Luminescent ruffled iridium(iii) porphyrin complexes containing N-heterocyclic carbene ligands: structures, spectroscopies and potent antitumor activities under dark and light irradiation conditions

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Luminescent ruﬄed iridium(III) porphyrin

complexes containing N-heterocyclic carbene

ligands: structures, spectroscopies and potent

antitumor activities under dark and light irradiation

conditions†

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of Chemistry

a

ab

Tsz-Lung Lam,

Ka-Chung Tong,^aChen Yang,

Wai-Lun Kwong,^a

Xiangguo Guan,^abMing-De Li,

Vanessa Kar-Yan Lo,^aSharon Lai-Fung Chan,‡^c

a

ab

*

David Lee Phillips, Chun-Nam Lok and Chi-Ming Che

A panel of iridium(III) porphyrin complexes containing axial N-heterocyclic carbene (NHC) ligand(s) were

synthesized and characterized. X-ray crystal structures of the bis-NHC complexes [Ir^III(ttp)(IMe)₂]⁺(2a),

[Ir^III(oep)(BIMe)₂]⁺(2d), [Ir^III(oep)(IⁱPr)₂]⁺(2e) and [Ir^III(F₂₀tpp)(IMe)₂]⁺(2f) display ruﬄed porphyrin rings

with mesocarbon displacements of 0.483–0.594 A˚ and long Ir–C_NHCbonds of 2.100–2.152 A˚. Variable-

temperature ¹H NMR analysis of 2a reveals that the macrocycle porphyrin ring inversion takes place in

solution with an activation barrier of 40 ꢀ 1 kJ mol^ꢁ1. The UV-vis absorption spectra of Ir^III(por)–NHC

complexes display split Soret bands. TD-DFT calculations and resonance Raman experiments show that

the higher-energy Soret band is derived from the ¹MLCT dp(Ir) / p*(por) transition. The near-infrared

phosphorescence of Ir^III(por)–NHC complexes from the porphyrin-based ³(p, p*) state features broad

emission bands at 701–754 nm with low emission quantum yields and short lifetimes (F_em< 0.01; s < 4

1

ms). [Ir^III(por)(IMe)₂]⁺complexes (por ¼ ttp and oep) are eﬃcient photosensitizers for O₂generation (F_so

¼ 0.64 and 0.88) and are catalytically active in the light-induced aerobic oxidation of secondary amines

and arylboronic acid. The bis-NHC complexes exhibit potent dark cytotoxicity towards a panel of cancer

cells with IC₅₀values at submicromolar levels. The cytotoxicity of these complexes could be further

enhanced upon light irradiation with IC₅₀values as low as nanomolar levels in association with the light-

induced generation of reactive oxygen species (ROS). Bioimaging of [Ir^III(oep)(IMe)₂]⁺(2c) treated cells

indicates that this Ir complex mainly targets the endoplasmic reticulum. [Ir^III(oep)(IMe)₂]⁺catalyzes the

photoinduced generation of singlet oxygen and triggers protein oxidation, cell cycle arrest, apoptosis

and the inhibition of angiogenesis. It also causes pronounced photoinduced inhibition of tumor growth

in a mouse model of human cancer.

Received 3rd July 2018

Accepted 27th September 2018

DOI: 10.1039/c8sc02920b

rsc.li/chemical-science

activities have beneted greatly from improved knowledge

regarding the coordination chemistry of metal–NHC

complexes.⁴Nonetheless, there are only a handful of examples

Introduction

The recent years have witnessed a bloom in the applications of

metal–N-heterocyclic carbene (NHC) complexes in catalysis,¹

materials science²and medicine.³These burgeoning research

of metalloporphyrins bearing NHC ligand(s) thus far. In this

regard, the groups of Albrecht,⁵Woo⁶and Che⁷have contrib-

uted to the synthesis and investigation of the spectroscopic

properties and/or catalytic activities of d⁶metalloporphyrin

complexes of Co^III, Rh^III, Ir^IIIand Ru^IIions bearing axial NHC

ligand(s). Several characteristics of these metalloporphyrins

have been noted, including (1) gentle dearomatization of the

porphyrin ligand; (2) elongation of the axial metal–ligand bond

trans to the NHC ligand; and (3) pronounced ruﬄing of the

porphyrin ligand scaﬀold.^5,6The last feature, namely, NHC-

induced ruﬄing deformation, is particularly intriguing

because the out-of-plane deformation of metalloporphyrin is

recognized to have a profound impact on its photophysical (e.g.,

^aState Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional

Materials, HKU-CAS Joint Laboratory on New Materials and Department of

Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.

E-mail: cmche@hku.hk

^bHKU Shenzhen Institute of Research and Innovation, Shenzhen, China

^cDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic

University, Hung Hom, Hong Kong, China

† Electronic supplementary information (ESI) available: Experimental procedures,

Tables S1–S8, Fig S1–S27. CCDC 1846458–1846461. For ESI and crystallographic

data in CIF or other electronic format see DOI: 10.1039/c8sc02920b

‡ Deceased 16 July 2017.

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electronic absorption, emission, excited state dynamics) and porphyrin was accomplished by reacting bis(NHC)silver(^I)

physiochemical properties (e.g., axial ligand aﬃnity, electron complex¹⁷with [Ir^III(por)Cl(CO)] via transmetalation. This

transfer rate), both of which have important implications in synthetic protocol oﬀers the advantage that the reaction can be

biological processes involving the ubiquitous tetrapyrrole conducted under mild, aerobic conditions. Mono-NHC

compounds.⁸While many studies on nonplanar metal- complexes [Ir^III(por)(NHC)Cl] (1a–1d) were prepared by stir-

loporphyrins have focused on metal ions of relatively small size, ring a mixture of [Ir^III(por)Cl(CO)] with half equivalents of the

II

III

11

III

such as Ni^IIand Zn ,¹⁰and those with Mn

and Fe ,¹²in respective bis(NHC)silver(^I) complexes in CH₂Cl₂at room

8a,9

which nonplanarity is primarily induced by the peripheral temperature for 12 h (Scheme 1). Aer the removal of AgCl salt by

substituents of the porphyrin, fewer studies have been per- ltration through a short plug of Celite (when por ¼ tmp, where

formed on axial ligand-induced porphyrin ring deformation in H₂tmp ¼ meso-tetramesitylporphyrin) or a silica gel column

d⁶metalloporphyrins.^5,6,13

(when por ¼ F₂₀tpp, where H₂F₂₀tpp ¼ meso-tetrakis(penta-

The Soret and Q bands in the electronic absorption spectra of uorophenyl)porphyrin), the desired complexes were recrystal-

metalloporphyrins of d⁶Ru^II, Os^II, Rh^IIIand Ir^IIIgenerally display lized from CH₂Cl₂/hexane and obtained in 60–74% isolated

marked hypsochromic shis with respect to their free base yields. Bis-NHC complexes 2a–2f were similarly synthesized by

porphyrins due to dp(M)–p*(por) interaction.¹⁴Axial ligand(s) reacting stoichiometric amounts of bis(NHC)silver(^I) complexes

can also perturb the absorption spectra by modulating the with [Ir^III(por)Cl(CO)] in CH₂Cl₂at room temperature or at 40 ^ꢂC

electronic properties of the metal ion and hence the metal– for 12 h to 4 days (Scheme 2). The complexes were then puried

porphyrin bonding interaction (cis-eﬀect).¹⁴The literature by ash column chromatography on a silica gel column using

reports that d⁶metalloporphyrins display red to infrared phos- CH₂Cl₂/EtOAc as the eluent and were obtained in 70–96% iso-

phorescence derived from the ³(p, p*) IL state of the porphyrin lated yields. [Ir^III(oep)(CNPhOMe)₂]⁺(3) and [Ir^III(oep)(py)₂]⁺(4)

3

ligand or the (dp, p*) metal-to-ligand charge transfer (MLCT) were also prepared for comparative study (see (ESI†)).

state upon photoexcitation.¹⁵Nevertheless, only Ir^III–porphyrin

The number of coordinated NHC ligands was revealed by the

complexes emit strong red to near-infrared (NIR) phosphores- ¹H NMR and FAB-MS analyses of the complexes and is dependent

cence in solution at room temperature, with emission quantum on the steric bulk of the porphyrin ligand. Specically, whereas

yields up to 0.30 and emission lifetimes up to 97 ms.^16a–cDue to

these advantageous luminescence properties, the use of cationic

Ir^III-oep-derived bioconjugates for cellular imaging and as

phosphorescent probes for intracellular oxygen sensing has

been reported by Papkovsky and co-workers.^16bOn the other

hand, two near-IR-absorbing BODIPY assemblies of Ir^III–

porphyrin, recently reported by Shen, Chan, Mack and co-

workers,^16dhave been shown to display excellent photostability

and eﬃciency in photosensitized singlet oxygen generation with

a quantum yield of up to 0.85.^16dThese encouraging ndings

have shed light on the potential photobiological uses of Ir^III–

porphyrin complexes, which remain unexplored.

Here, we describe the synthesis and characterization of a panel

of luminescent ruﬄed iridium(^III) porphyrin complexes containing

mono-NHC and bis-NHC ligand(s), namely, [Ir^III(por)(NHC)Cl] (1a–

Scheme 1 Synthesis of [Ir^III(por)(NHC)Cl] complexes 1a–1d.

1d) and [Ir^III(por)(NHC)₂]⁺(2a–2f), respectively. Steady-state and

time-resolved spectroscopic studies and theoretical calculations in

conjunction with resonance Raman spectroscopy were undertaken

to examine the eﬀects of NHC ligation on the photophysical

properties and electronic structures of the Ir^III–porphyrin

complexes. In addition, the photochemical reactivity via the light-

induced generation of singlet oxygen as well as the cytotoxicity and

phototoxicity of these bis-NHC iridium(^III) porphyrin complexes

were investigated both in vitro and in vivo.

Results

Synthesis

The reported synthetic approaches to metalloporphyrin-NHC

complexes include the thermal decarboxylation of imidazo-

lium carboxylate,⁵deprotonation of the imidazolium salt with

a strong base⁷and incorporation of the free imidazoylidene.⁶In

this work, the coordination of NHC ligands to iridium(^III) Scheme 2 Synthesis of [Ir^III(por)(NHC)₂]⁺complexes 2a–2f.

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a 1 : 1 bis(NHC)silver(I) complex with [Ir^III(por)Cl(CO)] (por ¼ ttp

or oep) recipe gave solely [Ir^III(por)(NHC)₂]⁺complexes, the same

stoichiometry furnished only [Ir^III(tmp)(NHC)Cl] and trace

[Ir^III(tmp)(NHC)]⁺complexes in the case of [Ir^III(tmp)Cl(CO)]. The

reaction of bis(NHC)silver(^I) complex with [Ir^III(F₂₀tpp)Cl(CO)] to

give [Ir^III(F₂₀tpp)(IMe)₂]⁺(2f) was completed at elevated temper-

ature with extended reaction time (reuxing CH₂Cl₂for 4 days).

The FAB-MS spectra of complexes 1a–1d all show peaks attrib-

uted to [M ꢁ Cl]⁺fragments, suggesting that the Ir–Cl bond is

weakened by the trans-axial NHC ligand. The IR oxidation-state

marker bands of all complexes 1a–1d and 2a–2f fall into the

Table 1 Selected bond lengths (A˚) and bond angles (^ꢂ) of 2a, 2d, 2e

and 2f

2a

2d

2e

2f

Ir–C_NHC1

Ir–C_NHC2

Ir–N_mean

2.140(17)

2.164(18)

2.027(11)

177.9(16)

2.128(3)

2.023(3)

177.62(15)

2.151(5)

2.143(5)

2.147(16)

179.4(16)

2.080(3)

2.120(3)

1.985(17)

174.5(10)

a

C_NHC1–Ir–C_NHC2

a

Ir–N_meanis the average bond distance of four Ir–N_porbonds.

range of 1018–1022 cm^ꢁ1, which is comparable to that of their planes of the NHC ligands are slightly to moderately tilted with

parental complexes [Ir^III(por)Cl(CO)] and consistent with the iri- respect to the Ir–C_NHCaxis. The mean pitch angles of the NHC

dium(^III) oxidation state.¹⁸Mono-NHC complexes 1a, 1b and 1d ligands (measurement of out-of-plane tilting) of 2a, 2d, 2e and

are stable in the solid state and in CDCl₃solution for 1 week with 2f are 7.5^ꢂ, 4.6^ꢂ, 1.4^ꢂand 5.1^ꢂrespectively. The pitch angle of 2a

the exception of 1c, which decomposes within 1 day under is slightly larger than that of [Ir^III(ttp)(IBuMe)Me] (6.4^ꢂ).⁶The

ambient conditions. Bis-NHC complexes 2a–2e are remarkably ruﬄing deformation of the porphyrin ring combined with the

air-stable in the solid state and in CDCl₃solution in the dark for 1 tilting of NHC ligands is considered to be a means to relieve the

month, as revealed by ¹H NMR spectroscopy and UV-vis absorp- unfavorable steric repulsion caused by the close proximity of the

tion spectroscopy, except for 2f, which gradually deteriorates in NHC ligands and porphyrin ring. Ruﬄing deformation of

CDCl₃in 3 days.

porphyrin rings has also been observed in other NHC-bearing

metalloporphyrin complexes.^5,6In all the X-ray crystal struc-

tures, the planes of the NHC ligands are approximately

orthogonal to each other, with an interplanar angle of 84.8^ꢂfor

2a, 69.2^ꢂfor 2d, 87.7^ꢂfor 2e and 80.9^ꢂfor 2f. The orientation of

NHC ligands with respect to Ir–N_por, described by the torsional

angle of N_NHC–C_NHC–Ir–N_por, has an average value of 40.3^ꢂfor

2a, 35.0^ꢂfor 2d, 43.5^ꢂfor 2e and 37.0^ꢂfor 2f. The near-staggered

orientation of the NHC ligands with respect to Ir–N_porsuggests

minimal Ir–C_NHCp bonding interaction.^5aEvidently, the

arrangement of NHC ligands is related to the structural

requirement for ruﬄing deformation of porphyrin ligands.

