As shown in Table 7, substrate 6e binds most
strongly to the iridium centre compared to other sub-
strates, presumably due to the better binding ability
of the more basic N atom, relative to a carbonyl O
atom. In addition, substrate 6h binds to the iridium
centre with a similar strength as displayed by sub-
strate 6a. In both cases the coordination proceeds via
interaction of the oxygen atom lone pair of electrons
to the metal core. Hence, it can be deduced that the
activation enthalpy, rather than the binding enthalpy,
dictates the more effective labelling via a 5- over a 6-
mmi.
Figure 8. Substrates used in the DFT calculations.
Table 6. Enthalpy changes for the oxidative addition step
with three different substrates.
DH[a,b]
Species
6a
6e
6h
16
0.00
18.13
1.20
0.00
17.53
2.73
0.00
23.04
5.11
TSACHTUNGTRENNUNG(16-13)
13
[a]
[b]
All enthalpy changes are in kcalmolꢀ1 at 298.15 K.
Calculations are based on the catalyst bearing the smaller
PMe3 ligand.
Table 7. Calculated binding energies (PR3 =PMe3).
Incorporation of Tritium
Substrate
6a
6e
6h
[a]
DHbind
ꢀ23.48
ꢀ31.42
ꢀ23.94
Following the success of our emerging iridium phos-
phine/carbene species for H/D exchange, and with an
improved understanding of the catalytic mechanism,
investigations were undertaken to ascertain whether
All relative enthalpies are in kcalmolꢀ1 at 298.15 K.
[a]
the difference in enthalpy between the enthalpy of these Ir species could also facilitate hydrogen–tritium
the optimised complex, 16, and the sum of the enthal- exchange reactions. Since radionuclides can be detect-
pies of the optimised substrate and the optimised ed more sensitively than stable isotopes, it is common
[(D2)IrACHTUNGTRENNUNG(PMe3)ACHTUNGTRENNUNG
(NHC)]+ complex. As illustrated by the practice within pharmaceutical laboratories to pre-
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Jack A. Brown et al.
pare both the stable isotopically-labelled molecule ated by-products being observed. Indeed, in previous
and the radio-labelled compound.[2c,9] Therefore, it studies we have revealed an appreciably different re-
was important to determine the activity of the devel- action profile, possessing an array of T-possessing by-
oped catalysts in the labelling of substrates with triti- products, when Crabtreeꢀs catalyst is employed.[9]
um. Due to the more challenging hydrogen–tritium
ꢀ
exchange process, based on the increased tritium tri-
tium bond strength, 5 mol% catalyst loading was re- Conclusions
quired. Nonetheless, over a relatively short reaction
time of only 2 h, a successful tritiation protocol was By embedding a bulky N-heterocyclic carbene ligand
achieved (Table 8).
in combination with different phosphine ligands,
Tritiation via a 5-mmi proved relatively facile with a series of highly active iridium-based catalysts has
high levels of T uptake being observed (19b, 19e, been developed for hydrogen isotope exchange. Such
19p). Perhaps as anticipated, hydrogen–tritium ex- catalysts have been shown to produce high incorpora-
change through a 6-mmi was less efficient, with only tions of deuterium and tritium adjacent to a good
7% incorporation achieved with acetanilide, 19h. As range of relevant functional units within a series of
anticipated, only the position activated through the 5- compounds, including pharmaceutically active agents.
mmi in 19j was labelled regioselectively and with Additionally, combined experimental and computa-
good levels of effectiveness. Of particular note was tional studies have led to a deeper understanding of
the extremely successful tritiation of the drug mole- the nature of such catalyst systems and the active spe-
cule Celecoxib, 19m; furthermore and in contrast with cies generated, as well the overall reaction mecha-
ꢀ
the analogous deuterium experiment, only the posi- nism. These investigations have indicated that the C
tions ortho to the pyrazole directing group displayed H activation process is the rate-limiting step within
ꢀ
tritium incorporation. With respect to all examples this HIE manifold. Furthermore, the C H activation
shown in Table 8, we were pleased to note that the event also constitutes the regiochemistry-determining
process was remarkably clean, with no significant triti- step when both 5- and 6-metallocyclic intermediates
are possible, leading to appreciable selectivities within
the established exchange processes.
