Palladium-catalyzed aryloxy- and alkoxycarbonylation of aromatic iodides in γ-valerolactone as bio-based solvent

Article abstract of DOI:10.1016/j.jorganchem.2020.121407

Fossil-based solvents and triethylamine as a toxic and volatile base were successfully replaced with γ-valerolactone as a non-volatile solvent and K₂CO₃ as inorganic base in the alkoxy- and aryloxycarbonylation of aryl iodides using phosphine-free Pd catalyst systems. By this, the traditional systems were not simply replaced but also significantly improved. In the study, the effects of different reaction parameters, i.e. the use of several other solvents, the temperature, the carbon monoxide pressure, the base and the catalyst concentrations, were evaluated in details on the efficiency of the carbonylations. To gather some information on the mechanism of these reactions, the effects of the electronic parameters (σ) of various aromatic substituents of the aryl iodides as well as the influence of para-substitution of phenol were investigated on the activity. For a comparison, the aryl-substituted aryl iodides were also reacted with methanol and aryl iodide was also alkoxycarbonylated using several different lower alcohols. From the observed correlations between the electronic parameters of the aromatic substituents and the rates, it appears that the rate determining step is the oxidative addition of Ar–I to Pd⁰, provided that sufficient amounts of nucleophiles are present for the ester formation. If this is not the case, the rate of nucleophile attack might determine the overall rate.

Full text of DOI:10.1016/j.jorganchem.2020.121407

Journal Pre-proof
Palladium-catalyzed aryloxy- and alkoxycarbonylation of aromatic iodides in γ-
valerolactone as bio-based solvent
József M. Tukacs, Bálint Marton, Eszter Albert, Imre Tóth, László T. Mika
PII:
S0022-328X(20)30309-0
DOI:
https://doi.org/10.1016/j.jorganchem.2020.121407
JOM 121407
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 29 May 2020
Revised Date: 12 June 2020
Accepted Date: 14 June 2020
Please cite this article as: Jó.M. Tukacs, Bá. Marton, E. Albert, I. Tóth, Láó.T. Mika, Palladium-catalyzed
aryloxy- and alkoxycarbonylation of aromatic iodides in γ-valerolactone as bio-based solvent, Journal of
Organometallic Chemistry (2020), doi: https://doi.org/10.1016/j.jorganchem.2020.121407.
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Palladium-catalyzed aryloxy- and alkoxycarbonylation of
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aromatic iodides in γ-valerolactone as bio-based solvent
József M. Tukacs,a Bálint Marton,a Eszter Albert,a Imre Tóthb and László T. Mikaa*
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a
Department of Chemical and Environmental Process Engineering, Budapest
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University of Technology and Economics, Műegyetem rkp. 3., H–1111, Budapest,
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Hungary.
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b Institute of Chemistry, University of Pannonia, Egyetem u. 10, H–8200 Veszprém,
Hungary.
Dedicated to Professor László Kollár on the occasion of his 65th birthday.
Keywords
Green solvents, aryl halides, homogeneous carbonylation, aromatic substituent
effects, palladium
Abstract
Fossil-based solvents and triethylamine as a toxic and volatile base were successfully
replaced with γ-valerolactone as a non-volatile solvent and K2CO3 as inorganic base
in the alkoxy- and aryloxycarbonylation of aryl iodides using phosphine-free Pd
catalyst systems. By this, the traditional systems were not simply replaced but also
significantly improved. In the study, the effects of different reaction parameters, i.e.
the use of several other solvents, the temperature, the carbon monoxide pressure, the
base and the catalyst concentrations, were evaluated in details on the efficiency of the
carbonylations. To gather some information on the mechanism of these reactions, the
effects of electronic parameters (σ) of various aromatic substituents of the aryl iodides
as well as the influence of para-substitution of phenol were investigated on the
activity. For a comparison, the aryl-substituted aryl iodides were also reacted with
methanol and aryl iodide was also alkoxycarbonylated using several different lower
alcohols. From the observed correlations between the electronic parameters of the
aromatic substituents and the rates, it appears that the rate determining step is the
oxidative addition of Ar–I to Pd0, provided that sufficient amounts of nucleophiles are
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present for the ester formation. If this is not the case, the rate of nucleophile attack
might determine the overall rate.