X-ray crystal structures

The structures of 2a, 2d, 2e and 2f were determined by X-ray

diﬀraction analysis, and their perspective views are depicted

in Fig. 1. Selected bond distances and angles are summarized in

Table 1. All complexes adopt a slightly distorted octahedral

geometry, with the porphyrin ring exhibiting a signicant

ruﬄing deformation. The mean deviations of the mesocarbon

atom from the least square plane of the porphyrin ring in 2a, 2d,

˚

2e and 2f are 0.483, 0.557, 0.561 and 0.594 A, respectively. The

Fig. 1 Perspective views of (A) [Ir^III(ttp)(IMe)₂]⁺2a, (B) [Ir^III(oep)(BIMe)₂]⁺2d, (C) [Ir^III(oep)(IⁱPr)₂]⁺2e and (D) [Ir^III(F₂₀tpp)(IMe)₂]⁺2f at 30% prob-

ability of the thermal ellipsoid. Hydrogen atoms, cocrystallized solvent molecules and counteranions are omitted for clarity. Insets show the side

views of the porphyrin cores and the average mesocarbon displacements (A˚) from the mean porphyrin planes.

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The average Ir–N distances of 2a, 2d, 2e and 2f are 2.027, complexes, meso-aryl ring rotation about the C_meso–C_Arbond

ǂ

˚

2.023, 2.017 and 1.985 A, respectively, which are comparable to was suggested to occur with the corresponding DG_ROT, which

those of other organoiridium(^III) porphyrin complexes.^16,19The measured 59–63 kJ mol^ꢁ1^5b,6In this work, the ¹H NMR spectra

.

mean Ir–C_NHCdistances of 2a, 2d, 2e and 2f are 2.152, 2.128, of 2a from 298 K to 193 K were recorded (Fig. 3) to study its

˚

2.147 and 2.100 A, respectively, which are longer than those of uxional behavior in solution. At 298 K, the H_oand H_msignals

non-porphyrin-type Ir–NHC complexes reported in the litera- of the meso-tolyl rings appear as two well-resolved doublets,

ture.²⁰The elongated Ir–C_NHCbond in the [Ir^III(por)(NHC)₂]⁺indicating that these nuclei are at their fast exchange limits. As

complexes is a consequence of the combination of (1) the strong the temperature is lowered, the H_osignal broadens and

trans inuence of the NHC ligands and (2) the unfavorable completely collapses (coalesces) at 223 K. Meanwhile, the H_m

steric interactions between the N-alkyl substituents on the NHC signal broadens and coalesces at 208 K. At 193 K, four new sets

ligands and the porphyrin ring. While the inuence of the N- of signals from H_oand H_mhave developed, though they are not

alkyl groups of the NHC ligand on the Ir–C_NHCdistance is well resolved. Notably, the two H_osignals are anomalously split

marginal (cf. 2d vs. 2e), the change of the porphyrin from tpp to by 1.4 ppm, with one of the H_osignals being farther upeld than

F₂₀tpp ligand reduces the Ir–C_NHCdistance by 0.052 A (cf. 2a vs. the H_msignals. With reference to the related VT ¹H NMR study

˚

2f). In comparison, the Ir–C_NHCdistances in [Ir^III(ttp)(IMe)₂]⁺of ruﬄed Ni^II–por complexes,^9athe observed splitting of the H_o

(2a) are discernibly shorter than that reported in [Ir^III(ttp) signal at the low-temperature limit reveals a situation in which

6

˚

(IBuMe)Me] (2.194(4)A). This nding indicates that the methyl half of H_olies above the shielding region of the relatively

ligand has a stronger trans inuence than NHC. In addition, the “frozen” porphyrin ring, which is in a ruﬄed conformation. The

extensive intermolecular p–p stacking interactions between the chemical equivalence of H_bof ttp as well as of H_aand N–Me

molecules of 2d to form 1D polymeric chains are worth noting from two IMe ligands is conserved, as these signals remain

(Fig. 2A). The neighboring BIMe ligands are parallel to one singlets throughout the experiment. Considering the symmetric

another with an interplanar angle of 0^ꢂand a short interplanar bis-ligation and symmetry of the IMe ligand and the meso-tolyl

˚

distance of 3.398 A. Intriguingly, the intermolecular interac- group, the observed temperature-dependent NMR behavior of

tions have presumably led to the self-assembled brous struc- 2a is associated with a single dynamic process in which

ture of 2d observed by TEM upon precipitating the complex in macrocyclic inversion is preferred over axial ligand rotation or

a THF/H₂O (1 : 90, v/v) mixture (Fig. 2B).

meso-tolyl ring rotation.²²From the coalescence temperature

and coalescence exchange rate (k_exch) of the H_oand H_msignals,

the activation barrier of the ring inversion (DG^ǂ_ROT) of 2a is

estimated to be 40 ꢀ 1 kJ mol^ꢁ1. In addition, the reversible

binding of NHC ligand(s) to Ir^IIIion is suggested not to take

place at room temperature because the ¹H signals from the

NHC ligand(s) (i.e., H_aand N–Me) remained unaltered

NMR study

The ¹H NMR spectra of all [Ir^III(por)(NHC)Cl] and

[Ir^III(por)(NHC)₂]⁺complexes show upeld signals of the N-alkyl

substituents on the NHC ligands at <0 ppm (TMS reference),

revealing the anisotropic eﬀect of the porphyrin ring current

upon these alkyl groups. The static crystal structures of 2a, 2d,

2e, and 2f have two-fold symmetry due to the ruﬄing defor-

mation of the porphyrin ligand. However, all iridium(^III)

porphyrin complexes in this work display a pseudo-four-fold

symmetry in solution; both H_b(when por ¼ tmp, F₂₀tpp or

ttp) and H_meso(when por ¼ oep) appear to be singlet.

Metalloporphyrins are known to exhibit a variety of confor-

mational dynamics in solution, and the dynamic processes

associated with porphyrin ligands include macrocyclic inver-

sion, meso- and b-substituent rotation.²¹For the related

[Rh^III(tpp)(IMe)Cl] and [M(ttp)(IBuMe)Me] (M ¼ Rh^IIIor Ir^III)

Fig. 2 (A) The crystal packing diagram of 2b viewed along the b-axis

and an enlarged image of a pair of 2b molecules with an interplanar Fig.

3

Selected region of ¹H NMR spectra (500 MHz) of

distance of 3.398 A˚. (B) TEM image obtained from THF/H₂O (1 : 90, v/v) [Ir^III(ttp)(IMe)₂]⁺2a in CD₂Cl₂from 298 K to 193 K. Asterisks (*) denote

mixture.

residual CHDCl₂signal.

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Table 3 Electrochemical data of 1–4^a

throughout the VT ¹H NMR experiment.⁶The chemical shis of

H_band H_mesoas well as of carbene C_NHCare summarized in

Table 2. The chemical shi of H_bor H_mesois a useful parameter

to assess the donor strength of the axial ligands.^15c,23For

instance, replacing a p-accepting CO ligand with a s-donating

NHC ligand in [Ir^III(tmp)(L)Cl] and [Ir^III(F₂₀tpp)(L)Cl] results in

an upeld shi of the H_bsignal by 0.30–0.43 ppm. The H_meso

signals for the [Ir^III(oep)(L)₂]⁺complexes diﬀer by ꢃ0.9 ppm

for L ¼ isocyanide ligand (3) and ꢃ0.8 ppm for L ¼ pyridine

ligand (4) versus L ¼ NHC ligand (2c–2e). The H_bor H_meso

signals for [Ir^III(por)(NHC)Cl] and [Ir^III(por)(NHC)₂]⁺complexes

bearing axial BIMe ligands are shied downeld by 0.04–

0.08 ppm compared to those of the IMe analogs, showing that

the latter is a stronger donor. The eﬀect of the N-alkyl substit-

uent on the NHC ligand was found to be insignicant, as

revealed by the H_mesosignals of 2c and 2e.

c

Complex

E_red(V)

E_ox(V)

E_oxꢁ E_red(V)

[Ir^III(tmp)(IMe)Cl]

[Ir^III(tmp)(BIMe)Cl]

1a ꢁ1.91

1b ꢁ1.87

+0.51, +1.15 2.42

+0.54, +1.19 2.41

+1.12, +1.39 2.43

+0.73, +1.37^b2.33

+0.85,+1.45^b2.33

+0.72, +1.25 2.52

+0.79, +1.24^b2.57

+0.75, +1.29 2.57

[Ir^III(F₂₀tpp)(BIMe)Cl] 1d ꢁ1.31

[Ir^III(ttp)(IMe)₂]⁺

[Ir^III(ttp)(BIMe)₂]⁺

[Ir^III(oep)(IMe)₂]⁺

[Ir^III(oep)(BIMe)₂]⁺

[Ir^III(oep)(IⁱPr)₂]⁺

[Ir^III(F₂₀tpp)(IMe)₂]⁺

[Ir(oep)(CNPhOMe)₂]⁺

[Ir(oep)(py)₂]⁺

2a ꢁ1.60

2b ꢁ1.48

2c ꢁ1.80

2d ꢁ1.78

2e ꢁ1.82

2f ꢁ1.77, ꢁ1.11 +1.31

2.42

3

4

ꢁ1.86

+0.72, +1.39^b2.58

+0.80, +1.44^b2.61

ꢁ1.81

a

E_1/2(V vs. Ag/AgNO₃, scan rate ¼ 100 mV s^ꢁ1) in CH₂Cl₂with 0.1 M

[ⁿBu₄N]PF₆as electrolyte at r.t.; E_1/2(Cp₂Fe^+/0) ¼ 0.14 V. E_paof

b

c

irreversible wave. Potential diﬀerence between the rst oxidation

and rst reduction.

Electrochemistry

The electrochemical data and cyclic voltammograms of

complexes 2a, 2e and 2f are displayed in Table 3 and Fig. 4,

respectively. The quasireversible/irreversible reduction waves of

these complexes appear at E_1/2¼ ꢁ1.31–2.01 V (vs. Ag/AgNO₃).

The rst reversible oxidation couple occurs at E_1/2¼ +0.51–

+1.12 V, while the second quasireversible/irreversible oxidation

takes place at E_1/2¼ +1.15–+1.45 V. To identify the site of the

rst oxidation and reduction of 2a, the spectroelectrochemistry

was studied. The UV-vis absorption spectra of 2a recorded at

various time intervals in the rst oxidation and reduction

display similar spectral characteristics; the intensity of the Soret

bands decrease considerably with the concomitant develop-

ment of a broad IR-range absorption in the Q bands, ca.

700–1000 nm (Fig. 5). These spectral features are typical of the

p-radical cation or anion of the porphyrin ring.²⁴On the other

hand, the E_oxꢁ E_redvalues for the rst oxidation and rst

reduction of the [Ir^III(por)(NHC)Cl] and [Ir^III(por)(NHC)₂]⁺

Fig. 4 Cyclic voltammograms of 2a, 2e and 2f in CH₂Cl₂(scan rate ¼

100 mV s^ꢁ1).

