Identification of key functionalization species in the Cp?Ir(iii)-catalyzed-: ortho halogenation of benzamides

Article abstract of DOI:10.1039/d0dt00565g

Cp?Ir(iii) complexes have been shown to be effective for the halogenation of N,N-diisopropylbenzamides with N-halosuccinimide as a suitable halogen source. The optimized conditions for the iodination reaction consist of 0.5 mol% [Cp?IrCl2]2 in 1,2-dichlor

Full text of DOI:10.1039/d0dt00565g

Dalton
Transactions
View Article Online
View Journal
PAPER
Identification of key functionalization species in
the Cp*Ir(III)-catalyzed-ortho halogenation of
benzamides†
Cite this: DOI: 10.1039/d0dt00565g
Alexis J. Guzmán Santiago, Caleb A. Brown, Roger D. Sommer
Elon A. Ison
and
*
Cp*Ir(III) complexes have been shown to be effective for the halogenation of N,N-diisopropylbenzamides
with N-halosuccinimide as a suitable halogen source. The optimized conditions for the iodination reac-
tion consist of 0.5 mol% [Cp*IrCl2]2 in 1,2-dichloroethane at 60 °C for 1 h to form a variety of iodinated
benzamides in high yields. Increasing the catalyst loading to 6 mol% and the time to 4 h enabled the bro-
mination reaction of the same substrates. Reactivity was not observed for the chlorination of these sub-
strates. A variety of functional groups on the para-position of the benzamide were well tolerated. Kinetic
studies showed the reaction dependence is first order in iridium, positive order in benzamide, and zero
order in N-iodosuccinimide. A KIE of 2.5 was obtained from an independent H/D kinetic isotope effect
study. Computational studies (DFT-BP3PW91) indicate that a CMD mechanism is more likely than an oxi-
dative addition pathway for the C–H bond activation step. The calculated functionalization step involves
an Ir(V) species that is the result of oxidative addition of acetate hypoiodite that is generated in situ from
N-iodosuccinimide and acetic acid.
Received 15th February 2020,
Accepted 13th April 2020
DOI: 10.1039/d0dt00565g
rsc.li/dalton
a high-yielding and versatile [Cp*Rh(III)]-catalysed system for
the ortho-halogenation of a variety of benzene and acrylic acid
Introduction
Directed catalytic C–H bond activation has become a valuable derivatives, as well as (electron-rich) heterocycles.3a,c Despite
strategy for the synthesis of functionalized molecules and has these advances, several questions remain about the mecha-
been exploited for the development of numerous C–C bond nism for this reaction. For example, the mechanism is believed
forming reactions.1 There have been significant advances in to proceed via a cyclometalated intermediate that arises from
the development of both selective and catalytic C–heteroatom C–H activation of the substrate. However, this type of inter-
(O, N), and C–X (X = halogen) bond forming reactions.2,3 mediate has not been isolated and examined for its catalytic
Organic halides are commonly used as electrophiles in substi- activity. Further, it is not clear whether C–H activation occurs
tution reactions, as core building blocks for the synthesis of prior to, or after the activation of the halogen source. In
nucleophilic organometallic reagents, like Grignard reagents,4 addition, there have been conflicting reports with regards to
and as suitable substrates for numerous cross-coupling reac- the existence of a Rh(V) intermediate which can undergo reduc-
tions.5 In addition, the C(sp2)–X motif plays a key role in the tive elimination to generate the desired product or whether,
properties of many natural products,6 agrochemicals7 and dependent on the substrate, as suggested by Lan and co-
pharmaceuticals.5 Therefore, the need for general direct C–H workers, the reaction proceeds through a Rh(III) species and a
bond halogenation strategies is evident.
bromonium intermediate.8
[Cp*Rh(III)] complexes have been well established as a suit-
More recently, the Martín-Matute group developed a
able catalyst for the activation and functionalization of other- [Cp*Ir(III)] system for the mild iodination of benzoic acids.3j
wise inert C–H bonds. For example, the Glorius group reported The solvent hexafluoroisopropanol (HFIP) was proposed to aid
in lowering the energy barrier for the rate determining step (RDS)
of the reaction (Scheme 1). Also, our group has demonstrated
Department of Chemistry, North Carolina State University, 2620 Yarborough Drive,
catalytic C–H bond activation by H/D exchange experiments
could be achieved with a variety of [Cp*Ir(III)] complexes.9 This
Raleigh, North Carolina 27695-8204, USA. E-mail: eaison@ncsu.edu
†Electronic supplementary information (ESI) available: Additional kinetic and
work led to the catalytic C–H bond activation and functionali-
computational data as well as Crystallographic data. CCDC 1982446–1982448.
For ESI and crystallographic data in CIF or other electronic format see DOI:
zation of benzoic acids with benzoquinones and alkynes to
form the respective benzochromenones10 and isocoumarins.1o
10.1039/d0dt00565g
This journal is © The Royal Society of Chemistry 2020
Dalton Trans.