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1. Introduction
Since the discovery of the Roelen reaction (hydroformylation) [1] and the
Reppe carbonylation, the transition metal-catalyzed carbonylation reactions,
providing facile and versatile methods for the introduction of C=O functionality to
various skeletons, have gained tremendous importance in numerous fields of synthetic
chemistry from laboratories to industrial applications [2]. While several functional
groups, i.e. C=C, C≡C, C–OH etc. can be subjected to carbonylation [3,4,5,6], the
conversion of alkyl– and aryl–X compounds (X = I, Cl, Br) and carbon monoxide in
the presence of a nucleophile represent a fundamental catalytic method for
manufacturing various amides, carboxamides, carboxylic acids, esters, heterocycles,
azides, etc. [7,8,9,10]. The transformation of aryl halides with alcohols and phenols as
O–nucleophiles provides a direct route towards the synthesis of aromatic esters. These
structures have been widely used as building blocks of biologically active compounds
[11] including anti-inflammatory and antiseptic pharmaceuticals [12,13] like those
found in liquid crystals [14,15], photosensitizers [16]. Thus, both alkoxycarbonylation
and aryloxycarbonylation reactions continue to receive significant interest.
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From the series of transition metals, Pd-based catalysts exhibit the highest
efficiencies for alkoxy- and aryloxycarbonylation reactions [7,10] operating under
either homogeneous [17,18,19] or heterogeneous conditions [20, 21, 22]. From the
view of green chemistry, most of the alkoxycarbonylation reactions could be
completed in the corresponding alcohols, i.e. in methanol or ethanol, which serve both
as the reagent and as the solvent. However, aryloxy- and aminocarbonylations either
in homogeneous or heterogeneous systems have been generally performed in fossil-
based common organic solvents such as toluene, tetrahydrofuran, 1,4-dioxane, N,N-
dimethylformamide or even in dichloromethane or 1,2-dichloroethane [6, 7].
Solvents, which have high toxicity and/or high vapor pressure, could have negative
impact on the environment. According to the FDA guidance for industry [23], these
solvents were classified into Class 1 and Class 2, which utilizations should be avoided
or strictly limited, particularly in the pharmaceutical industry [23]. Thus from this
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respect, the use of most of the above-mentioned solvents including methanol should
be restricted. It is well-known that conjugate bases including alkoxides, aryloxides or
amides are always better nucleophiles than their corresponding acid forms, i.e.
alcohols, phenols or amines, respectively. Thus, the problems associated with the use
of environmentally risky protic reagents and harmful solvents can be circumvented in
the carbonylation aryl or alkyl halides by using the appropriate conjugated base as
reagents in an appropriate aprotic solvent.
To exclude hazardous solvents from such alkoxy- and aryloxycarbonylation
reaction, supercritical carbon dioxide [24,25] and ionic liquids [26, 27] were already
successfully utilized as surrogates of conventional ones. However, if a “solvent from
nature” [28] can exhibit appropriate properties such as stability and polarity, which
have been described by Kamlet–Taft parameters [29], those applications should be
preferred. Horváth and co-workers identified γ-valerolactone (GVL) as a renewable
platform molecule [30]. Due to its outstanding physical and chemical properties e.g.
low-vapor pressure [ 31 ], low toxicity (LD50(rat,
= 8800 mg/kg) [30], low
oral)
flammability [32], no peroxide formation [33], GVL can be used as a surrogate of
conventional organic solvents for synthesis and catalysis. Beyond its first application
as a solvent for the dehydration of carbohydrates [34, 35], several important transition
metal catalyzed reactions such as cross-coupling [36, 37, 38], Pt- and Rh-catalyzed
hydroformylation [39, 40], and Pd-catalyzed aminocarbonylation [41] reactions were
successfully performed in GVL without significant changes in the efficiency of the
catalytic systems. Thus, its application for aryloxy- and alkoxycarbonylation reactions
of organic halides could also open an environmentally benign alternative for these
important catalytic transformations.
Herein we report on the phosphine-free Pd-catalyzed aryloxy- and
alkoxycarbonylation reactions of iodoaromatic compounds using γ-valerolactone as a
renewable, environmentally benign reaction medium. The effects of different reaction
parameters, i.e. the use of several other solvents, the temperature, the carbon
monoxide pressure, the base and the catalyst concentrations, were investigated in
details on the efficiency of the carbonylation. The functional group tolerances of
iodoaromatic compounds and O-nucleophiles were also studied.