Table 2 Chemical shifts of H_band H_mesoin CDCl₃

Complex

dH_b^a(ppm)

dH_meso^a(ppm)

[Ir^III(ttp)Cl(CO)]

8.96

8.66

—

10.31

—

[Ir^III(tmp)Cl(CO)]

[Ir^III(oep)Cl(CO)]

[Ir^III(F₂₀tpp)Cl(CO)]

[Ir^III(tmp)(IMe)Cl]

[Ir^III(tmp)(BIMe)Cl]

[Ir^III(F₂₀tpp)(IMe)Cl]

[Ir^III(F₂₀tpp)(BIMe)Cl]

[Ir^III(ttp)(IMe)₂]⁺

9.01

8.32

8.36

8.58

8.62

8.61

8.69

—

8.70

—

1a

1b

1c

1d

2a

2b

2c

2d

2e

2f

[Ir^III(ttp)(BIMe)₂]⁺

[Ir^III(oep)(IMe)₂]⁺

[Ir^III(oep)(BIMe)₂]⁺

[Ir^III(oep)(IⁱPr)₂]⁺

—

9.39

9.45

9.40

—

10.31

10.21

Fig. 5 UV-vis absorption spectral changes of 2a containing 0.1 M

[ⁿBu₄N]PF₆during the ﬁrst oxidation (top) and ﬁrst reduction (bottom).

Asterisk denotes an instrumental artifact.

[Ir^III(F₂₀tpp)(IMe)₂]^+b

[Ir^III(oep)(CNPhOMe)₂]⁺

[Ir^III(oep)(py)₂]⁺

3

4

complexes fall in the range of 2.33–2.61 V, which are compa-

rable to the conventional HOMO–LUMO gap of metal-

loporphyrin complexes.²⁵Thus, both the rst oxidation and rst

reduction are assigned to porphyrin-center processes. The E_1/2

a

b

Values reported with reference to dH(Si(CH₃)₄) ¼ 0 ppm. Measured

in CD₂Cl₂.

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values for the IMe complexes (1a, 2a and 2c) are less anodic

compared to the corresponding BIMe analogs (1b, 2b and 2d,

respectively; Table 5). This diﬀerence suggests that IMe is

a stronger donor ligand than BIMe, which is similar to the

ndings from the ¹H NMR analysis. Nonplanarity of metal-

loporphyrins is known to engender cathodic shi of redox

potential.^9b,d,10a,26However, the eﬀect of ruﬄing on redox

potential is negligible for 2c–2e because the redox potentials of

these complexes are comparable to those of the analogous bis-

isocyanide complex (3) and bis-pyridine complex (4), with DE

being less than 0.08 V.

Fig. 6 UV-vis absorption spectra of 2c, 3, 4 and [Ir(oep)Cl(CO)] in

CHCl₃(1 ꢄ 10^ꢁ5M).

UV-visible absorption spectroscopy

The UV-visible spectral data and photophysical data of 1–4 and

their parental [Ir^III(por)Cl(CO)] complexes are summarized in

Table 4. The UV-vis absorption spectra of complexes 1a–1d,

which bear mono-NHC ligands, exhibit a moderately intense

absorption band at 367–371 nm in addition to a Soret band at

431 nm (1a and 1b, por ¼ tmp) or 426 nm (1c and 1d, por ¼

F₂₀tpp) with one or two Q band(s) at 530–595 nm (Table 4). All

bis(NHC)iridium(^III) porphyrin complexes 2 display two intense

Soret bands with peaks at 372–375 nm and 428–440 nm,

respectively, with l_maxof the Q band spanning from 532 to

620 nm (Table 4). The separation of the two Soret bands of 1 and

2 is 54–66 nm. This type of absorption spectrum featuring two

Soret bands is classically termed a ‘hyperspectrum’.^14,15cFig. 6

compares a representative hyperspectrum from 2c to ‘normal’

spectra from [Ir^III(oep)Cl(CO)], 3 and 4. The degree of ‘hyper

character’ can be evaluated by Dlog 3 between the two Soret

bands (i.e., the larger Dlog 3, the greater the ‘hyper character’

is). Thus, the hyper character of the bis-NHC complexes 2 is

generally stronger than that of the mono-NHC complexes 1.

Moreover, the hyper character appears to be a function of the

porphyrin ligand; Dlog 3 ranges from 0.36 for 2a and 2b (por ¼

ttp) to 0.11 for 2f (por ¼ F₂₀ttp) and 0–0.06 for 2c–2e (por ¼ oep).

In addition to the presence of an extra Soret band, the Soret

and Q bands of the NHC complexes are broadened compared to

those of their parental [Ir^III(por)Cl(CO)]. Moreover, a sizable

redshi of the low-energy Soret band is noted. For example, in

the oep series, the low-energy Soret band of 2c is redshied by

26, 34 and 41 nm versus those of [Ir^III(oep)Cl(CO)], 3 and 4,

respectively. The same trend holds for the cases of 1c, 1d and 2f

versus their parental [Ir^III(F₂₀tpp)Cl(CO)] complex, where Dl_max

(redshi) are 12, 12 and 26 nm, respectively (Fig. S14†).

Complexes 1b, 1d, 2b and 2d, which contain BIMe ligand(s),

display an exclusive absorption of moderate intensity (log 3 ¼

4.41–4.63) at l_max¼ 296–301 nm, which can be attributed to p

Table 4 UV-visible absorption and emission data of [Ir^III(por)Cl(CO)] and 1–4

UV-vis absorption data^a

Emission data^a

Solution at 298 K

l_max/nm (s/ms)

Complex

l_maxnm^ꢁ1(log 3)

309 (4.50), 422 (5.58), 533 (4.41), 567 (3.89)

F_em[ꢄ10^ꢁ2

]

[Ir^III(ttp)Cl(CO)]

724 (47.2), 808 (sh)

721 (77.2), 800 (sh)

666 (83.3), 722 (sh)

676 (101.0), 746 (sh)

773 (1.8)

0.16

0.22

5.03

2.92

0.05

0.06

—

0.29

—

[Ir^III(tmp)Cl(CO)]

[Ir^III(oep)Cl(CO)]

311 (4.43), 422 (5.58), 533 (4.42), 564 (3.60)

342 (4.44), 403 (5.38), 518 (4.30), 549 (4.62)

329 (4.40), 414 (5.42), 526 (4.45), 557 (3.94)

[Ir^III(F₂₀tpp)Cl(CO)]

[Ir^III(tmp)(IMe)Cl]

[Ir^III(tmp)(BIMe)Cl]

[Ir^III(F₂₀tpp)(IMe)Cl]

[Ir^III(F₂₀tpp)(BIMe)Cl]

[Ir^III(ttp)(IMe)₂]⁺

1a

1b

1c

1d

2a

2b

2c

2d

2e

2f^d

3

345 (sh) (4.29), 368 (4.56), 431 (5.18), 542 (4.06), 593 (3.40)

301 (4.55), 367 (4.61), 431 (5.23), 545 (4.13), 592 (3.92)

346 (sh) (4.44), 371 (4.62), 426 (5.10), 533 (4.12)

775 (2.3)

b

—

296 (4.41), 346 (sh) (4.39), 369 (4.55), 426 (5.10), 535 (4.12)

374 (4.76), 438 (5.12), 547 (3.87), 620 (3.82) (br)^c

297 (4.63), 372 (4.63), 437 (4.99), 564 (3.85) (br)^d, 611 (3.87) (br)^c

351 (sh) (4.52), 372 (4.86), 429 (4.89), 532 (4.10), 556 (4.01)

297 (4.42), 373, (4.76), 428 (4.82), 533 (4.03), 557 (3.95)

353 (sh) (4.49), 375 (4.82), 432 (4.82), 537 (4.09), 560 (4.02)

355 (sh) (4.63), 374 (4.89), 418 (sh) (4.72), 440 (5.00), 537 (4.13)

266 (4.70), 344(sh) (4.36), 395 (5.20), 515 (4.17), 547 (4.50)

388 (5.25), 507 (4.11), 539 (4.54)

729 (1.7), 811 (sh)

Nonemissive

701 (2.7), 766 (sh)

701 (3.6), 765 (sh)

701 (1.9), 763 (sh)

754 (0.5), 829 (sh)

663 (124.7), 717(sh)

651(55.2), 711(sh)

[Ir^III(ttp)(BIMe)₂]⁺

[Ir^III(oep)(IMe)₂]⁺

[Ir^III(oep)(BIMe)₂]⁺

[Ir^III(oep)(IⁱPr)₂]⁺

—

0.41

0.66

0.03

0.08

6.40

12.30

[Ir^III(F₂₀tpp)(IMe)₂]⁺

[Ir^III(oep)(CNPhOMe)₂]⁺

[Ir^III(oep)(py)₂]⁺

4

a

Measurements were performed in degassed CHCl₃. ^bComplex 1d was unstable for emission measurements. ^cBroad absorption band spans from

d

ca. 510 to 670 nm. Measurements were performed in degassed CH₂Cl₂.

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/ p* transition of the BIMe ligand. The absorption l_maxof the

Soret band is relatively insensitive to the NHC ligand (i.e., IMe,

BIMe, IPr), and Dl_maxis less than 4 nm in all cases for

complexes with the same porphyrin scaﬀold. In addition, sol-

vatochromism was found to be negligible for 2e (Table S2 and

Fig. S15†). The variation in l_maxof the Soret and Q bands in

various solvents is less than 3 nm. These ndings indicate

predominantly porphyrin-based frontier molecular orbitals

(FMOs) for Ir^III(por)–NHC complexes despite the nonplanarity

of the porphyrin ring.

Resonance Raman spectroscopy

Resonance Raman (RR) spectroscopy is an eﬀective method to

probe the nature of an electronic transition because the vibra-

tions associated with the resonant chromophore can be selec-

tively enhanced.²⁷To help verify the parentage of the split Soret

bands, the RR spectra of 2a were recorded using excitation at

368.9 and 435.7 nm in MeCN. The former excitation wavelength

is within the higher-energy Soret band, while the latter excita-

tion wavelength is covered by the lower-energy Soret band. The

experimental RR spectra and simulated ground-state Raman

spectrum of 2a from 1100–1800 cm^ꢁ1are shown in Fig. 8, and

the assignment of vibrational bands is listed in Table S4.† The

calculated Raman frequencies match well with the experimental

ones. The RR spectra exhibit diﬀerent intensity enhancements

in response to excitation at 435.7 and 368.9 nm. The band at

1607 cm^ꢁ1, which results from C–C bond stretching within the

tolyl rings and rocking of their hydrogen atoms without any

contribution from the pyrrole rings, appears only under exci-

tation at 435.7 nm. The other two enhancements at 1240 and

1206 cm^ꢁ1also result largely from the vibrational modes of the

tolyl rings. The resonance in the excited state associated with

the low-energy Soret band (435.7 nm) enhances the vibrational

modes associated with tolyl rings more than those associated

with pyrrole rings. In the case of excitation at 368.9 nm, four

vibrational bands are relatively enhanced, namely, those at

1172, 1281, 1437 and 1521 cm^ꢁ1. Vibrational mode analysis

shows that these four Raman bands all contain major compo-

nents of the vibrational modes within the pyrrole rings. For

example, the Raman band at 1437 cm^ꢁ1is mainly from

symmetric stretching of the C_a–C_meso–C_abonds and bending

deformation of pyrrole rings, including rocking of the hydrogen

atoms within the pyrrole rings. Thus, the resonance in the

excited state associated with the higher-energy Soret band

enhances the vibrational modes in pyrrole rings more than

those in tolyl rings. The Raman bands that appear at 1356 and

1473 cm^ꢁ1under both excitation wavelengths (435.7 nm and

368.9 nm) are attributed to vibrational modes from both tolyl

rings and pyrrole rings.

TD-DFT calculations on split Soret bands

To unveil the nature of the split Soret bands, time-dependent

density functional theory (TD-DFT) calculations on the elec-

tronic transitions of 2a were performed. The geometry of the

ground-state singlet (S₀) was optimized, and vertically excited

states were obtained via TD-DFT calculations. Notably, the

composition and spin density distribution of the FMOs of 2a are

in excellent agreement with the classical four-orbital model

proposed by Gouterman;¹⁴the contributions from the

porphyrin ligand to HOMOꢁ1, HOMO, LUMO and LUMO+1

amount to 99.8%, 95.5%, 97.5% and 97.7%, respectively

(Fig. 7A). The simulated UV-vis absorption spectrum of 2a,

which shows high resemblance to the one obtained experi-

mentally, is depicted in Fig. 7B. The calculations show that the

Q bands at 565 nm originated mainly from HOMO / LUMO

(S1, 79%) and HOMO / LUMO+1 (S2, 79%), which can be

categorized as IL p / p* transitions of porphyrin. Neverthe-

less, assigning the nature of the transitions that constitute the

low-energy (412 nm, S7/S8) and high-energy Soret bands

(377 nm, S9/S10) is not straightforward, as both Soret bands

consist of several vertical transitions involving 4 to 6 pairs of

molecular orbitals. Accordingly, we examined the natural-

transition orbitals (NTOs), which can provide a much more

compact description of the excitations than the MOs. As listed

in Table S3,† the excitation S7/S8, which relates to the low-

energy Soret band, can be described as 68% porphyrin-based

p–p* transition and 32% MLCT, while S9/S10, in association

with the higher-energy Soret band, are attributed to MLCT

transition mixed with intraligand charge transfer (ILCT)

character.