View Article Online
Paper
Dalton Transactions
Scheme 2 Substrate scope for the iodination of benzamides.
lyst loadings (6 mol%), and reaction times (4 h) were required
for full conversion of the model substrate 1a. A variety of para-
substituted benzamides was tolerated under the optimized
reaction conditions and the yields for a series of brominated
products are shown in Scheme 3. It is worth mentioning that
lower yields were observed overall for all substrates for the bro-
mination reaction. This is particularly true for the naphthyl
Scheme 1 Summary of previous and current work.
1
substituted substrate, as no product was detected by H-NMR
spectroscopy or GC.
Herein, we report the conditions for the Cp*Ir-catalysed halo-
genation of benzamides with N-halossuccinimides as the
halogen source (Scheme 1).
Mechanistic studies
Kinetic data for the catalytic reaction was obtained by
gas chromatography (GC). For these studies 1a was used
as the model substrate. The reaction was observed to have
Results and discussion
Substrate scope
a
positive order dependence with respect to 1a, and
The optimal reaction conditions for the synthesis of haloge- iridium, and approximately a zeroth order dependence on
nated product 2a were utilized for a variety of para-substituted N-iodosuccinimide (see ESI†). Traditionally, proposed mecha-
benzamides (Scheme 2). Overall both electron donating and nisms for directed C–H activation begin with coordination of
electron withdrawing groups were well tolerated under the the substrate to the metal centre, followed by C–H activation.
optimized reaction conditions. In general, electron rich sub-
An H/D kinetic isotope effect experiment was undertaken to
strates resulted in better yields than electron poor substrates. determine if C–H activation occurs prior to or during the turn-
It is worth noting that the 4-methoxy-N,N-diisopropyl- over limiting step of the reaction. The rate of the reaction was
benzamide was low yielding. Although we are still trying to measured independently using 1a and d5-N,N-diisopropyl-
rationalize this, the same result was observed in previous work benzamide. The reaction with d5-benzamide was found to be
focused on the Cp*Ir(III)-catalysed synthesis of isocoumarins.1o approximately half as fast as the reaction with the fully pro-
Based on the success of the iodination reaction, the analo- teated substrate, resulting in a KIE (kH/kD) of 2.5. The observed
gous bromination reaction using N-bromosuccinimide (NBS) value for the KIE is significant and suggests that C–H acti-
as the halogen source was pursued. The reaction proceeded vation occurs prior to or in the turnover limiting step for the
smoothly with NBS as a suitable halogen source. Higher cata- mechanism.11
Dalton Trans.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Dalton Transactions
Paper
Scheme 4 Proposed mechanism for the halogenation of benzamides
involving NXS as the active halogen source.
Scheme 3 Substrate scope for the bromination of benzamides.
Mechanistic proposal
Based on the data, two preliminary mechanisms are proposed
where the functionalization step differs in the halogen source.
The first mechanism begins with chloride abstraction of the
[Cp*IrCl2]2 by AgOTf to generate the active Cp*Ir(OAc)2
complex 4. Benzamide coordination then occurs displacing
the κ1 acetate ligand to form complex 5. C–H activation can
then occur to form the cyclometalated iridacycle 6 with the for-
mation and loss of acetic acid. Incoming halosuccinimide
then coordinates to the iridium centre to form complex 7.
Halogenation then occurs to form complex 8. Two equivalents
of acetic acid regenerate the active Cp*Ir(III) complex
(Scheme 4).
The lack of an observed dependence in iodosuccinimide
suggests that this species may not be the active halogen
source. An alternative mechanism is proposed, where a acetyl
hypohalite is produced in situ, from an off-cycle equilibrium
between acetic acid and the halosuccinimide, and this species
acts as the active halogen source. This acetyl hypohalite can
coordinate to the iridium centre to form complex 9. Upon
coordination, halogenation of the substrate occurs to form 10.
One equivalent of acetate completes the catalytic cycle and
regenerates the Cp*Ir(III) catalyst (Scheme 5).
Scheme 5 Proposed mechanism for the halogenation of benzamides
involving X(OAc) as the active halogen source.
Isolation of complex 6(DMSO)
An analogous cyclometalated complex to the proposed (DMSO)Cl2, N,N-diisopropylbenzamide and acetic acid was
complex 6, stabilized by DMSO has been successfully syn- treated with two equivalents of silver triflate, to abstract
thesized and characterized (Scheme 6). A 1 : 1 : 1 ratio of Cp*Ir the chlorides from the iridium complex and generate the cyclo-
This journal is © The Royal Society of Chemistry 2020
Dalton Trans.

View Article Online
Paper
Dalton Transactions
Scheme 6 Synthesis of complex 6(DMSO).
Chart 1 Examples of stable iodine(I) compounds.
Fig. 1 Thermal ellipsoid plot (50% ellipsoids) of the cationic fragment
of 6(DMSO). The triflate anion is omitted for clarity. Selected bond
lengths (Å): Ir1–S1, 2.267; Ir1–O1, 2.115; Ir1–C2, 2.036; Ir1–Cp*(average),
2.209.