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2. Experimental
2.1 General
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Toluene, γ-valerolactone, iodobenzene and its derivatives, phenol and its
derivatives, palladium(II)-acetate, triethylamine, inorganic salts (Na2CO3, K2CO3,
KH2PO4) were obtained from Sigma-Aldrich Kft. Budapest, Hungary. Conversions
and yields were determined by GC–FID analysis performed on HP 5890 instrument
(column RESTEC 30 m × 0.25 m × 0.25 µm, injection temperature: 250 °C; starting
oven temperature: 50 °C; rate-1: 2 °C/min; final temperature: 150 °C; rate-2: 25
°C/min; final temperature: 230 °C/min; carrier gas: H2 1.30 mL/min). For the
analysis, 10 µL of the reaction mixture was added to 1 mL of methylene chloride
followed by the addition of 10 µL p-xylene as an internal standard. The products were
identified by GC–MS using Shimadzu QP2010 SE instrument.
2.2 Carbonylation reactions
In a typical experiment, catalyst precursor (Pd(OAc)2, if otherwise not stated:
0.280 mg, 0.00125mmol), 0.5 mmol of iodoaromatic compounds, 0.625 mmol (1.5
equiv.) of O-nucleophile were dissolved in 2.5 mL solvent followed by addition of
1.25 mmol (2.5 equiv.) of base. The reaction mixture was placed in a glass inlet tube
into a 25 mL Parr Hastelloy-C high-pressure reactor equipped with manometer, safety
relief, thermometer and a magnetic stirrer. The reactor was flushed with 10 bar of CO
three times and placed into a pre-heated oil bath to the given temperature. The final
pressure was adjusted at the elevated temperature. The reaction mixture was then
stirred for 4 h. The pressure was monitored and maintained throughout the reaction.
After cooling and venting of the autoclave after a given reaction time, the solution
was removed and immediately analyzed by GC-FID and/or GC–MS.
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3. Results and Discussion
3.1 Phenoxycarbonylation reactions
In order to verify the utilization of γ-valerolactone as a biomass-based alternative
solvent for aryloxycarbonylation reactions, the carbonylative transformation of 0.5
mmol of iodobenzene (1a) and 1.5 equiv. of phenol (2a) to phenyl benzoate (3a) was
selected as a model reaction in 2.5 mL of solvent (Scheme 1). First, the yields were
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compared in the presence of 2.5 equiv. of Et3N as a base using the selected
conventional organic solvents and GVL under literature conditions [18]. Expectedly,
the model substrates showed negligible reactivity in the apolar n-octane (Table 1,
entry 1), however, by the use of common aprotic dipolar media, moderate yields of 3a
were detected at 100 °C after 3 h. GVL gave the highest yield of 3a (70%,
TON=280), which was 1.3 times higher compared to DMSO under identical condition
(Table 1, entries 2–6). Because there are no significant differences between the
polarity/polarizability of DMF, DMSO, and GVL, on the other hand their dielectric
constant is quite similar; its effect on the reaction could be rather limited. The
differences may be explained by the different rates of the oxidative addition of PhI to
zero-valent Pd-carbonyl (Pd(CO)n, n = 1–3) species in different solvents (see step II
in Scheme 2 vide infra), where n probably also depends on the nature of the reaction
medium. Kégl and co-workers have recently calculated that the addition of PhI (1a)
was the most favorable to a 14 electronic Pd-species in DMF, which is the dicarbonyl,
Pd(CO)2 in the absence of a strong donor PPh3 ligand. [42]. The same might be the
case with GVL, which has quite similar solvatochromic parameters to DMF (Table 1).
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Scheme 1. Phenoxycarbonylation of iodobenzene (1a) in the presence of palladium-catalyst
Table 1. Phenoxycarbonyaltion reaction of iodobenzene (1a) in different solventsa
Kamlet–Taft parameters d
LD50 oral rat
(mg kg–1)c
#
Solvent b
TONf
Yield 3a
α
β
π
(%) d
1
2
3
4
5
6
n-octane
toluene
1,4-dioxane
DMF
5000
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.11
0.37
0.69
0.76
0.60
0.01
0.54
0.55
0.88
1.00
0.83
< 5
37
30
51
52
70
< 20
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120
204
208
280
5000[41]
5200[41]
2800[41]
14500[43]
8800[32]
DMSO
GVL
a
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Reaction conditions: 0.5 mmol of iodobenzene (1a), 0.625 mmol of phenol (2a), 0.00125 mmol
(0.25 mol%) of Pd(OAc)2, 2.5 equiv. of Et3N, pCO = 7 bar, 2.5 mL of GVL, T = 100 °C, t = 3 h; RPM
= 400 min–1; b α: DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide; c LD50 from references;
d α: acidity, β: basicity, π: polarity/polarizability obtained from ref. [29]; e GC yield; f TON: Turnover
Number = mmol product/mmol Pd catalyst.