Fig. 7 (A) Frontier molecular orbitals (HOMOꢁ1, HOMO, LUMO and

LUMO+1), (B) simulated (solid line) and experimental (dashed line) UV- Fig. 8 Resonance Raman spectra of 2a with excitation wavelengths of

vis absorption spectra of 2a (number in parenthesis is the experimental (a) 435.7 nm and (b) 368.9 nm; (c) Raman spectrum of 2a calculated by

abs l_max).

DFT.

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Nanosecond time-resolved absorption spectroscopy

The nanosecond time-resolved absorption diﬀerence (ns-TA)

spectrum of 2c, as a representative of bis-NHC complexes, is

examined, and the following spectral features are noted (Fig. 9,

top): (1) there are two intense positive absorption peaks at 388

and 468 nm, respectively, which are redshied from the ground-

state double Soret bands; (2) a broad, moderately intense

positive absorption lies from ca. 550 nm to 800 nm. Indeed,

despite a marked redshi of the excited-state Soret band by over

30 nm and a shorter-lived triplet state decay (s_468nm¼ 2.6 ms),

the ns-TA spectrum of 2c resembles the spectral prole of its

counterparts 3, 4, and [Ir^III(oep)Cl(CO)] (Fig. 9, bottom).

Fig. 10 Normalized emission spectra of 2c, 3, 4 and [Ir^III(oep)Cl(CO)] in

degassed CHCl₃.

Emission spectroscopy

parent (F_em¼ 0.08–0.29% vs. 2.92%; s ¼ 0.5–1.7 vs. 101.0 ms). (3)

Modication of NHC ligand exerts a negligible eﬀect on both

the emission prole and emission l_max, as demonstrated for

2c–2e (Fig. S16†). (4) Increasing the number of NHC ligands, as

shown in the case of [Ir^III(F₂₀tpp)Cl(CO)], 1d and 2f, results in

a progressive redshi in the emission l_maxfrom 676 to 754 nm

(Fig. S17†). (5) Varying the porphyrin ligand causes the emission

l_maxto range from 701 to 775 nm, and l_maxwas found to

increase in the order oep < F₂₀tpp < ttp z tmp. Similar ndings

have previously been reported for Pd^II- and Pt^II-porphyrin

complexes.²⁸

Upon photoexcitation, complexes 1 and 2 (except 2a and 2b)

produce NIR emission with l_maxspanning from 701 to 775 nm

in degassed CHCl₃solution (degassed CH₂Cl₂for 2f) at room

3

temperature. The emission is assigned to the (p, p*) state of

porphyrin; the emission spectra generally feature a broad

though indistinct vibronic shoulder, akin to that of typical

phosphorescent metalloporphyrins.^16,28Several characteristics

can be noted for the emissions of complexes 1 and 2. (1) Their

emission bands are much broader and are redshied with

respect to those of their counterparts. For instance, the Full-

Width-at-Half-Maximum (FWHM) for 2c is two to three times

greater than those of [Ir^III(oep)Cl(CO)], 3 and 4 (i.e., 66 nm vs.

26, 19 and 20 nm, respectively). In addition, the emission l_max

of 2c is 701 nm, which is redshied by more than 35 nm

compared to those of its counterparts (Fig. 10). (2) The solution

emission quantum yields and lifetimes at room temperature are

substantially lower and shorter, respectively. For example, the

F_emvalues of 2c–2e supported by an oep ligand are only 0.03–

0.66%, and s ranges from 1.9 to 3.6 ms. This result is in stark

contrast to the observations of [Ir^III(oep)Cl(CO)] and of the bis-

ligand counterparts 3 and 4, all of which show long-lived (s ¼

55.2–124.7 ms) and strongly emissive ³(p, p*) states of porphyrin

(F_em¼ 5.03–12.30%). Likewise, these observations hold for

complexes supported by F₂₀tpp ligands 1d and 2f versus their

Photochemistry

Recently,

a

panel of Ir^III–porphyrin^16dand Ir^III–corrole²⁹

complexes were found to be eﬃcient singlet oxygen photosen-

sitizers (Table 5).

In particular, the quantum yield of singlet oxygen production

(F_so) by BODIPY conjugates of Ir^III-ttp upon excitation at 690 nm

is up to 0.85. In this work, [Ir^III(por)(NHC)₂]⁺complexes were

also found to be highly eﬃcient photosensitizers for singlet

oxygen production. With reference to the ¹O₂emission intensity

(l_max¼ 1270 nm) of H₂tpp (F_so¼ 0.55 in CHCl₃),³⁰the F_so

values of oxygen-saturated CHCl₃solutions of 2a and 2c were

found to be 0.64 and 0.88, respectively, upon excitation at their

Soret bands (Fig. 11). As described in the previous section, upon

bis-ligation of the NHC ligand to iridium porphyrin, complexes

2 show redshied and broadened Soret and Q bands, resulting

in broad coverage of the visible light spectral region. This

Table 5 The quantum yield of singlet oxygen production (F_so) by 2a,

2c and reported Ir^III–porphyrin and corrole complexes

Complex

F_so

2a

2c

0.64^a

0.88^a

[Ir^III(corrole)(pyridine)₂]

[Ir^III(ttp)(aza-BODIPY)]

0.09–0.15^a29

0.79–0.85^b16d

a

Measured in CHCl₃with reference to the ¹O₂emission intensity of

b

Fig. 9 (Top) The ns-TA spectra of 2c evolved from 0 to 7 ms; inset:

Decay kinetics of absorption diﬀerence at 468 nm. (Bottom) Overlaid

ns-TA spectra of 2c, 3, 4, and [Ir(oep)Cl(CO)] recorded at 0 ms.

H₂tpp. Measured in CH₂Cl₂with reference to the photooxidation of

1,3-diphenylisobenzofuran by methylene blue.

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Table 7 Light-induced aerobic oxidation of arylboronic acid catalyzed

by 2c^a

Entry

R

Convn. (%)^c

Yield (%)^d

1

2

3

4

Cl

Br

CHO

Ph

CN

Br

100

<5%

92%

98%

82%

99%

n.d.^e

5

6^b

Fig. 11 Singlet oxygen emission spectra of H₂tpp, 2a and 2c in

O₂-saturated CHCl₃.

a

Reaction conditions: arylboronic acid (0.1 mmol), diisopropylamine

(0.4 mmol) and 2c (0.5 mmol) in DMF (1.5 mL), O₂bubbling, xenon

lamp (>400 nm). No 2c added. Determined by ¹H NMR analysis of

b

c

the crude reaction mixture. Determined by ¹H NMR analysis using

d

e

spectral feature and the high singlet oxygen quantum yield

enable 2 to act as a photosensitizer for catalytic aerobic oxida-

tion reactions and prompted us to examine the aerobic oxida-

tion of secondary amines and arylboronic acids. When

a solution of dibenzylamine treated with 0.1 mol% of 2a was

bubbled with O₂under light irradiation (l > 400 nm) at room

temperature for 5 h, the corresponding imine was produced in

92% yield with complete substrate conversion (entry 1, Table 6).

Changing the photosensitizer to 2c led to a higher product yield

of 99% (entry 2, Table 6). The reaction also worked for

substrates with halogen/methyl substituted benzyl groups and

tert-butyl groups, furnishing the respective imine products in

96–99% yields (entry 3–5, Table 6). In another reaction, irradi-

ating (l > 400 nm) solutions of para-substituted arylboronic

acids in the presence of diisopropylamine and 0.5 mol% of 2c

for 3 h at room temperature gave rise to the corresponding aryl

alcohols in yields of 82 to 99% (Table 7). The control experi-

ments indicated the necessity of 2a or 2c for both reactions

(entry 6, Table 6; entry 6, Table 7). The mechanisms of the

photochemical reactions were investigated by experiments on

1,1-diphenylethylene as an internal standard. n.d. ¼ not determined.

the quenching of 2a or 2c. The presence of a large excess (1000

equiv.) of amine (i.e., dibenzylamine and diisopropylamine) or

arylboronicacid (i.e., 4-chlorophenylboronic acid) did not have

signicant eﬀect on the lifetimes of the photogenerated 2a* and

2c* under degassed conditions (Fig. S19†). Nevertheless, the

lifetimes of 2a* and 2c* were considerably reduced to 0.16 ms

and 0.09 ms in oxygen-saturated solution, respectively (Fig. 12).

On the basis of these ndings, both photoinduced aerobic

amine oxidation and arylboronic acid oxidation reactions begin

with the oxygen quenching of photogenerated 2a*/2c* by energy

transfer to give ¹O₂, which subsequently oxidizes the secondary

amines to imines or the arylboronic acids to aryl alcohols.

Anticancer properties

We have previously reported various cationic metalloporphyrins,

particularly gold(^III) porphyrins, and metal–NHC complexes that

Table 6 Light-induced aerobic oxidation of secondary amine to

imine, catalyzed by 2a or 2c^a

Entry

PS

X/R

Convn.^b(%)

Yield^c(%)

1

2

3

4

5

6

2a

2c

—

H/Bn

100

<5%

92%

99%

96%

n.d.^d

Cl/^tBu

Br/^tBu

Me/^tBu

H/Bn

a

Reaction conditions: dibenzylamine (0.1 mmol) and catalyst

Fig. 12 Nanosecond time-resolved absorption diﬀerence spectra of

2a in O₂-saturated MeCN (top) and 2c in O₂-saturated DMF (bottom).

Inset: decay kinetic of absorption diﬀerence at 490 nm (top) and

470 nm (bottom).

(0.1 mmol) in MeCN (1.5 mL), O₂bubbling, xenon lamp (>400 nm).

b

Determined by ¹H NMR analysis of the crude reaction mixture.

Determined by ¹H NMR analysis using 1,1-diphenylethylene as an

c

internal standard. ^dn.d. ¼ not determined.

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exhibit promising anticancer and antitumor activities.³¹In this

work, iridium(^III) porphyrin complexes bearing NHC ligand(s)

were found to be stable against ligand exchange with DMSO

or glutathione up to an 24 h incubation, as determined by UPLC-

QTOF mass spectrometry (Fig. S21 and S22†). DMSO-substituted

forms (ca. 8%) were found for 3 (Fig. S21f†). All of the cationic

iridium(^III) complexes exhibit potent cytotoxicity towards a panel

of human cancer cell lines with submicromolar IC₅₀values, while

3 shows generally reduced cytotoxicity (Table 8). Among the bis-

NHC complexes, the higher cellular uptake of 2c (with octae-

thylporphyrin) than that of 2a (with meso-tetratolylporphyrin)

and 2f (with meso-tetrakis(pentauorophenyl)porphyrin) results

in higher cytotoxicity towards diﬀerent cancer cell lines. In

addition, the charge-neutral [Ir^III(oep)Cl(CO)], which showed the

lowest cellular uptake and lipophilicity, is relatively noncytotoxic,

with an IC₅₀value >50 mM to all the cancer cell lines. These

ndings highlight that the cationic character and porphyrin

scaﬀold of iridium(^III) bis-NHC complexes are crucial for facili-

tating eﬃcient accumulation in cells for anticancer activities. On

the basis of the potent in vitro cytotoxicity of 2c, its in vivo anti-

tumor properties were examined. Nude mice bearing NCI-H460

human non-small cell lung cancer xenogras were adminis-

tered 2c (3 mg kg^ꢁ1) via intravenous injection thrice weekly. The

tumor size was reduced by 41% aer a 16 day treatment without

apparent toxicity, including body weight loss and death (Fig. 13).