Fig. 2 1H-NMR spectrum for the reaction of 11 (generated in situ) with
6(DMSO). The blue spectrum is the spectrum for 6(DMSO) before the
addition of the halogenation source. The red spectrum is the spectrum
after the addition of 11 (generated in situ) and heating the solution for
2 h. Signals for the organic product are indicated with an asterisk.
metalated complex, 6(DMSO) as a yellow solid in 90% yield
(Scheme 6). This complex has been characterized by 1H,
13C-NMR spectroscopy, elemental analysis (see ESI†). The X-ray
crystal structure for 6(DMSO) is shown in Fig. 1. Bond lengths
and angles are similar to the analogous complex with a benzo-
ate ligand that has been previously reported by our group.1o
1H-NMR spectroscopy (ESI†). This mixture, with a known con-
centration of 11, was then filtered and added to a solution of 6
(DMSO). A 1H-NMR spectrum of the crude reaction mixture
Stoichiometric halogenation
Recently, hypervalent iodine reagents (Chart 1) have gained shows clear product formation after the reaction time (Fig. 2).
interests in the synthetic community for the oxidative
From the 1H-NMR spectrum of a solution containing
functionalization of hydrocarbons as an alternative source of N-halosuccinimide with tetrabutylammonium acetate (TBAOAc),
electrophilic iodine.12 In this class of reagent, dioxoiodanes a shift can be observed for the signal corresponding to the
have been shown to be effective in the oxyiodination of methyl of the acetate group from 1.95 ppm (TBAOAc) to
alkenes and alkynes, where the proposed active halogen source 2.70 ppm (NIS) and to 2.85 ppm for NCS (see ESI†). The corres-
is an acetyl hypoiodite monomer generated in situ from the ponding complex from NIS and TBAOAc, 12, was further
acid promoted decomplexation of such reagents.13
characterized by 13C-NMR and X-ray crystallography (see ESI†)
Acetyl hypoiodite has also been proposed in earlier work by and the crystal structure of 12 is shown in Fig. 3. As expected,
Colobert and coworkers,12a and it was shown that a variety of the structure features an approximately linear geometry
electron-rich substrates can be readily iodinated by NIS in the (174°) around the central iodine atom. The iodine–oxygen
presence of catalytic amounts of trifluoroacetic acid. Based on bond length is significantly longer (2.29 Å) than the analogous
this work, the reactivity of 6(DMSO) towards both acetyl benzoate complexes reported by Muniz and co-workers
hypoiodite and NIS as potential halogen sources in the reac- (2.16–2.20 Å).
tion was investigated.
Complex 12 was examined as a halogen source (Table 1). In
Acetyl hypoiodite, 11, was generated in situ from molecular the absence of a proton source very little reactivity was
iodine and silver acetate. The presence of 11 was confirmed by observed, Table 1 (entry 1). When a polar protic solvent was
Dalton Trans.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Dalton Transactions
Paper
Fig. 3 Thermal ellipsoid plot (50% ellipsoids) for the anion in
[(C4H4O2N)I(OCOCH3)][Bu4N], 12. The cation has been omitted for
clarity. Selected bond lengths (Å) and angles: N1–I1–O3, 174°; I1–O3,
2.293; I1–N1, 2.166. Tetrabutylammonium counterion is not shown for
clarity.
Fig. 4 DFT (B3PW91-D3) calculated energetics for the association of
acetate anion (OAc) with N-halosuccinimide in 1,2-dichloroethane
solvent.
Table 1 Stoichiometric reactivity for 12 with 6(DMSO)
computationally (Fig. 4). The association to form 12 is exergo-
nic (ΔG° = −5.9 kcal mol−1) for X = I, but endergonic for X = Br
(ΔG° = 10.8 kcal mol−1) and X = Cl, (ΔG° = 14.5 kcal mol−1).
The results are consistent with the observed catalytic reactions
as iodination was most facile, followed by bromination (which
required higher temperature and catalysts loadings). However,
chlorination was not observed under any catalytic conditions.
Entrya
Solvent
Additive
% Conversion
C–H activation
1
2
3
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethaned
MeCN
—
—
10b
Tracesc
63
For the C–H activation step of the mechanism, both a (con-
certed-metalation–deprotonation) CMD14 and a direct oxi-
dative addition pathway were considered (Fig. 5). Starting from
a proposed iridium bisacetate, INT-1, addition of benzamide
was considered via one of two coordination modes to yield
INT-2 and INT-3. Benzamide coordination through the oxygen
resulted in INT-2 (ΔG° = 15.7 kcal mol−1). Alternatively, coordi-
nation of benzamide through the nitrogen yields INT-3 (ΔG° =
42.8 kcal mol−1). INT-3 is too high in energy compared to
INT-2, which suggests that oxygen coordination is more likely.
The CMD pathway for C–H bond activation can occur through
TS-1 (ΔG‡ = 24.9 kcal mol−1). On the other hand, the oxidative
addition pathway resulted in a ground state energy for INT-4 at
41.2 kcal mol−1. The high energy of this intermediate (INT-4)
indicates that this pathway is unlikely for C–H bond activation.
