Challenges in cyclometalation: Steric effects leading to competing pathways and η1,η2-cyclometalated iridium(iii) complexes

Article abstract of DOI:10.1039/c8dt02639d

The iridation of (R)-N,N-dimethyl-1-(1-naphthyl)ethylamine in the presence of a base afforded an assortment of products ranging from organic molecules to coordinated systems and cyclometalated complexes. The transformation affirmed the postulation where steric effects within the coordination sphere favor a β-hydride elimination-like decomposition pathway, competing alongside ortho-metalation, thus leading to iminium intermediates. The same procedure also generated an unprecedented carbocyclic η¹,η²-cycloiridated species that could not be attained from the direct cyclometalation of its organic ligand.

Full text of DOI:10.1039/c8dt02639d

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Challenges in Cyclometalation: Steric Effects Leading to
Competing Pathways and η1,η2-Cyclometalated Iridium(III)
Complexes
Received 00th January 20xx,
Accepted 00th January 20xx
Houguang Jeremy Chen,a Ronald Hong Xiang Teo,a Jonathan Wong,a Yongxin Li,a Sumod A.
Pullarkata and Pak-Hing Leung*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
The iridation of (R)-N,N-dimethyl-1-(1-naphthyl)ethylamine in the presence of base afforded an assortment of products
ranging from organic molecules to coordinated systems and cyclometalated complexes. The transformation affirmed the
postulation where steric effects within the coordination sphere favors a β-hydride elimination-like decomposition pathway,
competing alongside ortho-metalation, thus leading to iminium intermediates. The same procedure also generated an
unprecedented carbocyclic η1,η2-cycloiridated species that could not be attained from the direct cyclometalation of its
organic
ligand.
Introduction
The evolution of cyclometalation from an endeavor into
new coordination modes to its modern stance into
applications has brought forth its compounds to the forefront
of research. Cyclometalated complexes can serve as potent
catalysts,1 auxiliaries,2 photo-luminescing agents3 and
biotherapeutic drugs,4 and its concepts can be applied to
obtain an extensive assortment of compounds through C–H
bond functionalization protocols as reactive intermediates.5
Generally, the principles of cyclometalation revolve about
the electronic nature of both the metal center and the donor,
as well as steric factors along the projected organometallic ring
system.6 Previously, we uncovered an undocumented
consequence of unsuccessful cyclometalation where
a
competing pathway competed against the former procedure.7
We had postulated that the latter process involved reactive
iminium intermediates which, for the first time, we were able
to provide experimental evidence to affirm our hypothesis.
The article also extends the phenomenon to complexes
beyond palladium (in this case, iridium) and steric factors
about the coordination sphere (instead of the cyclometalating
ligand). Additionally, we were able to isolate an
unprecedented carbocyclic alkene-type η1,η2-cycloiridated
Scheme 1. Schematic representation of previous and current
works in competing pathways of cyclometalation.
While the field of cyclometalation has been recognized as
one of the most explored areas within organometallic
chemistry,6a,8 the process leading to alternative pathways is
not well-defined since its prevalence is uncommon (and/or
likely to be overlooked or undocumented). A quick review of
literature depicted some of these protocols to be simplified as
oxidation processes to their respective products.9 Moreover,
the mode of activation to access vinyl-derived cyclometalated
species has not been reported. With the interest to
understand the chemistry behind these reactions, our
intentions were to investigate the origins and mechanistic
pathways to these compounds. More importantly, with the
advent of catalytic C–H bond functionalization reactions
becoming a mainstream research area,10 the work could serve
complex, with its olefinic
the metal center.
π-electrons coordinatively bonded to
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as a reference to byproducts and/or new modes of activation in several N-dealkylation experiments.13 Whilst efforts were
to access synthetically-useful chemicals.
made to conduct the experiment under anhydrous conditions,
Results and Discussion
The iridation of optically-active (R)-N,N-dimethyl-1-(1-
naphthyl)ethylamine (R)-L1 with [IrCp*Cl2]2 in the presence of
NaOAc at elevated temperatures afforded six isolable
compounds – four coordinated species, three of which were
cyclometalated, and two organic molecules (Scheme 2).