In view of the advantageous photophysical properties (including

high emission quantum yield and long-lived electronic excited

state) of 2c among the bis-NHC iridium(^III) complexes, cellular

imaging of 2c was performed to examine its subcellular locali-

zation in NCI-H460 cells. As shown in Fig. 14A, the resulting

images clearly revealed that the red-emitting 2c mainly colo-

calized with the green-emitting stain of the endoplasmic retic-

ulum (ER-Tracker) with a high Pearson's correlation coeﬃcient

(R) of 0.903. In contrast, a relatively poor overlap was observed

between the uorescence images of the complex and Mito-

Tracker green or Lyso-Tracker green, with an R-value of 0.548

and 0.210. These ndings indicated that 2c accumulated mainly

Fig. 13 In vivo antitumor activity of complex 2c in nude mouse model

bearing NCI-H460 xenograft. (A) Tumor volume and (B) body weight

of mice. Data are expressed as the mean ꢀ standard error; *p < 0.05.

in the ER and only somewhat in the mitochondria or lysosome in

NCI-H460 cells. We therefore examined if 2c induced ER stress to

the NCI-H460 cells.³²By the western blot analysis, the ER stress-

associated proteins including CHOP and phosphorylated eIF2a

were found to be dose- and time-dependently upregulated upon

treatment with 2c compared to the DMSO vehicle (Fig. 14B),

conrming the induction of ER stress. The impact of 2c on

mitochondria was also examined by monitoring the changes in

mitochondrial membrane potential (MMP, DJ_m). With the use

of a MMP-dependent ratiometric uorescence probe (JC-1), time-

dependent decrease in MMP of NCI-H460 cells was shown upon

the treatment of 2c, as indicated by the progressive change in

uorescence from red to green compared with DMSO vehicle

(Fig. 14C).

Photocytotoxicity

Prompted by the nding that the iridium(^III) porphyrin

complexes are excellent singlet oxygen photosensitizers, we

examined their photocytotoxicity. NCI-H460 lung cancer cells

incubated with the complexes were exposed to a low dose of

visible light irradiation (2.8 mW cm^ꢁ2) for 1 h. The cytotoxicity

of the iridium(^III) porphyrin complexes increased markedly by

10- to 27-fold upon irradiation, and [Ir^III(oep)(IⁱPr)₂]⁺(2e)

Table 8 In vitro cytotoxicity of the selected iridium(III) porphyrin complexes against a panel of human cancer cell lines^abc

IC₅₀(mM)^b

IC₅₀(mM)

NCI-H460

(dark)

NCI-H460

(light)

HeLa

HepG2

MCF-7

HCT116

HCC827

PI^c

Uptake^d

Log P^e

1d⁰

2a

2c

2e

2f

3

0.37 ꢀ 0.10 1.60 ꢀ 0.21 0.71 ꢀ 0.04 0.42 ꢀ 0.06 0.55 ꢀ 0.11 0.46 ꢀ 0.10 0.04 ꢀ 0.003 11.5 235.9 ꢀ 9.81 2.67

0.17 ꢀ 0.1 2.1 ꢀ 0.3 0.65 ꢀ 0.2 0.14 ꢀ 0.04 2.29 ꢀ 0.50 1.22 ꢀ 0.03 0.11 ꢀ 0.08 11.1 147.6 ꢀ 6.4 3.03

0.03 ꢀ 0.01 0.93 ꢀ 0.1 0.16 ꢀ 0.1 0.14 ꢀ 0.1 1.1 ꢀ 0.3 0.15 ꢀ 0.05 0.009 ꢀ 0.004 16.7 309.7 ꢀ 46.7 2.96

0.10 ꢀ 0.1 2.4 ꢀ 0.2 0.73 ꢀ 0.5

0.10 ꢀ 0.1 0.94 ꢀ 0.1 0.26 ꢀ 0.1

7.9 ꢀ 0.5 >100 >100

0.11 ꢀ 0.03. 0.69 ꢀ 0.01. 0.16 ꢀ 0.04 0.006 ꢀ 0.002 26.7 158.7 ꢀ 29.5 3.23

0.4 ꢀ 0.2

23 ꢀ 3.3

1.23 ꢀ 0.10 0.31 ꢀ 0.04 0.03 ꢀ 0.002 10.3 131.3 ꢀ 10.2 2.76

50 ꢀ 3.6 2.9 ꢀ 0.02 0.12 ꢀ 0.02 24.2 116.2 ꢀ 20.6 3.11

4

0.10 ꢀ 0.01 1.32 ꢀ 0.10 0.12 ꢀ 0.02 0.25 ꢀ 0.08 1.27 ꢀ 0.32 0.11 ꢀ 0.005 0.005 ꢀ 0.001 23.1 305.1 ꢀ 57.2 2.83

[Ir^III(oep)Cl(CO)] >50

>50

19.70 ꢀ 1.0

>2.5 34.1 ꢀ 2.8

0.86

2.38

—

Cisplatin

3.80 ꢀ 0.51 6.18 ꢀ 0.82 13.20 ꢀ 1.03 6.94 ꢀ 0.54 9.61 ꢀ 0.81 3.96 ꢀ 0.48 4.61 ꢀ 0.31

—

a

HeLa, cervical epithelial carcinoma; HepG2, hepatocellular carcinoma; MCF-7, breast carcinoma; HCT-116, colorectal carcinoma; HCC827, non-

small cell lung carcinoma; NCI-H460, non-small cell lung carcinoma. ^bIC₅₀values were examined by MTT assay aer incubation of drugs for 72 h.

c

d

PI ¼ IC₅₀(dark)/IC₅₀(light). Cellular uptake was determined by the iridium content (mg) in the cellular proteins (g) aer treatment of the NCI-

e

H460 cells with each complex (1 mM) for 2 h. Lipophilicity was determined by measuring the ratio of the amount of iridium (mg) in each

complex partitioned in n-octanol and saline solution (0.9%, w/v).

302 | Chem. Sci., 2019, 10, 293–309

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Fig. 15 (A) Generation of ROS examined by DCF ﬂuorescence

measurement in NCI-H460 cells treated with or without iridium(^III)

porphyrin complexes (1 mM) for 2 h with or without irradiation by visible

light. (B) Confocal microscopy imaging of ROS generation in cells

incubated with complex 2c with or without irradiation by visible light.

Scale bar: 20 mm. (C) Photooxidation of peptide from thioredoxin by

2c. ESI-MS/MS spectra of the triply charged disulﬁde-bridged peptide

(m/z 421.8638; top) and oxidized peptides (m/z 427.1954; middle, m/z

433.1978; bottom). Fragments with blue labels indicate sites of disul-

ﬁde bond formation, and red labels represent oxidative modiﬁcation

sites.

Fig. 14 (A) Confocal microscopy imaging of NCI-H460 cells treated

with complex 2c (1 mM; l_ex¼ 555 nm, l_em¼ 650–750 nm) for 2 h and

organelle trackers, including ER-Tracker green, Mito-Tracker green

and Lyso-Tracker green (50 nM, l_ex¼ 488 nm, l_em¼ 500–530 nm) for

15 min. The merged images of red and green channels, and the bright

ﬁeld were also shown. Scale bar: 20 mm. (B) Western blot analysis of ER

stress protein markers in NCI-H460 cells after treatment with 2c in

time- and dose-dependent manner. (C) Eﬀect of 2c (1 mM) on mito-

chondrial membrane potential (MMP) analyzed by the ﬂuorescence

ratio of NCI-H460 cells stained with JC-1 (l_ex¼ 488 nm, l_em¼ 530 nm

(green) and 585 nm (red)). Treatments with carbonylcyanide

m-chlorophenylhydrazone (CCCP, 50 mM, 10 min) and DMSO were

served as positive and vehicle controls, respectively.

DCF uorescence intensity, revealing elevated cellular ROS

levels. In particular, a 10-fold elevation in ROS levels in cells

treated with 2c was observed. The result was further corrobo-

rated by the strong green uorescence observed from DCF when

cells were treated with 2c followed by light irradiation (Fig. 15B).

These results conrmed the generation of ROS, possibly ¹O₂, in

NCI-H460 cells treated with Ir(^III) complexes upon visible light

irradiation. We further examined the possibility of protein

oxidation as a consequence of photoinduced oxidative stress

showed the largest enhancement among the complexes exam- caused by 2c. A peptide (RIMKCPGCWTA) from thioredoxin

ined (Table

and Fig. S23†). [Ir^III(oep)(IMe)₂]⁺(2c), (Trx) was employed as a model to investigate the possible

8

[Ir^III(oep)(IⁱPr)₂]⁺(2e) and [Ir^III(oep)(py)₂]⁺(4) exhibited very oxidative modication sites by electrospray ionization tandem

potent cytotoxicity with nanomolar IC₅₀values. For the mono- mass spectrometry (ESI-MS/MS). The peptide was found to

NHC complex [Ir^III(F₂₀tpp)(BIMe)(NH₃)]⁺(1d⁰), signicant undergo oxidative modications in the presence of 2c upon

potentiation of the cytotoxicity was also found under the same irradiation. Three diﬀerent types of oxidized products,

conditions. The cytotoxicity of [Ir^III(oep)Cl(CO)] was also evalu- including the formation of a disulde bridge and the oxidation

ated for comparison. This complex is relatively noncytotoxic in of the sulfur atoms of cysteine and methionine, were charac-

the dark with an IC₅₀value >50 mM and increased to 19.7 ꢀ terized (Fig. 15C, S25 and Tables S6–S8†). The peptide alone as

1.0 mM upon visible light irradiation. For cisplatin, the diﬀer- a control was shown to remain unchanged when incubated in

ence in the phototoxicity index (PI) was <1, indicating an the dark or upon light irradiation (Fig. S24 and Table S5†). As

absence of photoinduced cytotoxicity under our experimental shown in Fig. 15C and S25,† three triplycharged species were

conditions. Thus, the cytotoxicity of the iridium(^III) porphyrin detected with mass diﬀerences of ꢁ0.671 (top), +4.660 (middle)

complexes with the incorporation of axial bis-carbene ligands is and +10.662 (bottom) Da, respectively, from the unmodied

signicantly enhanced under light irradiation.

peptide. Further MS/MS analysis revealed that the most intense

To examine the relationship between photocytotoxicity and peak (m/z 421.8638; Fig. 15C (top), Table S6†) corresponds to the

the photosensitizing properties of the complexes, we measured formation of an intramolecular disulde bond, in which the

the cellular reactive oxygen species (ROS) generation using the resulting fragment y5 and y8 ions bearing free cysteine and

ROS probe H₂DCF-DA aer treatment of cancer cells with the cysteine thioaldehyde residues, respectively, were observed

iridium(^III) porphyrin complexes. As shown in Fig. 15A, no when comparing with the peptide alone (Fig. S26†).

signicant change in DCF uorescence was observed in NCI-

Moreover, additional oxidative modication of the methio-

H460 lung cancer cells incubated with the complexes in the nine residue to give sulfoxide (y3) with a shi of +16 Da was also

dark. Exposure to visible light irradiation resulted in increased found on the disulde-bridged peptide (m/z 427.1954; Fig. 15c

This journal is © The Royal Society of Chemistry 2019

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(middle), Table S7†). In addition, another oxidation product eﬃcacy of 2c was also examined. NCI-H460 tumor-bearing mice

(m/z 433.1978) with a mass increment of +10.662 in a triply were divided into four groups, vehicle control, 2c (3.0 mg kg^ꢁ1),

charged state is ascribed to the addition of two oxygen atoms vehicle control with irradiation, and 2c (3.0 mg kg^ꢁ1) with

(+32 Da) in the singly charged species. MS/MS sequence analysis irradiation, and subjected to two intratumoral injections of the

displayed the identied y-ions, which are attributed to the compounds in a period of 15 days. Mice in the irradiation

oxidized methionine (y3; O-Met, Met +16 Da) and cysteine (y8; groups were injected with 2c or solvent vehicle followed by

O-Cys, Cys +16 Da) of the peptide (Fig. 15c (bottom) and Table exposure of the tumor site to white light (400–800 nm) at

S8†). These results show that treatment with 2c combined with a power density of 110 mW cm^ꢁ2for 30 min on the rst and

light activation promoted the oxidation of cysteine and methi- seventh days. The other two groups of mice received the same

onine residues through a singlet oxygen-mediated mechanism. treatment without irradiation as a control. As shown in Fig. 17A,

To examine the photoinduced cytotoxicity, the apoptotic cell the tumor growth of mice treated with 2c and irradiation was

death and cell cycle progression of the cancer cells treated with markedly decreased by 72% in comparison to that of the vehicle

2c and visible light irradiation were analyzed by ow cytometry.