2 equiv. H2O
—
4
20
5
6
7
8
9
10
MeCN
MeOH
2 equiv. H2O
—
2 equiv. H2O
—
37
27
34
52
75
29
MeOH
tAmylOH
tAmylOH
2 equiv. H2O
tAmylOH
2 equiv. TFAAd
a General reaction conditions: 15 mg (0.02 mmol) of 6(DMSO),
(0.02 mmol) of the halogen source, and (0.04 mmol) of an additive in
1 mL of 1,2-dichloroethane under air. Percent conversion was deter-
mined by GC with the use of hexafluorobenzene as an internal stan-
dard. b Reaction was carried out under the optimized reaction con-
ditions using 12. c The halogen source was changed to [I(OAc)2](TBA).
d TFAA = trifluoroacetic acid.
utilized, or two equivalents of H2O, were included as an addi-
tive, significant yields of 2a from complex 6(DMSO) were
observed (entries 3–10). These results suggest that an acidic
proton is needed to generate the active I(OAc) species in situ. It
should also be noted that protic sources with coordinating
counterions like acetate could result in the formation of other
stabilized complexes which are less reactive. This was demon-
strated when [I(OAc)2](TBA) (Table 1, entry 2) was utilized.
Moreover, a bis-succinimide stabilized complex was identified
by X-ray crystallography in the reaction of NIS with TBAOAc
(see ESI†).
Computational mechanistic analysis
The formation of the proposed acetyl hypohalite by the associ-
Fig. 5 DFT (B3PW91-D3) calculated energetics for the C–H activation
ation of acetate anion with NXS (X = Cl, Br, I) was modelled step in 1,2-dichloroethane.
This journal is © The Royal Society of Chemistry 2020
Dalton Trans.

View Article Online
Paper
Dalton Transactions
Thus, the acetate assisted CMD pathway is lower in energy
than that the oxidative addition pathway and is more likely to
occur for C–H bond activation.
Functionalization with N-iodosuccinimide
The functionalization with N-iodosuccinimide was explored in
Fig. 6. Addition of N-iodosuccinimide to INT-6 results in
INT-7. Oxidative addition of the coordinated NIS occurs
through TS-2 with an associated energy of 35.5 kcal mol−1, to
yield an Ir(V) iodide complex INT-8 (ΔG° = 8.2 kcal mol−1).
This step is followed by reductive elimination through TS-3
with an energy barrier of 29.1 kcal mol−1, and results in INT-9
(ΔG° = −8.9 kcal mol−1). Product release from INT-9 and proto-
nation with acetic acid results in the regeneration of the cata-
lyst through TS-4 (21.4 kcal mol−1).
Fig. 8 DFT (B3PW91-D3) calculated energetics for the oxidative
addition of X(OAc) (X = halide) in 1,2-dichloroethane.
35.3 kcal mol−1). Oxidative addition will yield INT-16
(ΔG° = 5.0 kcal mol−1). From there reductive elimination can
occur through TS-8 (14.8 kcal mol−1) to yield INT-17 (ΔG° =
−7.4 kcal mol−1). To complete the catalytic cycle product is
released to regenerate INT-13. On the other hand, the direct
functionalization pathway remains unfavourable for the acetyl
hypoiodite pathway due to the high energy associated with
TS-6 (ΔG‡ = 36.8 kcal mol−1). An alternative functionalization
mechanism that was pursued involved the formation of acetyl
hypoiodite in situ, which acts as the substrate for iodination
(vide supra). From INT-6, initial NIS coordination through the
N–I bond was found to be the most favourable coordination
mode.
Functionalization with iodoacetate
The viability of generating acetyl hypohalite under our reaction
conditions has been demonstrated experimentally, therefore a
pathway using acetyl hypoiodite as the halogen source was
investigated (Fig. 7). Even though iodine coordination is
favoured over oxygen coordination (INT-14 is lower in energy
than INT-15 by 13.7 kcal mol−1), the barrier for oxidative
addition is lower for the oxygen bound acetyl hypoiodite with a
TS energy (TS-7) of 28.2 kcal mol−1 compared to TS-5 (ΔG‡ =
Computational data support a mechanism where the iodosucci-
nimide reacts with acetic acid to generate acetyl hypoiodite
in situ which serves as the halogen source. C–H bond activation
occurs through a CMD type mechanism and the halogenation
of the substrate appears to proceed through an Ir(V) intermedi-
ate which is formed as the oxidative addition product of the
cyclometalated iridacycle (INT-6) and the acetyl hypoiodite. To
account for the differences in reactivity between NIS, NBS and
NCS we compared the energies for the oxidative addition of
the acetyl hypoiodite with each halogen (Fig. 8).
Fig. 6 DFT (B3PW91-D3) calculated energetics for the Ir(III)-catalysed
iodination with N-iodosuccinimide in 1,2-dichloroethane.
From Fig. 8, there is a substantial difference between the
oxidative addition of XOAc dependent on the halogen. The oxi-
dative addition for IOAc proceeds through an accessible
barrier of 26.9 kcal mol−1, whereas the chlorination reaction
was not observed experimentally and proceeds through a calcu-
lated barrier of 33.1 kcal mol−1 (TS-7). The increased catalyst
loading, and the reaction times required for the bromination
reaction are also consistent with a calculated energy for TS-7 of
28.2 kcal mol−1
.