Among these compounds were ortho-iridated N-demethylated
complex (RC,RN,SIr)-1, 1-acetonaphthone
2 and coordinated
dimethylamine complex
3
which corresponded to products
expected from the postulated competing pathway. The
remaining three compounds, namely, cycloiridated imine-
derived complex rac-
4, carbocyclic cyclometalated species rac-
5
and 1-ethylnaphthalene
6, were not observed in our prior
studies.7 It should also be noted that the same procedure did
not proceed when conducted at ambient temperature. Lastly,
while the reaction proceeded in the absence of external base,
longer reaction time was required to attain the products in
comparable quantities.
we were unsuccessful in isolating the transient species prior to
hydrolysis or spectroscopic identification.
Scheme 3. Proposed mechanism for the competing pathway in
the iridation procedure (X = Cl, OAc).
It is important to reiterate that the ligand motif is known to
cyclometalate well with various metal salts.14 As such, we can
extend the considerations of the competing pathway from the
nature of the ligand to steric effects about the coordination
sphere. In this instance, the ortho-metalation procedure was
believed to be impeded by the bulky Cp* spectator ligand. To
investigate the extent of its effects on the cyclometalating
ligand, we proceeded to expose its corresponding phenyl
derivative (R)-L2 and N,N-dimethyl-1-naphthylmethylamine L3
to our experimental conditions. The iridation of phenyl-based
tertiary amine (R)-L2 (Scheme 4a) returned similar
observations to the earlier metalation attempt but with fewer
byproducts. This result indicates that the failed
cyclometalation attempt was not a consequence of the known
spatial interaction between the α-methyl substituent and its
neighbouring proton on the aromatic ring within the ligand.15
Scheme 2. The iridation reaction of (R)-N,N-dimethyl-1-(1-
naphthyl)ethylamine (R)-L1 11
.
The formation of the former three products can be derived
from a β-hydride elimination-like process (“the competing
pathway”). The abstraction of the hydrogen atom by the base,
assisted by agostic C–H bond activation, produced a reactive
iminium intermediate that can be readily hydrolyzed to
provide the said products, albeit the absence of formaldehyde,
possibly due to its volatility in the heated mixture (Scheme 3).
The mechanism was supported by the retention of
stereochemistry at the
Pathway A which emphasized the lack of involvement of the
acidic -proton within the mechanism. Similarly, deuterium
labelling studies (with the proton at the -carbon in the
α-carbon in iridacycle (RC,RN,SIr)-1 along
α
α
racemic ligand replaced by deuterium) mirrored comparable
The isolation of coordinated dimethylamine complex
3 and
experimental observations with its corresponding complex d1-
acetophenone 7 from the procedure reflects part of the
rac-1 isolated in similar deuteration levels (Scheme 7). The
proposed mechanistic pathway of the competing reaction. On
the other hand, the ortho-iridation of the achiral naphthalene-
based isomer L3 was successful with the procedure providing
transformation along Pathway B mimicked the iridium(III)
intermediates proposed by Stirling,12 although hydrolysis of
the iminium derivative was observed under our reaction
conditions. Likewise, its palladium counterpart was suggested
the desired metallacycle rac-9, albeit sluggishly at room
temperature (Scheme 4b). This sheds light on the possible
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Scheme 7. Deuterium labelling experiment on the iridation of in acidified 1,2-dichloroethane. Full conversion to the
tertiary amine d1-rac-L1
.
hydrocarbon was observed in the experiment (Scheme 9). We
postulated that the source of dihydrogen originate from the
dehydrogenation protocol of cycloiridated secondary amine
complex (RC,RN,SIr)-1 (Scheme 5). As such, following the
hydrogenation process, the monodentate C-coordinated
species was believed to undergo further protonlysis to provide
1-ethylnaphthalene
conjecture, we note that the earlier deuterium studies
produced two variants of hydrocarbon , namely d1-6a and d1-
6 and [IrCp*Cl2]2. To support this
Scheme 8. Proposed mechanism to carbocyclic olefin-directed
cycloiridated complex rac- via complexed cyclic intermediate.