NCI-H460 cells were incubated with 2c at 0.1 mM, a concentra-

tion that could not lead to strong antiproliferative eﬀects in the

dark. Upon exposure to light irradiation, the proportion of cells

treated with 2c undergoing apoptotic cell death increased from

5.9% to 81.7%, as shown by the annexin-V-FITC/propidium

iodide assay (Fig. 16A). On the other hand, complex 2c

(0.1 mM) did not exhibit a marked eﬀect on the progression of

the cell cycle in the dark, showing only a mild increase in the

G₀/G₁-population from 59.6% to 66.3%. In agreement with the

annexin-V/propidium iodide ow cytometry results above,

visible light irradiation led to a signicant increase in the sub-

G₁population (from 2.2% to 96.9%) as a result of extensive DNA

fragmentation due to cell death (Fig. 16B). We also examined

the antiangiogenic property of 2c in the inhibition of endothe-

lial cell tube formation. As shown in Fig. 16C, moderate inhi-

bition of MS-1 cell tube formation was observed aer treatment

of the complex in the dark, while tube formation was completely

abrogated upon light irradiation. The above results showed that

Fig. 17 In vivo antitumor eﬀects of complex 2c in nude mouse model

bearing NCI-H460 lung cancer xenografts. (A) Tumor volume. (B) Body

weight of mice. (C) Tumor weight after the experiment. Red arrows

indicate the injection of the mice with 2c together with irradiation on

day 0 and day 7. (D) Photo of tumors of each group after treatment for

15 days. Data are expressed as the mean ꢀ standard error; **p < 0.01.

a low dose of 2c causes very low-level cellular damage in the

dark but could induce pronounced apoptosis and inhibition of

angiogenesis upon visible light irradiation. Noticeably, other

iridium porphyrin complexes were also observed to exert similar

eﬀects (Fig. S27–S29†). The in vivo photoinduced therapeutic

Fig. 16 Anticancer properties of 2c (0.1 mM) upon visible light irradiation. (A) Apoptosis/necrosis in NCI-H460 cells as examined by ﬂow

cytometry of annexin-V-FITC/propidium iodide-stained cells. (B) Cell cycle progression in NCI-H460 cells as examined by ﬂow cytometry. (C)

Inhibition of angiogenesis of MS-1 endothelial cells.

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group with light irradiation aer only two injections. In enhances vibrational modes involving the core skeleton to

contrast, treatment with 2c without irradiation was able to which the Ir(^III) ion is directly linked, while the latter (p–p*)

inhibit tumor growth by only 41%. All of the mice displayed excitation enhances mainly the vibrational modes within the

negligible changes in body weight throughout the treatment tolyl rings to which the porphyrin core is connected. Overall, the

period (Fig. 17B). Moreover, the tumor weight of 2c-treated mice experimental ndings from the RR study of 2a concur with the

in the photoirradiation group was found to be much lower than conclusion from DFT calculations that the extra Soret band is

that in the dark control group (Fig. 17C and D), demonstrating associated with an Ir-to-porphyrin MLCT excitation.

the markedly enhanced antitumor eﬃcacy of the combination

of dark and photoinduced tumor inhibitory activities.

Interestingly, the intensity of the MLCT band is found to vary

with the number of NHC ligands, as exemplied in the series

[Ir^III(F₂₀tpp)Cl(CO)] (log 3_MLCT¼ 0), [Ir^III(F₂₀tpp)(IMe)Cl] (1c)

(log 3_MLCT¼ 4.62) and [Ir^III(F₂₀tpp)(IMe)₂]⁺(2f) (log 3_MLCT

¼

Discussion

4.89). Thus, NHC ligands play an indispensable role in

enhancing the allowedness of the MLCT transition. Notably, the

extra Soret band (LMCT band) of high-spin [Mn^III(tpp)]⁺

complexes, typical d-type hyperporphyrins, also displays

comparable intensity to their ‘conventional’ p–p* Soret

band.^14,34This observation was explained by the fact that the

high-lying dp(d_xz, d_yz) orbitals of the Mn^IIIion can undergo

substantial interaction with the porphyrin e_g(p*) orbitals due to

their energetic proximity, which leads to strong mixing of the

The coordination of the NHC ligand to Ir^III–porphyrins causes

several major alterations to the spectral and photophysical

parameters compared to those of the [Ir^III(por)Cl(CO)]

and [Ir(por)L₂]⁺(L

complexes.^16a

¼

isocyanide, pyridine or imidazole)

Split Soret band

All NHC complexes in this work feature two distinct Soret bands p(por) / dp(Mn^III) LMCT and Soret p–p* states.^14,33Thus, we

with comparable intensity. Metalloporphyrins showing split propose that in our case, the strongly electron-donating NHC

Soret bands are classically termed hyperporphyrins.^14,15cThe ligand(s) can boost the Ir dp orbitals to a higher level at which

valence of the metal ions and the nature of the axial ligand(s) they can mix eﬃciently with the porphyrin p* orbitals. This

are known to dictate this spectral attribute. Hyperporphyrins phenomenon in turn enables borrowing of the oscillator

can be divided into p-type and d-type. In d-type hyper- strength from the Soret p–p* transition to enhance the allow-

porphyrins, which are relevant to our case, the metal ions are edness of the MLCT transition. In fact, the intensity of the

generally trivalent or at a higher oxidation state with low metal MLCT Soret band increases at the expense of the p–p* Soret

reduction potential and partially lled dp orbitals. As a result, band from [Ir^III(F₂₀tpp)Cl(CO)], 1c to 2f with log 3_MLCT/log 3_Soret

the extra Soret band is attributed to the ring-to-metal LMCT values of 0/5.42, 4.62/5.10 and 4.89/5.00, respectively. Inciden-

transition of

a_1u(p),a_2u(p) / e_g(dp) character. Metal- tally, the possibility that ruﬄing deformation also contributes

loporphyrins of Fe^III, Mn^IIIand Cr^IIIions are canonical examples to enhancing the MLCT band intensity cannot be ruled out, as

of this type.¹⁴However, this scenario is not applicable to 1 and 2, all reported Ir^III- and Rh^III-porphyrin complexes with such an

which contain a d⁶Ir^IIIion, because all nominal dp (d_xz, d_yz) extra Soret band were found or calculated to have a ruﬄed

orbitals are fully occupied, and no such LMCT transition can porphyrin ring.^5b,6,33

take place in the UV-visible spectral region. Notably, the double

Soret band found in d⁶metalloporphyrin is not unique to our

Spectral redshi, reduced emission quantum yield and

lifetime

Ir–NHC system; a few Ir^III- and Rh^III-porphyrin complexes

bearing phenyl(alkoxycarbonyl)carbene or NHC with a trans

methyl ligand, recently described by Woo and co-workers, also The ruﬄed porphyrin ring, as revealed by X-ray crystallographic

exhibit this spectral attribute.^6,33Woo and co-workers suggested analysis, is a key structural feature of [M^III(por)-NHC] (M ¼ Ir

that orbital mixing with relatively low-energy doubly excited and Rh) complexes.^5b,6Here, the extent of ruﬄing increases with

states, [e_g(dp)]³[a_1u(p),a_2u(p)]³[e_g(p*)]², may be responsible for the number of NHC ligands owing to the enhanced steric

the extra Soret band. Our TD-DFT calculations on 2a indicated congestion. In the literature, out-of-plane ring deformation in

that the high-energy (extra) Soret band mainly comes from the form of either ruﬄing or saddling is well documented to

electronic transitions from the hybrid of the iridium d_xyorbital engender a spectral redshi in both free base porphyrins and

and the p orbitals of the porphyrin's peripheral tolyl groups to metalloporphyrins; the extent of redshi is usually proportional

the core p* porphyrin orbitals (pyrrole rings + mesocarbons), to the magnitude of distortion, albeit in a nonlinear fashion.⁸In

which is best described as an MLCT transition with mixed ILCT addition, metalloporphyrins with deformed porphyrin rings are

character, while the low-energy (conventional) Soret band known to undergo rapid macrocyclic inversion in both the

mainly comes from p / p* IL transitions within the porphyrin ground state and the excited state. This inversion generally

ligand. Based on RR experiments, the independent excitation of leads to diminished luminescence and emission lifetime

2a at the extra Soret band (435.7 nm) and at the conventional compared to those of planar metalloporphyrins as a result of

Soret band (368.9 nm) results in the selective enhancement of the surging nonradiative decay activities in the form of low-

diﬀerent vibrational modes, corroborating that the excited energy out-of-plane vibrations in the excited state.^8a,e,9cIndeed,

states associated with the two bands have diﬀerent character- the mono- and bis-NHC complexes of Ir(^III)-porphyrin in this

istics. In particular, the former (MLCT) excitation primarily work exhibit the aforementioned photophysical attributes of

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nonplanar metalloporphyrins; their Soret and Q bands and from the triplet excited state to molecular oxygen.^35aConsid-

their porphyrin-based ³(p, p*) emissions are markedly ering that the heavy iridium ion with its large spin orbit

redshied by up to 80 nm with respect to the parental [Ir^III(por) coupling constant (x_Ir¼ 3909 cm^ꢁ1) oen confers an ultrafast

Cl(CO)] complexes and bis-ligand analogs (Table 4; Fig. 6 and intersystem crossing rate and triplet-excited-state formation

10). Furthermore, the emission quantum yield and lifetime yield close to unity,³⁸the higher singlet oxygen formation

drop to less than 0.7% and 3.6 ms respectively, with the bis-NHC quantum yield of 2c than of 2a is attributed to the former having

analogs suﬀering more severely. As revealed by the excited-state a longer triplet-state lifetime (s ¼ 2.3 vs. 0.4 ms) (Fig. S19†).

photophysical parameters in Table 9, the increase in the non-

radiative decay constant of the emissive excited state of up to

200 times underlies the decrease in emission quantum yield

and lifetime, although the radiative decay rate constants

increase slightly by 3–14-fold.

Stability, cytotoxicity and photochemical activities

Our previous works showed that porphyrin ligand can stabilize

gold(^III) ion against demetallation under physiological condi-

tions rendering gold(^III) porphyrins to display eﬀective anti-

cancer activity against multiple cancer cell types in vitro and in

vivo.^31a–dWe have also found that as a result of strong s-

Photosensitized singlet oxygen generation

Metalloporphyrins and their derivatives, such as metal- donating property of NHC ligand, pincer gold(^III) and plati-

locorroles, are important classes of photochemical singlet num(^II) complexes containing NHC auxiliary ligand are stable

oxygen sensitizers that exhibit good biocompatibility, strong against ligand exchange reaction under physiological condi-

visible light absorption, high triplet-state quantum yields and tions and these complexes display potent antitumor proper-

long triplet-state lifetimes.^29,35They have been extensively ties.^31e,39By using both porphyrin and NHC ligands altogether,

studied as sensitizers for photodynamic therapy and photo- we prepared a panel of stable octahedral iridium(^III) porphyrin

driven aerobic oxidation reactions.^28c,36,37Several iridium(III)- complexes containing NHC ligand that exhibit potent in vitro

porphyrin and corrole complexes have recently been found to anticancer activities and show signicant inhibition of tumor

exhibit such favorable inherent properties and are capable of growth in vivo upon photo-irradiation.

generating singlet oxygen photochemically.^16d,29In particular,

The Ir(^III) porphyrin complexes bearing bis-NHC or mono-

two s-bonded aza-BODIPY complexes of Ir^III(ttp) were reported NHC axial ligand(s) display a good stability against ligand

to have F_sovalues of 0.79 and 0.85, which are more than 100 exchange with DMSO solvent or glutathione (Fig. S21 and S22†).

times greater than those of the respective free aza-BODIPY Complex 3 bearing bis-isocyanide ligands is more substitution

ligands, revealing the eﬀectiveness of the iridium(^III) labile (Fig. S21f†). Most of the [Ir^III(por)(NHC)₂]⁺complexes

porphyrin moiety in promoting singlet oxygen sensitization.

exhibit cytotoxicity to diﬀerent cancer cell lines with IC₅₀values

Two cationic bis-NHC complexes examined in this work, 2a down to submicromolar concentrations (Table 8). Incorpora-

and 2c, were found to be eﬃcient photosensitizers for the tion of NHC ligand(s) into iridium porphyrin increases lip-

photoinduced aerobic oxidation of secondary amines and aryl- ophilicity of the complexes hence their cellular uptake and

boronic acids. Quenching experiments suggested that singlet accumulation in cancer cells. Complex 2f with meso-tetrakis

oxygen generated by quenching of the excited state of 2a or 2c is (pentauorophenyl)porphyrin ligand displays the lowest

presumably the active oxidant for these photooxidation reac- cellular uptake and lipophilicity among the bis-NHC complexes.

tions. This nding is in good agreement with their high F_soCationic iridium porphyrin complexes show more eﬃcient

values of 0.64 and 0.88, respectively. The singlet oxygen cellular internalization and hence increase in anticancer activity

quantum yield of a photosensitizer is determined by the triplet- as indicated by lower IC₅₀values compared to those of the

excited-state quantum yield and the eﬃciency of energy transfer neutral complex [Ir^III(oep)Cl(CO)] and the isoelectronic

Table 9 k_rand k_nrvalues of Ir^III(por) complexes in CHCl₃solutions at 298 K

Complex

F_em[ꢄ10^ꢁ2

]

s_em/ms

k_r^a[ꢄ10]/s

k_nr^b[ꢄ10³]/s

[Ir^III(tmp)Cl(CO)]

[Ir^III(oep)Cl(CO)]

0.22

5.03

2.92

0.05

0.06

0.29

0.41

0.66

0.03

0.08

6.40

12.30

77.2

83.3

101.0

1.8

2.3

1.7

2.7

3.6

1.9

0.5

2

60

29

28

13

11

10

[Ir^III(F₂₀tpp)Cl(CO)]

[Ir^III(tmp)(IMe)Cl]

[Ir^III(tmp)(BIMe)Cl]

[Ir^III(F₂₀tpp)(BIMe)Cl]

[Ir^III(oep)(IMe)₂]⁺

[Ir^III(oep)(BIMe)₂]⁺

[Ir^III(oep)(IⁱPr)₂]⁺

1a

1b

1d

2c

2d

2e

2f

3

555

435

587

368

276

526

1998

8

26

171

152

183

16

160

52

[Ir^III(F₂₀tpp)(IMe)₂]^+c

[Ir^III(oep)(CNPhOMe)₂]⁺

[Ir^III(oep)(py)₂]⁺

124.7

55.3

4

222

16

a

b

c

Radiative decay rate constant determined by k_r¼ F_em/s. Nonradiative decay rate constant determined by k_nr¼ (1 ꢁ F_em)/s. Data in CH₂Cl₂.