Conclusions
The Cp*Ir(III) catalysed halogenation of benzamides using
N-iodosuccinimides has been optimized and probed mechan-
istically. A variety of para-substituted benzamides were well tol-
erated in this reaction. Additionally, the reaction was adapted
Fig. 7 DFT (B3PW91-D3) calculated energetics for the Ir(III)-catalysed
iodination with I(OAc) in 1,2-dichloroethane.
Dalton Trans.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Dalton Transactions
Paper
to enable the analogous bromination reaction. It was deter- General procedure for the iridium catalysed bromination of
mined that the catalytic reaction has a first order dependence benzamides
in iridium, a positive dependence in benzamide and an
approximately zero order dependence in N-iodosuccinimide.
A foil covered screw cap test tube with a magnetic stirrer was
charged
with
benzamide
(1
mmol,
1.0
equiv.),
Based on these data two reaction mechanisms were proposed,
which differ solely on the nature of the halogen source. These
were then investigated computationally. It was demonstrated
that the formation of acetyl hypoiodite is favourable under our
reaction conditions. Furthermore, for the C–H bond activation
step, an acetate-assisted CMD mechanism was found to be
more likely than an oxidative addition mechanism due to the
high ground state energy of the intermediates for the oxidative
addition pathway. Computational results suggest that
functionalization from acetyl hypoiodite formed in situ is
favoured over direct N-iodosuccinimide functionalization due
to the difference in barriers for the oxidative addition of these
(acetyl hypohalite and N-halosuccinimide) substrates. Finally,
experimental evidence supporting the proposed acetyl hypoio-
dite pathway with a series of stoichiometric studies has been
provided. Thus, the implications of this study are that directed
functionalization of the benzamide substrates utilized here is
facilitated by the ease of oxidative addition of the halogenating
substrate. This result is important for the further development
of methods for the halogenation of aromatic substrates.
N-bromosuccinimide (1.5 mmol, 1.5 equiv.), [Cp*IrCl2]2
(0.06 mmol, 6 mol%), silver triflate (0.24 mmol, 24 mol%),
acetic acid (2 mmol, 2 equiv.) and 1 mL of 1,2-dichloroethane.
The reaction mixture was stirred at 60 °C for 4 hours in an oil
bath. Upon completion, the solution was diluted with di-
chloromethane and filtered through Celite. The solvent was
removed under reduced pressure and the crude reaction
mixture was purified by column chromatography on silica gel.
Synthesis of Cp*Ir(DMSO)(C13H19NO) (6(DMSO))
In a 5 mL storage tube equipped with a stir bar, was added
Cp*Ir(DMSO)Cl2 (119 mg, 0.25 mmol), N,N-diisopropyl-
benzamide (51.3 mg, 0.25 mmol), acetic acid (2 equiv.,
28.6 μL), and AgOTf (2 equiv., 128.5 mg) to 1,2-dichloroethane
(2 mL) and stirred at 60 °C for 1 h. The crude reaction mixture
was then filtered and concentrated under reduced pressure to
remove excess solvent. The resulting residue was dissolved in
minimal dichloromethane. To the concentrated dichloro-
methane solution excess pentane was added to afford a yellow
precipitate. The precipitate was filtered to afford a yellow
powder in 90% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.68
(d, J = 6.0 Hz, 1H, aromatic proton), 7.56 (d, J = 6.0 Hz, 1H, aro-
matic proton), 7.38 (t, J = 6.0, 2H, aromatic proton), 7.20 (m,
1H, aromatic proton), 4.91 (bs, 1H, CH(iPr), 3.76 (bs, 1H, CH
(iPr), 2.93 (s, 3H, CH3(DMSO), 2.56 (s, 3H, CH3(DMSO)), 1.78
(bs, 15H, Cp*), 1.65–1.30 (m, 12H, 4 × CH3(iPr)). 13C-NMR
(100.6 MHz, CD2Cl2) δ (ppm): 8.95, 43.13, 44.20, 52.92, 53.19,
53.46, 53.73, 54.00, 95.37, 124.67, 129.36, 133.71, 137.49.
Elemental analysis: theory: (C, 40.49; H, 5.78; N, 1.57). Found:
(C, 40.98; H, 5.15; N, 1.87).
Experimental
General considerations
IrCl3·3H2O was purchased from Pressure Chemical Company.
The following Ir complexes: [Cp*IrCl2]2,15 Cp*Ir(Me2SO)(OAc)2,1o
Cp*Ir(NHC)(Cl2)2,1o and [Cp*Ir(H2O)3]OTf2 were prepared as
16
previously reported. All other reagents were purchased from
commercial sources and used as received unless stated other-
wise. All reactions were performed under air and using non-dry
1
solvents unless otherwise noted. H and 13C NMR spectra were
Computational analysis
obtained at room temperature on a Varian Mercury 400 MHz
spectrometer or a Varian Mercury 300 MHz spectrometer.