6
5
6b, with the latter having deuterium on the α-carbon and the
former deuterated at the β-carbon. Spectroscopically, the
results were particularly intriguing. While we observed the
presence of deuterium on both α- and β-carbon of the organic
molecules, deuterium levels were relatively low at 18.8% and
4.6% respectively (compared to 92.5% at the α-carbon of
ligand d1-rac-L1 prior to the reaction). The result signified an
alternate source of dihydrogen outside our prediction within
the reaction mixture. Otherwise, the olefin-based iridacycle
could undergo a separate distinct mechanism that adds the
hydrogen atoms to its organic framework differently to
Crystallographically, the isolated yellow block-like complex
provided some insights into the coordination mode of the
compound. The C=C olefinic bond length (141 pm) within the
complex was found to be slightly longer than that to an
uncoordinated alkene (134 pm), in line with reported
iridium(III) complexes containing coordinated olefins.20 Along
the plane of the naphthalene system, the alkene moiety was
found to lie out of the plane by 63.8°, tilting 30.4° off along the
Ir–Cl axis. Spectroscopically, the NMR spectra were also in
agreement with the crystal structure of the complex. The 13C
NMR spectrum depicted the coordinated olefin moiety with its
distinctive upfield chemical shifts at 56.16 (ArCH=CH2) and
produce the hydrocarbon.
Scheme 9. Hydrogenation of carbocyclic olefin-directed
cycloiridated complex rac-5 to 1-ethylnaphthalene 6.
Conclusions
The iridation of tertiary amine (R)-N,N-dimethyl-1-(1-
naphthyl)ethylamine (R)-L1 using [IrCp*Cl2]2 revealed the limits
of cyclometalation from the viewpoint of the ortho-metalating
ligand. In this instance, the commonly-known optically-active
cyclometalating ligand was unable to cyclize due to the
sterically-bulky Cp* spectator ligand that was present on the
Figure 1. Molecular structure of cycloiridated complex rac-5 with metal center. This resulted in the less favorable β-hydride
thermal ellipsoids shown at 50% probability. Hydrogen atoms are
omitted for clarity. Selected bond lengths and angles: Ir−C1
(2.050(6) Å), Ir−C11 (2.171(7) Å), Ir−C12 (2.131(7) Å), Ir−Cl
(2.4057(16) Å), C11–C12 (1.407(10) Å), C1−Ir−Cl (83.66(18)°), C11–Ir–
C12 (38.2(3)°), C7–C11–C12 (122.1(6)°).
elimination-like process to take place leading to hydrolyzed
products (and consequently its corresponding carbonyl and/or
N-demethylated compounds) from the reactive iminium
species. Whilst the experiment was not chemoselective, the
reaction offered evidence into both mechanistic pathways of
the competing reaction. It is vital to consider both steric bulk
of the substrates and ligands about the metal center when
synthesizing cyclometalated systems or performing catalytic
C–H bond functionalization protocols. The same concept can
also be exploited to access synthetically-challenging or novel
secondary amines through the N-dealkylation procedures.
Next, the iridation procedure also provided an exclusive
access to a rare olefin-directed metallacycle that cannot be
synthesized from direct cyclometalation. With the scope of
cyclometalated compounds expanded, the carbocyclic complex
could exhibit greater potential in novel studies and
80.82 (ArCH=CH2) ppm. Coupling between the olefinic protons
in the 1H NMR spectrum were within expected values
averaging 8.8 Hz and 11.3 Hz for cis and trans H–H coupling
respectively. Lastly, like its imine counterpart, the alkene-
coordinated species returned no optical activity denoting a
loss of stereogenic information from its optically-active
substrate.
Examining 1-ethylnaphthalene
6, it can be thought that the
compound was a hydrogenated fragment of the ligand
framework in the carbocyclic complex. With that in mind, we
performed a simple hydrogenation procedure on the complex
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7
(a) J. S. L. Yap, Y. Ding, X.-Y. Yang, J. Wong, Y. Li, S. A.
Pullarkat, P.-H. Leung Eur. J. Inorg. Chem. 2014, 5046; (b) J. S.
L. Yap, H. J. Chen, Y. Li, S. A. Pullarkat, P.-H. Leung
Organometallics 2014, 33, 930.
applications. Moreover, the in-situ generation of the
metallacycle by catalytic means could bring forth new
methodologies that add moieties across the C=C olefinic bond,
as well as functionalizing the ipso-carbon to construct new
compounds.