ꢀ
With regards the pivotal C H activation, we be-
lieve that the electron-rich ligand set employed as
Table 8. Tritiation studies with catalysts 5a–c.[a,b]
part of the emerging catalyst systems is central to the
facilitation of the requisite oxidative addition step
within the catalytic cycle. Furthermore, the sterically
crowded ligand sphere will, in turn, aid reductive
elimination. In relation to this latter point, when steri-
cally less demanding phosphine/NHC combinations
were applied within our laboratory, the resulting com-
plexes displayed appreciably lowered activity within
HIE processes. It should also be noted that the bulky
NHC and phosphine ligands used within our series of
iridium complexes could provide the active catalytic
species, formed within the reaction manifold, with en-
hanced levels of stability by preventing the existence
of inactive iridium clusters[12] or driving the presence
of monomeric active iridium species.[11b]
Overall, the novel catalysts developed for HIE re-
actions within this programme have the clear poten-
tial to replace Crabtreeꢀs catalyst as the industry stan-
dard in this area. Moreover, these complexes are
stable in air and at room temperature, retaining their
activity over prolonged storage periods. The experi-
mental and computational methods employed here,
aligned with the associated mechanistic and theoreti-
cal insights delivered through this study, are now
being employed within our laboratory in endeavours
to develop catalyst systems of further enhanced activi-
ty and more widespread substrate applicability.
[a]
5 mol% of Ir catalyst employed over 2 h.
Tx (where x=0, 1, 2, 3, 4) refers to the number of tritium
atoms incorporated into the molecule, for example, for
19b, T1 (23) indicates that 23% of the sample contained
one tritium atom. See the Supporting Information for
further details.
[b]
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The Synthesis of Highly Active Iridium(I) Complexes and their Application
1H NMR spectroscopy. The level of isotope incorporation
into the substrate was determined by H NMR analysis of
Experimental Section
1
the reaction products. As such, the residual proton signal
from the site of incorporation was compared against that of
a site where incorporation was not expected or occurred.
Full details of all experimental procedures, analyses, and
DFT calculations (including optimised Cartesian coordi-
nates) can be found in the Supporting Information.
Computational Methods
Density functional theory (DFT) was employed to calculate
the electronic structures and energies for all species in-
volved in H/D exchange reactions. A hybrid meta-GGA ex-
change correlation functional M06[23] was used in conjunc-
tion with the 6–31GACTHNUTRGNEUNG
(d,p)[24] basis set for main group non-
metal atoms and the Stuttgart RSC[25] effective core poten-
tial along with the associated basis set for Ir. Harmonic vi-
brational frequencies are calculated (with the incorporation
of deuterium wherever needed) at the same level of theory
to characterise respective minima (reactants, intermediates,
and products with no imaginary frequency) and first order
saddle points (TSs with one imaginary frequency). All calcu-
lations have been performed with the GAUSSIAN 09 quan-
tum chemistry programme package. More detailed discus-
sion of the computational methods, with full references, can
be found in the Supporting Information.
Acknowledgements
We thank the University of Strathclyde (J.A.B.), AstraZeneca,
R&D Mçlndal (S.I. and A.R.C.), and the Carnegie Trust
(M.R.) for postgraduate studentship funding. Mass spectrom-
etry data were acquired at the EPSRC UK National Mass
Spectrometry Facility at Swansea University. T.T. thanks the
Glasgow Centre for Physical Organic Chemistry for funding.
General Procedure for the Synthesis of Complexes
5a–5e
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Adv. Synth. Catal. 2014, 356, 3551 – 3562