Chemical shifts are listed in parts per million (ppm) and refer-
enced to their residual protons or carbons of the deuterated sol-
vents. Gas chromatography (GC) was performed on a Varian
3800 Gas Chromatograph with a Varian VF-53 ms column.
Elemental analyses were performed by Atlantic Micro Labs, Inc.
This study was carried out using density functional theory
(DFT) with the Gaussian09,17 implementation of the B3PW91
functional.18 All geometry optimizations were carried out
using tight convergence criteria (“opt = tight”) on an ultrafine
grid (“int = ultrafine”). The Stuttgart-Dresden (SDD)19 relativis-
tic effective core potential (RECP) basis set was used for
iridium with an additional f polarization function.20 The def2-
TZVP effective core potential (ECP)21 and basis set was used
for the halogens. The 6-31G** basis set22 was used for all other
General procedure for the iridium catalysed iodination of
benzamides
A foil covered screw cap test tube with a magnetic stirrer was atoms. Solvation energies were computed with geometries
charged with benzamide (1 mmol, 1.0
equiv.), optimized in the gas phase using the SMD method,23 with
N-iodosuccinimide (1.5 mmol, 1.5 equiv.), [Cp*IrCl2]2 dichloroethane as the solvent, as implemented in Gaussian 09.
(0.005 mmol, 0.5 mol%), silver triflate (0.02 mmol, 2 mol%), In this method an IEFPCM calculation is performed with radii
acetic acid (2 mmol, 2 equiv.) and 1 mL of 1,2-dichloroethane. and electrostatic terms from Truhlar and co-workers’ SMD
The reaction mixture was stirred at 60 °C for 1 hour in an oil solvation model.24 Energetics were calculated using the
bath. Upon completion, the solution was diluted with di- 6-311++G** basis set for all atoms and the SDD basis set with
chloromethane and filtered through Celite. The solvent was an added f polarization function on iridium. The def2-TZVP
removed under reduced pressure and the crude reaction ECP and basis set was used for the halogens. All energies are
mixture was purified by column chromatography on silica gel.
reported in kcal mol−1
.
This journal is © The Royal Society of Chemistry 2020
Dalton Trans.

View Article Online
Paper
Dalton Transactions
Chem. – Eur. J., 2014, 20, 12421–12425; (k) D. Gwon, S. Park
and S. Chang, Tetrahedron, 2015, 71, 4504–4511;
(l) S. Mochida, K. Hirano, T. Satoh and M. Miura, Org. Lett.,
2010, 12, 5776–5779; (m) S. Mochida, K. Hirano, T. Satoh
and M. Miura, J. Org. Chem., 2011, 76, 3024–3033;
(n) P. Patel and S. Chang, Org. Lett., 2014, 16, 3328–3331;
(o) H. Kim, K. Shin and S. Chang, J. Am. Chem. Soc., 2014,
136, 5904–5907; (p) C. Suzuki, K. Hirano, T. Satoh and
M. Miura, Org. Lett., 2015, 17, 1597–1600; (q) J. F. Hull,
D. Balcells, J. D. Blakemore, C. D. Incarvito, O. Eisenstein,
G. W. Brudvig and R. H. Crabtree, J. Am. Chem. Soc., 2009,
131, 8730–8731; (r) U. Hintermair, S. W. Sheehan,
A. R. Parent, D. H. Ess, D. T. Richens, P. H. Vaccaro,
G. W. Brudvig and R. H. Crabtree, J. Am. Chem. Soc., 2013,
135, 10837–10851; (s) M. Zhou, N. D. Schley and
R. H. Crabtree, J. Am. Chem. Soc., 2010, 132, 12550–12551;
(t) M. Zhou, D. Balcells, A. R. Parent, R. H. Crabtree and
O. Eisenstein, ACS Catal., 2012, 2, 208–218; (u) M. Zhou,
U. Hintermair, B. G. Hashiguchi, A. R. Parent,
S. M. Hashmi, M. Elimelech, R. A. Periana, G. W. Brudvig
and R. H. Crabtree, Organometallics, 2013, 32, 957–965;
(v) S. Hohloch, S. Kaiser, F. L. Duecker, A. Bolje, R. Maity,
J. Košmrlj and B. Sarkar, Dalton Trans., 2015, 44, 686–693.
3 (a) N. Schröder, J. Wencel-Delord and F. Glorius, J. Am.
Chem. Soc., 2012, 134, 8298–8301; (b) N. Kuhl, N. Schröder
and F. Glorius, Org. Lett., 2013, 15, 3860–3863;
(c) N. Schröder, F. Lied and F. Glorius, J. Am. Chem. Soc.,
2015, 137, 1448–1451; (d) H. Hwang, J. Kim, J. Jeong and
S. Chang, J. Am. Chem. Soc., 2014, 136, 10770–10776;
(e) P. Zhang, L. Hong, G. Li and R. Wang, Adv. Synth. Catal.,
2015, 357, 345–349; (f) G. Qian, X. Hong, B. Liu, H. Mao
and B. Xu, Org. Lett., 2014, 16, 5294–5297; (g) T.-S. Mei,
D.-H. Wang and J.-Q. Yu, Org. Lett., 2010, 12, 3140–3143;
(h) J.-J. Li, T.-S. Mei and J.-Q. Yu, Angew. Chem., 2008, 120,
6552–6555; (i) R. B. Bedford, J. U. Engelhart, M. F. Haddow,
C. J. Mitchell and R. L. Webster, Dalton Trans., 2010, 39,
10464–10472; ( j) E. Erbing, A. Sanz-Marco, A. Vázquez-
Romero, J. Malmberg, M. J. Johansson, E. Gómez-Bengoa
and B. Martín-Matute, ACS Catal., 2018, 8, 920–925.