8
9
Ryabov, A. D. Chem. Rev. 1990, 90, 403.
(a) R. A. Arthurs, M. Ismail, C. C. Prior, V. S. Oganesyan, P. N.
Horton, S. J. Coles, C. J. Richards Chem. Eur. J. 2016, 22,
3065; (b) L. Barloy, J.-T. Issenhuth, M. G. Weaver, N.
Pannetier, C. Sirlin, M. Pfeffer Organometallics 2011, 30,
1168.
Finally, while much efforts have been placed in the
prescribed iridation procedure, we strongly believe that the
idea can be applied to metalation protocols of other transition
metal elements.
10 Selected recent articles on transition metal-catalyzed C–H
bond functionalization reactions: (a) Y. Qiu, W.-J. Kong, J.
Struwe, N. Sauermann, T. Rogge, A. Scheremetjew, L.
Ackermann Angew. Chem. Int. Ed. 2018, 57, 5828; (b) P. J.
Cabrera, M. Lee, M. S. Sanford J. Am. Chem. Soc. 2018, 140,
5599; (c) R.-Y. Zhu, Z.-Q. Li, H. S. Park, C. H. Senanayake, J.-Q.
Yu J. Am. Chem. Soc. 2018, 140, 3564; (d) Z. Jin, L. Chu, Y.-Q.
Chen, J.-Q. Yu Org. Lett. 2018, 20, 425; (e) K. Shin, Y. Park,
M.-H. Baik, S. Chang Nat. Chem. 2018, 10, 218.
11 Isolated yields (in parenthesis). It should be noted that the
products do not account for all tertiary amine ligand (R)-L1
present in the reaction mixture. In most cases, isolation of
the unreacted amine was difficult unless the reaction time
was short, typically below 48 h. On the other hand, residual
[IrCp*Cl2]2 could be almost quantifiably recovered majority
of the time.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the Ministry of Education
Academic Research Fund (AcRF-RG108/15). We are also
grateful to Nanyang Technological University for Ph.D.
scholarships to H. J. Chen, R. H. X. Teo and J. Wong.
12 M. J. Stirling, J. M. Mwansa, G. Sweeney, A. J. Blacker, M. I.
Page Org. Biomol. Chem. 2016, 14, 7092.
13 J. Muzart J. Mol. Catal. A.: Chem. 2009, 308, 15, and the
references therein.
14 (a) J.-B. Sortais, N. Pannetier, A. Holuigue, L. Barloy, C. Sirlin,
M. Pfeffer, N. Kyritsakas Organometallics 2007, 26, 1856; (b)
S. Y. M. Chooi, J. D. Ranford, P.-H. Leung, K. F. Mok
Tetrahedron: Asymmetry 1994, 5, 1805; (c) D. G. Allen, G. M.
McLaughlin, G. B. Robertson, W. L. Steffen, G. Salem, S. B.
Wild Inorg. Chem. 1982, 21, 1007.
15 (a) N. W. Alcock, D. I. Hulmes, J. M. Brown J. Chem. Soc.,
Chem. Commun. 1995, 395; (b) N. W. Alcock, J. M. Brown, D.
I. Hulmes Tetrahedron: Asymmetry 1993, 4, 743.
16 H. J. Chen, R. H. X. Teo, Y. Li, S. A. Pullarkat, P.-H. Leung
Organometallics 2018, 37, 99.
17 T. Jerphagnon, A. J. A. Gayet, F. Berthiol, V. Ritleng, N. Mršić,
A. Meetsma, M. Pfeffer, A. J. Minnaard, B. L. Feringa, J. G. de
Vries Chem. Eur. J. 2009, 15, 12780.
18 Crabtree, R. H., Complexes of π-Bound Ligands. In The
Organometallic Chemistry of the Transition Metals, John
Wiley & Sons, Inc.: 2005; pp 125-158.
19 (a) I. I. Padilla-Martínez, M. L. Poveda, E. Carmona, M. A.
Monge, C. Ruiz-Valero Organometallics 2002, 21, 93; (b) T. D.