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[Ru^II(oep)(CO)] reported by Bogoeva and co-workers.⁴⁰Complex manuscript. Ka-Chung Tong and Wai-Lun Kwong carried out

2c accumulates preferentially in cellular ER and somewhat in the biological experiments. Chen Yang was responsible for X-ray

mitochondria as shown by the confocal laser microscopy crystal structure determinations and assisted the time-resolved

images in the co-staining experiments, which could account for spectroscopic measurements. Ming-De Li and David Lee Phil-

the subsequent induction of ER stress and mitochondrial lips carried out the resonance Raman spectroscopic measure-

membrane depolarization by this complex.

ments. Xianguo Guan, Vanessa Kar-Yan Lo, and Sharon

Incorporation of bis-NHC ligands to iridium(^III) porphyrin Lai-Fung Chan were responsible for the DFT/TDDFT calcula-

also endows the complexes to display remarkable singlet oxygen tions on UV-vis absorption spectra as well as resonance Raman

production capability. Complex 2c (with octaethylporphyrin) has spectra and the associated vibrational mode assignments. All

the highest F_socompared to 2a (with meso-tetratolylporphyrin) authors reviewed the manuscript.

and other iridium(^III) complexes ([Ir^III(corrole)(pyridine)₂] and

[Ir^III(ttp)(aza-BODIPY)]) without bis-NHC ligands; it exhibits

potent cytotoxicity with an IC₅₀value in the nano-molar range

Conﬂicts of interest

and triggers the generation of ROS upon visible light irradiation. There are no conicts to declare.

1

The photo-induced production of ROS (e.g., O₂) was found to

lead to oxidation of sulfur-containing residues of peptides,

which is presumably a cytotoxic, protein-damaging mechanism.

Acknowledgements

The photo-cytotoxic eﬀects led to induction of apoptotic cell We thank Faisal Mehmood and Pui-Yan Lee for the help on bio-

death and inhibition of angiogenesis. The in vivo photo-induced logical studies. This work is nancially supported by Hong Kong

antitumor eﬀect of 2c was demonstrated in a mouse xenogra Research Grants Council, General Research Fund (17303815),

model of human lung cancer. Overall, given the synergetic Innovation and Technology Fund (ITS/130/14FP) and Basic

anticancer properties of the prototype bis-NHC iridium(^III) Research Program-Shenzhen Fund (JCYJ20160229123546997 and

porphyrin complexes in the dark and upon light activation as JCYJ20170412140257516).

well as the exibility in derivatization of NHC ligand, cationic

[Ir^III(por)(NHC)_n]⁺(H₂por ¼ porphyrin; n ¼ 1 or 2) complexes

Notes and references

have great potential for development as a new class of photo-

activated anticancer agents.

1 Selected reviews: (a) N-Heterocyclic Carbenes in Synthesis, ed.

S. P. Nolan, Wiley-VCH, New York, 2006; (b) N-Heterocyclic

Carbenes in Transition Metal Catalysis, ed. F. Glorius,

Springer-Verlag, Berlin, Heidelberg, 2007, vol. 21; (c)

Conclusions

´

We synthesized a panel of luminescent ruﬄed iridium(III)

porphyrin complexes bearing mono- and bis-NHC ligands, four

of which were structurally characterized by X-ray crystallog-

raphy. The unique photophysical properties resulting from the

coordination of NHC ligands, including split Soret bands,

broadened and redshied absorption and emission spectra and

substantially reduced emission quantum yield and lifetime,

were investigated by spectroscopic and theoretical means and

discussed. In spite of the low triplet-state energy, which limits

their use as a photoredox mediator, the bis-NHC complexes are

versatile photochemical singlet oxygen generators that can

eﬃciently catalyze the photoinduced aerobic oxidation of

secondary amines and arylboronic acids. In addition, the bis-

NHC complexes are stable in physiological conditions and

exhibit potent cytotoxicity and photocytotoxicity, presumably

via the generation of ROS, against a panel of cancer cell lines,

and one was demonstrated to have signicant inhibitory eﬀects

against tumor growth in a nude mouse model.

S. Dıez-Gonzalez, N. Marion and S. P. Nolan, Chem. Rev.,

2009, 109, 3612–3676; (d) L.-A. Schaper, S. J. Hock,

W. A. Herrmann and F. E. Kuhn, Angew. Chem., Int. Ed.,

2013, 52, 270–289; (e) A. Nasr, A. Winkler and M. Tamm,

Coord. Chem. Rev., 2016, 316, 68–124; (f) D. Janssen-Muller,

C. Schlepphorst and F. Glorius, Chem. Soc. Rev., 2017, 46,

4845–4854.

¨

2 Selected reviews: (a) L. Meres and M. Albrecht, Chem. Soc.

Rev., 2010, 39, 1903–1912; (b) R. Visbal and M. C. Gimeno,

Chem. Soc. Rev., 2014, 43, 3551–3574; (c) M. Elie,

J.-L. Renaud and S. Gaillard, Polyhedron, 2018, 140, 158–168.

3 Selected reviews: (a) K. M. Hindi, M. J. Panzner, C. A. Tessier,

C. L. Cannon and W. J. Youngs, Chem. Rev., 2009, 109, 3859–

3884; (b) M.-L. Teyssot, A.-S. Jarrousse, M. Manin, A. Chevry,

S. Roche, F. Norre, C. Beaudoin, L. Morel, D. Boyer,

R. Mahiou and A. Gautier, Dalton Trans., 2009, 6894–6902;

(c) L. Oehninger, R. Rubbiani and I. Ott, Dalton Trans.,

2013, 42, 3269–3284; (d) W. Liu and R. Gust, Chem. Soc.

Rev., 2013, 42, 755–773; (e) F. Cisnetti and A. Gautier,

Angew. Chem., Int. Ed., 2013, 52, 11976–11978; (f) C. Hu,

X. Li, W. Wang, R. Zhang and L. Deng, Curr. Med. Chem.,

2014, 21, 1220–1230; (g) W. Liu and R. Gust, Coord. Chem.

Rev., 2016, 329, 191–213.

Author contributions

Chi-Ming Che designed and initiated this research project.

Chun-Nam Lok designed the biological experiments. Tsz-Lung

Lam synthesized and characterized all complexes in this work,

performed the spectroscopic and electrochemical measure-

ments and carried out the photocatalytic reactions. Tsz-Lung

Lam, Chun-Nam Lok, and Chi-Ming Che wrote the

4 Selected reviews: (a) P. L. Arnold and I. J. Casely, Chem. Rev.,

2009, 109, 3599–3611; (b) H. Jacobsen, A. Correa, A. Poater,

C. Costabile and L. Cavallo, Coord. Chem. Rev., 2009, 253,

687–703; (c) J. C. Y. Lin, R. T. W. Huang, C. S. Lee,

Chem. Sci., 2019, 10, 293–309 | 307

View Article Online

Chemical Science

Edge Article

A. Bhattacharyya, W. S. Hwang and I. J. B. Lin, Chem. Rev.,

2009, 109, 3561–3598; (d) P. G. Edwards and F. E. Hahn,

Dalton Trans., 2011, 40, 10278–10288; (e) S. J. Hock,

M. Nakamura, Inorg. Chem., 2010, 49, 10400–10408; (d)

M. Li, A. G. Oliver, T. J. Neal, C. E. Schulz and

W. R. Scheidt, J. Porphyrins Phthalocyanines, 2013, 17, 118–

124; (e) D. Sahoo and S. P. Rath, Chem. Commun., 2015, 51,

16790–16793.

¨

L.-A. Schaper, W. A. Herrmann and F. E. Kuhn, Chem. Soc.

Rev., 2013, 42, 5073–5089; (f) C. Fliedel, G. Schnee,

´

T. Aviles and S. Dagorne, Coord. Chem. Rev., 2014, 275, 63– 13 (a) R. Salzmann, C. J. Ziegler, N. Godbout, M. T. McMahon,

86; (g) S. Bellemin-Laponnaz and S. Dagorne, Chem. Rev.,

K. S. Suslick and E. Oldeld, J. Am. Chem. Soc., 1998, 120,

11323–11334; (b) Z. Yao, C. E. Schulz, N. Zhan and J. Li,

Inorg. Chem., 2017, 56, 12615–12624.

´

2014, 114, 8747–8774; (h) V. Charra, P. de Friemont and

P. Braunstein, Coord. Chem. Rev., 2017, 341, 53–176.

¨

5 (a) M. Albrecht, P. Maji, C. Hausl, A. Monney and H. Muller- 14 M. Gouterman, in The Porphyrins, ed. D. Dolphin, Academic

Bunz, Inorg. Chim. Acta, 2012, 380, 90–95; (b) J. Olguin, Press, New York, 1978, vol. 3, pp. 1–165.

H. Mullen-Bunz and M. Albrecht, Chem. Commun., 2014, 15 (a) L. K. Hanson, M. Gouterman and J. C. Hanson, J. Am.

¨

50, 3488–3490.

Chem. Soc., 1973, 95, 4822–4829; (b) A. Antipas,

J. W. Buchler, M. Gouterman and P. D. Smith, J. Am. Chem.

Soc., 1978, 100, 3015–3024; (c) A. Antipas, J. W. Buchler,

M. Gouterman and P. D. Smith, J. Am. Chem. Soc., 1980,

102, 198–207; (d) L. M. A. Levine and D. Holten, J. Phys.

Chem., 1998, 92, 714–720.

6 B. J. Anding, A. Ellern and L. K. Woo, Organometallics, 2014,

33, 2219–2229.

7 K.-H. Chan, X. Guan, V. K.-Y. Lo and C.-M. Che, Angew.

Chem., Int. Ed., 2014, 53, 2982–2987.

8 (a) C. M. Drain, C. Kirmaier, C. J. Medforth, D. J. Nurco,

K. M. Smith and D. Holten, J. Phys. Chem., 1996, 100, 16 (a) K. Koren, S. M. Borisov, R. Saf and I. Klimant, Eur. J. Inorg.