Conflicts of interest
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript. The authors declare no competing financial
interests.
Acknowledgements
We acknowledge North Carolina State University and the
National Science Foundation (CHE-1664973) for funding and
the NCSU Office of Information Technology High Performance
Computing Services for computational support.
Notes and references
1 (a) S. Rakshit, F. W. Patureau and F. Glorius, J. Am. Chem.
Soc., 2010, 132, 9585–9587; (b) J. Zhang, H. Qian, Z. Liu,
C. Xiong and Y. Zhang, Eur. J. Org. Chem., 2014, 8110–8118;
(c) T. K. Hyster and T. Rovis, J. Am. Chem. Soc., 2010, 132,
10565–10569; (d) M. Keisuke, H. Koji, S. Tetsuya and
M. Masahiro, Chem. Lett., 2011, 40, 600–602; (e) M. Satoshi,
U. Nobuyoshi, H. Koji, S. Tetsuya and M. Masahiro, Chem.
Lett., 2010, 39, 744–746; (f) N. Guimond, C. Gouliaras and
K. Fagnou, J. Am. Chem. Soc., 2010, 132, 6908–6909;
(g) C.-Z. Luo, J. Jayakumar, P. Gandeepan, Y.-C. Wu and
C.-H. Cheng, Org. Lett., 2015, 17, 924–927; (h) K. Morimoto,
K. Hirano, T. Satoh and M. Miura, Org. Lett., 2010, 12,
2068–2071; (i) K. Morimoto, K. Hirano, T. Satoh and
M. Miura, J. Org. Chem., 2011, 76, 9548–9551; ( j) J. Jia,
J. Shi, J. Zhou, X. Liu, Y. Song, H. E. Xu and W. Yi, Chem.
Commun., 2015, 51, 2925–2928; (k) S. Mochida, K. Hirano,
T. Satoh and M. Miura, J. Org. Chem., 2009, 74, 6295–6298;
(l) Y. Unoh, Y. Hashimoto, D. Takeda, K. Hirano, T. Satoh
and M. Miura, Org. Lett., 2013, 15, 3258–3261; (m) Z. Qi,
M. Wang and X. Li, Org. Lett., 2013, 15, 5440–5443;
(n) N. Umeda, K. Hirano, T. Satoh, N. Shibata, H. Sato and
M. Miura, J. Org. Chem., 2011, 76, 13–24; (o) D. A. Frasco,
C. P. Lilly, P. D. Boyle and E. A. Ison, ACS Catal., 2013, 3,
2421–2429.
2 (a) T. Satoh and M. Miura, Chem. – Eur. J., 2010, 16, 11212–
11222; (b) G. Song, F. Wang and X. Li, Chem. Soc. Rev.,
2012, 41, 3651–3678; (c) N. Kuhl, N. Schröder and
F. Glorius, Adv. Synth. Catal., 2014, 356, 1443–1460;
(d) K. Shin, H. Kim and S. Chang, Acc. Chem. Res., 2015, 48,
1040–1052; (e) D.-G. Yu, M. Suri and F. Glorius, J. Am.
Chem. Soc., 2013, 135, 8802–8805; (f) C. Zhang, Y. Zhou,
Z. Deng, X. Chen and Y. Peng, Eur. J. Org. Chem., 2015,
1735–1744; (g) S. H. Park, J. Kwak, K. Shin, J. Ryu, Y. Park
and S. Chang, J. Am. Chem. Soc., 2014, 136, 2492–2502;
4 P. E. Rakita, Safe Handling Practices of Industrial Scale
Grignard Reagents, in Handbook of Grignard Reagents,
ed. G. S. Silverman and P. E. Rakita, Marcel Dekker Inc.,
New York, 1996, pp. 79–88.
5 E.-I. Negishi and A. de Meijere, Handbook of organopalla-
dium chemistry for organic synthesis, Wiley-Interscience,
2002, vol. 2.
6 G. W. Gribble, Acc. Chem. Res., 1998, 31, 141–152.
7 P. Jeschke, Pest Manage. Sci., 2010, 66, 10–27.
8 T. Zhang, X. Qi, S. Liu, R. Bai, C. Liu and Y. Lan, Chem. –
Eur. J., 2017, 23, 2690–2699.