Tran, Y.-M. Kim, T. T. Nguyen, X. C. Le, V. M. Nguyen, H. D.
Nguyen Organometallics 2008, 27, 3611; (c) R. Beck, S.
Footnotes and References
1
Selected review articles on cyclometalated complexes as
catalysts: (a) C. Wang, J. Xiao, Chem. Commun. 2017, 53,
3399; (b) R. J. Chew, P.-H. Leung Chem. Rec. 2016, 16, 141;
(c) C. Michon, K. MacIntyre, Y. Corre, F. Agbossou
‐
Niedercorn ChemCatChem 2016, 8, 1755; (d) N. Selander, K.
J. Szabό Chem. Rev. 2011, 111, 2048; (e) T. Jerphagnon, R.
Haak, F. Berthiol, A. J. A. Gayet, V. Ritleng, A. Holuigue, N.
Pannetier, M. Pfeffer, A. Voelklin, L. Lefort, G. Verzijl, C.
Tarabiono, D. B. Janssen, A. J. Minnaard, B. L. Feringa, J. G.
de Vries Top. Catal. 2010, 53, 1002.
2
3
Selected articles on cyclometalated complexes as auxiliaries:
(a) V. V. Dunina Curr. Org. Chem. 2011, 15, 3415; (b) P.-H.
Leung Acc. Chem. Res. 2004, 37, 169; (c) S. B. Wild Coord.
Chem. Rev. 1997, 166, 291.
Selected review articles on cyclometalated complexes as
photo-luminescent agents: (a) E. V. Puttock, M. T. Walden, J.
A. G. Williams Coord. Chem. Rev. 2018, 367, 127; (b) T.
Fleetham, G. Li, J. Li Adv. Mater. 2017, 29, 1601861; (c) D.-L.
Ma, S. Lin, W. Wang, C. Yang, C.-H. Leung Chem. Sci. 2017, 8,
878; (d) S. Huo, J. Carroll, D. A. K. Vezzu Asian J. Org. Chem.
2015, 4, 1210.
4
5
Selected review articles on cyclometalated complexes as
biotherapeutic drugs: (a) C. Gaiddon, M. Pfeffer Eur. J. Inorg.
Chem. 2017, 12, 1639; (b) J. Sophie, E. K. Fritz, C. Angela Curr.
Med. Chem. 2017, 24, 1; (c) T. Zou, C. T. Lum, C.-N. Lok, J.-J.
Zhang, C.-M. Che Chem. Soc. Rev. 2015, 44, 8786; (d) Z. Liu,
P. J. Sadler Acc. Chem. Res. 2014, 47, 1174.
Camadanli, U. Flörke, H.-F. Klein Eur. J. Inorg. Chem. 2015
2543.
,
20 (a) S. M. Whittemore, R. J. Yoder, J. P. Stambuli
Organometallics 2012, 31, 6124; (b) M. Prinz, M. Grosche, E.
Herdtweck, W. A. Herrmann Organometallics 2000, 19, 1692;
(c) J. B. Wakefield, J. M. Stryker Organometallics 1990, 9,
2428.
Selected review articles on cyclometalated complexes as
reactive intermediates: (a) Y. Xu, G. Dong Chem. Sci. 2018, 9,
1424; (b) R. Shang, L. Ilies, E. Nakamura Chem. Rev. 2017
,
117, 9086; (c) T. Yoshino, S. Matsunaga Adv. Synth. Catal.
2017, 359, 1245; (d) R. Shang, L. Ilies, E. Nakamura Chem.
Rev. 2017, 117, 9086; (e) J. R. Hummel, J. A. Boerth, J. A.
Ellman Chem. Rev. 2017, 117, 9163; (f) J. He, M. Wasa, K. S.
L. Chan, Q. Shao, J.-Q. Yu Chem. Rev. 2017, 117, 8754; (g) M.
Moselage, J. Li, L. Ackermann ACS Catal. 2016, 6, 498.
6
(a) M. Albrecht Chem. Rev. 2010, 110, 576; (b) V. V. Dunina,
O. A. Zalevskaya, V. M. Potapov Russ. Chem. Rev. 1988, 57,
250; (c) M. I. Bruce Angew. Chem. Int. Ed. Engl. 1977, 16, 73.
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