11984–11993; (b) J. A. Shelnutt, X.-Z. Song, J.-G. Ma,

S.-L. Jia, W. Jentzen and C. J. Medforth, Chem. Soc. Rev.,

1998, 27, 31–42; (c) A. B. Parusel, T. Wondimagegn and

A. Ghosh, J. Am. Chem. Soc., 2000, 122, 6371–6374; (d)

R. E. Haddad, S. Gazeau, J. Pecaut, J.-C. Marchon,

C. J. Medforth and J. A. Shelnutt, J. Am. Chem. Soc., 2003,

125, 1253–1268; (e) A. Y. Lebedev, M. A. Filatov,

Chem., 2011, 1531–1534; (b) K. Koren, R. I. Dmitriev,

S. M. Borisov, D. B. Papkovsky and I. Klimant,

ChemBioChem, 2012, 13, 1184–1190; (c) B.-B. Wang, H. Zho,

J. Mack, P. Majumdar, T. Nyokong, K. S. Chan and

Z. Shen, J. Porphyrins Phthalocyanines, 2015, 19, 973–982;

(d) J. Zhou, L. Gai, Z. Zhou, J. Mack, K. Xu, J. Zhao, H. Qiu,

K. S. Chan and Z. Shen, RSC Adv., 2016, 6, 72115–72120.

A. V. Cheprakov and S. A. Vinogradov, J. Phys. Chem. A, 17 Selected examples of coordinating NHC ligand to iridium

2008, 112, 7723–7733; (f) F. Niatis, W. Su, J. E. Haley,

J. E. Slagle and T. M. Copper, J. Phys. Chem. A, 2011, 115,

13764–13772; (g) M. O. Senge, S. A. MacGowan and

J. M. O'Brien, Chem. Commun., 2015, 51, 17031–17063.

9 (a) C. J. Medforth, M. O. Senge, K. M. Smith, L. D. Sparks and

J. A. Shelnutt, J. Am. Chem. Soc., 1992, 114, 9859–9869; (b)

K. M. Kadish, M. Lin, E. Van Caemelbecke, G. De Stefano,

metal center via transmetallation of [Ag(NHC)₂]⁺

complexes: (a) S. Burling, M. F. Mahon, S. P. Reade and

M. K. Whittlesey, Organometallics, 2006, 25, 3761–3767; (b)

L. N. Appelhans, C. D. Incarvito and R. H. Crabtree,

J. Organomet. Chem., 2008, 693, 2761–2766; (c)

U. Hintermair, U. Englert and W. Leitner, Organometallics,

2011, 30, 3726–3731.

C. J. Medforth, D. J. Nurco, N. Y. Nelson, B. Krattinger, 18 C.-M. Che and W.-Y. Yu, Pure Appl. Chem., 1999, 71, 281–288.

C. M. Muzzi, L. Jaquinod, Y. Xu, D. C. Shyr, K. M. Smith

and J. A. Shelnutt, Inorg. Chem., 2002, 41, 6673–6687; (c)

A. Rosa, G. Ricciardi, E. J. Baerends, M. Zimin,

Oxidation state marker band of [Ir^III(tmp)Cl(CO)]: n ¼

1022 cm^ꢁ1; [Ir^III(F₂₀tpp)Cl(CO)]: n ¼ 1026 cm^ꢁ1; [Ir^III(ttp)

Cl(CO)]: n ¼ 1017 cm^ꢁ1; [Ir^III(oep)Cl(CO)]: n ¼ 1022 cm^ꢁ1

.

M. A. J. Rodgers, S. Matsumoto and N. Ono, Inorg. Chem., 19 (a) X. Song and K. S. Chan, Organometallics, 2007, 26, 965–

2005, 44, 6609–6622; (d) N. Grover, M. Sankar, Y. Song and

K. M. Kadish, Inorg. Chem., 2016, 55, 584–597; (e)

J. Schindler, S. Kupfer, A. A. Ryan, K. J. Flanagan,

970; (b) C. W. Cheung and K. S. Chan, Organometallics,

2008, 27, 3043–3055; (c) C. W. Cheung and K. S. Chan,

Organometallics, 2011, 30, 4269–4283.

M. O. Senge and B. Dietzek, Coord. Chem. Rev., 2018, 360, 20 Selected examples: (a) J. M. Meredith, R. Robinson Jr,

1–16.

K. I. Goldberg, W. Kaminsky and D. M. Heinekeym,

Organometallics, 2012, 31, 1879–1887; (b) M. C. Lehman,

P. D. Boyle, R. D. Sommer and E. A. Ison, Organometallics,

2014, 33, 5081–5084; (c) S. Sabater, M. Baya and J. A. Mata,

10 (a) F. D'Souza, M. E. Zandler, P. Tagliatesta, Z. Ou, J. Shao,

E. V. Caemelbeck and K. M. Kadish, Inorg. Chem., 1998, 37,

¨

4567–4572; (b) B. Roder, M. Buchner, I. Ruckmann and

´

M. O. Senge, Photochem. Photobiol. Sci., 2010, 9, 1152–1158.

Organometallics, 2014, 33, 6830–6839; (d) L. Rubio-Perez,

´

11 (a) R. Guilard, K. Perie, J.-M. Barbe, D. J. Nurco, K. M. Smith,

M. Iglesias, J. Munarriz, V. Polo, V. Passarelli, J. J. Perez-

E. Van Caemelbecke and K. M. Kadish, Inorg. Chem., 1998,

Torrente and L. A. Oro, Chem. Sci., 2017, 8, 4811–4822.

37, 973–981; (b) I. Akira and N. Mikio, Chem. Lett., 2005, 21 C. J. Medforth, in The Porphyrin Handbook, ed. K. M. Kadish,

34, 1046–1047l; (c) A. Ikezaki and M. Nakamura,

J. Porphyrins Phthalocyanines, 2016, 20, 1–13.

K. M. Smith and R. Guilard, Academic Press, Boston, 2000,

vol. 5, pp. 1–80.

12 (a) T. Sakai, Y. Ohgo, A. Hoshino, T. Ikeue, T. Saitoh, 22 (a) J. R. Polam, T. K. Shokhireva, K. Raﬃi, U. Simonis and

M. Takahashi and M. Nakamura, Inorg. Chem., 2004, 43,

5034–5043; (b) M. Nakamura, Coord. Chem. Rev., 2006, 250,

2271–2294; (c) A. Tozuka, A. Ikezaki, M. Taniguchi and

F. A. Walker, Inorg. Chim. Acta, 1997, 263, 109–117; (b)

C. J. Medforth, C. M. Muzzi, K. M. Smith, R. J. Abraham,

J. D. Hobbs and J. A. Shelnutt, J. Chem. Soc., Chem.

308 | Chem. Sci., 2019, 10, 293–309

View Article Online

Edge Article

Commun., 1994, 1843–1844; (c) C. J. Medforth, R. E. Haddad,

Chemical Science

C.-N. Lok, C.-H. Leung, N. Zhu and C.-M. Che, Chem.–Eur.

J., 2010, 16, 3097–3113; (e) R. W.-Y. Sun, A. L.-F. Chow,

X.-H. Li, J. J. Yan, S. S.-Y. Chui and C.-M. Che, Chem. Sci.,

2011, 2, 728–736; (f) C.-T. Lum, R. W.-Y. Sun, T. T. Zou and

C.-M. Che, Chem. Sci., 2014, 5, 1579–1584; (g) C. Y. Chung,

S. K. Fung, K.-C. Tong, P.-K. Wan, C.-N. Lok, Y. Huang,

T. Chen and C.-M. Che, Chem. Sci., 2017, 8, 1942–1953; (h)

S. K. Fung, T. Zou, B. Cao, P.-Y. Lee, E. Y. M. Fung, D. Hu,

C.-N. Lok and C.-M. Che, Angew. Chem., Int. Ed., 2017, 56,

3892–3896.

C. M. Muzzi, N. R. Dooley, L. Jaquinod, D. C. Shyr,

D. J. Nurco, M. M. Olmstead, K. M. Smith, J.-G. Ma and

J. A. Shelnutt, Inorg. Chem., 2003, 42, 2227–2241.

23 (a) H. Scheer and J. J. Katz, in Porphyrins and

Metalloporphyrins, ed. K. M. Smith, Elsevier, Amsterdam,

1975, pp. 399–524; (b) Y. Li, J.-S. Huang, G.-B. Xu, N. Zhu,

Z.-Y. Zhou, C.-M. Che and K.-Y. Wong, Chem.–Eur. J., 2004,

10, 3486–3502; (c) C.-M. Che, C.-M. Ho and J.-S. Huang,

Coord. Chem. Rev., 2007, 251, 2145–2166.

24 C. Swistak, J.-L. Cornillon, J. E. Anderson and K. M. Kadish, 32 T. T. Zou, C.-N. Lok, Y.-M. Fung and C.-M. Che, Chem.

Organometallics, 1987, 6, 2146–2150. Commun., 2013, 49, 5423–5425.

25 (a) R. H. Felton, in The Porphyrins, ed. D. Dolphin, Academic 33 B. J. Anding, J. Brgoch, G. J. Miller and L. K. Woo,

Press, San Diego, 1978, vol. 5, pp. 53–126; (b) P. Chen, Organometallics, 2012, 31, 5586–5590.

O. S. Finikova, Z. Ou, S. A. Vinogradow and K. M. Kadish, 34 L. J. Boucher, Coord. Chem. Rev., 1972, 7, 289–329.

Inorg. Chem., 2012, 51, 6200–6210.

35 (a) M. C. DeRosa and R. J. Crutchley, Coord. Chem. Rev., 2002,

233–234, 351–371; (b) H.-G. Jeong and M.-S. Choi, Isr. J.

Chem., 2016, 56, 110–118; (c) M. Soll, K. Sudhakar,

26 C.-J. Liu, W.-Y. Yu, S.-M. Peng, T. C. W. Mak and C.-M. Che,

J. Chem. Soc., Dalton Trans., 1998, 1805–1812.

27 R. Horvath and K. C. Gordon, Coord. Chem. Rev., 2010, 254,

2505–2518.

¨

N. Fridman, A. Muller, B. Roder and Z. Gross, Org. Lett.,

2016, 18, 5840–5843.

28 (a) S.-W. Lai, Y. J. Hou, C.-M. Che, H.-L. Pang, K.-Y. Wong, 36 (a) G. S. D. Tyler, Y.-Y. Huang and H. R. Michael, in

C. K. Chang and N. Zhu, Inorg. Chem., 2004, 43, 3724–

3732; (b) D. B. Papkovsky and T. C. O'Riordan, J. Fluoresc.,

2005, 15, 569–584; (c) W.-P. To, Y. Liu, T.-C. Lau and

C.-M. Che, Chem.–Eur. J., 2013, 19, 5654–5664.

Handbook of Porphyrin Science, ed. K. M. Kadish, K. M.

Smith and R. Guilard, World Scientic, London, 2014, vol.

27, pp. 255–301; (b) S. Sunaina, A. Aggarwal,

N. V. D. K. Bhupathiraju, G. Arianna, K. Tiwari and

C. M. Drain, Chem. Rev., 2015, 115, 10261–10306.

29 W. Sinha, L. Ravotto, P. Ceroni and S. Kar, Dalton Trans.,

2015, 44, 17767–17773.

30 F. Wilkinson, W. P. Helman and A. B. Ross, J. Phys. Chem.

Ref. Data, 1993, 22, 113–262.

31 (a) C.-M. Che, R. W.-Y. Sun, W.-Y. Yu, C.-B. Ko, N.-Y. Zhu and

H. Z. Sun, Chem. Commun., 2003, 1718–1719; (b) C.-T. Lum,

37 Y.-Z. Chen, Z. U. Wang, H. Wang, J. Lu, S.-H. Yu and

H.-L. Jiang, J. Am. Chem. Soc., 2017, 139, 2035–2044.

38 (a) L. Flamigni, A. Barbieri, C. Sabatini, B. Ventura and

F. Barigelletti, Top. Curr. Chem., 2007, 281, 143–203; (b)

Y. You and W. Nam, Chem. Soc. Rev., 2012, 41, 7061–7084.

Z. F. Yang, H.-Y. Li, R. W.-Y. Sun, S.-T. Fan, R. T.-P. Poon, 39 J. J. Yan, A. L.-F. Chow, C.-H. Leung, R. W.-Y. Sun, D.-L. Ma

M. C.-M. Lin, C.-M. Che and H.-F. Kung, Int. J. Cancer, and C.-M. Che, Chem. Commun., 2010, 46, 3893–3895.

2006, 118, 1527–1538; (c) Y. Wang, Q. Y. He, R. W.-Y. Sun, 40 V. Bogoeva, M. Siksjø, K. G. Sæterbø, T. B. Melø, A. Bjørkøy,

C.-M. Che and J.-F. Chiu, Cancer Res., 2005, 65, 11553–

11564; (d) R. W.-Y. Sun, C. K.-L. Li, D.-L. Ma, J. J. Yan,

M. Lindgren and O. A. Gederaas, Photodiagn. Photodyn. Ther.,

2016, 14, 9–17.

Chem. Sci., 2019, 10, 293–309 | 309

Article Doi

Luminescent ruffled iridium(iii) porphyrin complexes containing N-heterocyclic carbene ligands: structures, spectroscopies and potent antitumor activities under dark and light irradiation conditions

DOI: 10.1039/C8SC02920B

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