9 M. C. Lehman, J. B. Gary, P. D. Boyle, M. S. Sanford and
E. A. Ison, ACS Catal., 2013, 3, 2304–2310.
(h) N. Wang, R. Li, L. Li, S. Xu, H. Song and B. Wang, J. Org. 10 K. L. Engelman, Y. Feng and E. A. Ison, Organometallics,
Chem., 2014, 79, 5379–5385; (i) Y. Yang, W. Hou, L. Qin, 2011, 30, 4572–4577.
J. Du, H. Feng, B. Zhou and Y. Li, Chem. – Eur. J., 2014, 20, 11 For comparable KIE values: (a) Ref. 3a; (b) L. Wang and
416–420; ( j) D. Gwon, D. Lee, J. Kim, S. Park and S. Chang,
L. Ackerman, Chem. Commun., 2014, 50, 1083–1085.
Dalton Trans.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Dalton Transactions
Paper
12 (a) A.-S. Castanet, F. Colobert and P.-E. Broutin, 16 B. J. Wik, C. Rømming and M. Tilset, J. Mol. Catal. A:
Tetrahedron Lett., 2002, 43, 5047–5048; (b) F. C. Küpper, Chem., 2002, 189, 23–32.
M. C. Feiters, B. Olofsson, T. Kaiho, S. Yanagida, 17 M. Frisch, G. Trucks, H. Schlegel, G. Scuseria, M. Robb,
M. B. Zimmermann, L. J. Carpenter, G. W. Luther, Z. Lu,
J. Cheeseman, G. Scalmani, V. Barone, B. Mennucci and
M. Jonsson and L. Kloo, Angew. Chem., Int. Ed., 2011, 50,
G. Petersson, Gaussian 09 package, 2009.
11598–11620; (c) F. C. Küpper, M. C. Feiters, B. Olofsson, 18 R. G. Parr and W. Yang, Density-Functional Theory of Atoms
T. Kaiho, S. Yanagida, M. B. Zimmermann, L. J. Carpenter,
and Molecules, vol. 16 of International series of monographs
G. W. Luther, Z. Lu, M. Jonsson and L. Kloo, Angew. Chem.,
on chemistry, Oxford University Press, New York, 1989.
2011, 123, 11802–11825; (d) K. Muñiz, B. García, 19 D. Andrae, U. Haeussermann, M. Dolg, H. Stoll and
C. Martínez and A. Piccinelli, Chem. – Eur. J., 2017, 23,
1539–1545.
13 (a) J. Barluenga, J. M. González, P. J. Campos and
G. Asensio, Angew. Chem., Int. Ed. Engl., 1985, 24, 319–320;
H. Preuss, Theor. Chim. Acta, 1990, 77, 123–141.
20 (a) W. J. Hehre, R. Ditchfield and J. A. Pople, J. Chem. Phys.,
1972, 56, 2257–2261; (b) M. Dolg, H. Stoll, H. Preuss and
R. M. Pitzer, J. Chem. Phys., 1993, 97, 5852–5859.
(b) J. Barluenga, Pure Appl. Chem., 1999, 71, 431–436; 21 (a) P. J. Hay and W. R. Wadt, J. Chem. Phys., 1985, 82, 299–
(c) Y. Ashikari, A. Shimizu, T. Nokami and J.-I. Yoshida,
J. Am. Chem. Soc., 2013, 135, 16070–16073.
14 (a) S. I. Gorelsky, D. Lapointe and K. Fagnou, J. Am. Chem.
310; (b) P. J. Hay and W. R. Wadt, J. Chem. Phys., 1985, 82,
270–283; (c) W. R. Wadt and P. J. Hay, J. Chem. Phys., 1985,
82, 284–298.
Soc., 2008, 130, 10848–10849; (b) A. P. Walsh and 22 (a) V. A. Rassolov, M. A. Ratner, J. A. Pople, P. C. Redfern
W. D. Jones, Organometallics, 2015, 34, 3400–
3407; (c) S. I. Gorelsky, D. Lapointe and K. Fagnou,
J. Org. Chem., 2012, 77, 658–668; (d) J. Jiang, R. Ramozzi
and K. Morokuma, Chem. – Eur. J., 2015, 21, 11158–
11164; (e) L. Ackermann, Chem. Rev., 2011, 111, 1315–
1345.
and L. A. Curtiss, J. Comput. Chem., 2001, 22, 976–984;
(b) V. A. Rassolov, J. A. Pople, M. A. Ratner and T. L. Windus,
J. Chem. Phys., 1998, 109, 1223–1229; (c) R. Krishnan,
J. S. Binkley, R. Seeger and J. A. Pople, J. Chem. Phys., 1980,
72, 650–654.
23 J. Tomasi, B. Mennucci and R. Cammi, Chem. Rev., 2005,
105, 2999–3094.
15 C. White, A. Yates, P. M. Maitlis and D. M. Heinekey, (η5-
Pentamethylcyclopentadienyl)Rhodium
Compounds, in Inorganic Syntheses, 2007.
and
-Iridium 24 A. V. Marenich, C. J. Cramer and D. G. Truhlar, J. Phys.
Chem. B, 2009, 113, 6378–6396.
This journal is © The Royal Society of Chemistry 2020
Dalton Trans.