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Next, we have focused on the replacement of Et3N as volatile and toxic (LD50,rat( oral) =
560–590 mg/kg [44]) base in the carbonylation protocol. Thus, the model reaction
was also carried out by using several different of non-volatile, inorganic bases by
varying parallel also the catalyst concentration. By comparing the results (Table 2,
entries 1–6), it was observed that at the catalyst loading above (0.25 mol%), the use of
K2CO3 gave slightly lower yield of 3a than an equivalent amount of Et3N. Similar
difference was reported by Bhanage et al. [18]. By increasing the catalyst
concentration, the difference between the inorganic and organic base become
negligible, except in the case of K2HPO4, proving the Et3N can be replaced either by
potassium or sodium carbonate in this system. Thus, K2CO3 was selected for the
subsequent experiments. The investigation of the effect of catalyst concentration on
the conversion reveals that the Pd-loading could be lowered to 0.5 mol% without a
significant drop in product yields (Table 2, entries 6–10). However, when the activity
or the catalyst costs are considered, 0.1 mol % of Pd-loading or lower seems to be the
best. The carbon monoxide pressure could also be a crucial factor. It was shown that
too low pressure has a deteriorating effect on the yields below 7 bar (Table 2, entries
7, 14, 15), but the yields were not increased by increasing the pressure from 7 to 14
bar. Apparently in this range, CO-insertion either into a Pd-Ph bond (or eventually
into a Pd–OPh bond, Scheme 2) is already fast enough not to be rate determining. By
monitoring the influence of the temperature on the activity it appears that
temperatures below 100 °C are not advantageous for the production of 3a in GVL
(Table 2, entries 8, 11–13).
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Table 2. Phenoxycarbonylation reaction of iodobenzene (1a) and phenol (2a) in
GVLa
Catalyst loading
(mol%)
pCO
(bar)
7
Time
(h)
3
Yield
(%)b
#
Base
T (°C)
TONc
1
0.25
100
100
100
100
100
100
Et3N
K2CO3
Et3N
70
60
97
31
97
98
280
240
48
2
3
4
5
6
0.25
7
3
4
4
4
4
2
2
2
2
14
14
14
14
K2HPO4
Na2CO3
K2CO3
15
48
49
7
8
9
10
1
14
14
14
14
K2CO3
K2CO3
K2CO3
K2CO3
100
100
100
100
4
4
4
4
97
92
69
59
97
0.5
0.25
0.1
184
276
590
6

11
12
13
14
15
0.5
0.5
0.5
1
7
3.5
1
K2CO3
K2CO3
K2CO3
K2CO3
100
100
100
90
4
4
4
4
4
91
65
39
78
34
182
130
78
14
14
78
1
80
K2CO3
34
a
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195
196
197
Reaction conditions: Catalyst precursor: Pd(OAc)2, 0.5 mmol iodobenzene (1a), 0.625
mmol phenol (2a), 2.5 equiv. of base, 2.5 mL of GVL, b GC yield,c TON: Turnover Number
= mmol product/mmol Pd catalyst.
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Scheme 2. Plausible mechanisms for the alkoxy- and aryloxycarbonylation of aryl halogenides
using homogeneous ligand-free Pd-systems based on proposals for Pd-PPh3 analogues.
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Regarding the extensive literature on metal-catalyzed carbonylation [2] relatively
little is known about the exact mechanism of aryloxycarbonylation of aryl halides
using phosphine-free Pd-catalyst systems in the presence of added bases [42].
Generally, two major paths, an alkoxycarbonyl (or aryloxycarbonyl) route (A) and
acyl route (B) have been proposed for phosphine modified Pd-catalysts (Scheme 2)
[45]. Generally, the acyl-route (B) was found to be the operative path with the
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alcoholysis, phenolysis of the formed acyl complexes as rate determing steps (V in
Scheme 2), especially in the absence of added bases [45,46,47]. It has also been
revealed that route A is strongly retarded under CO-pressure in methanol as
coordinated CO blocks the coordination of –OMe (from added NaOMe) to form a Pd-
C(O)OMe (Pd-carbalkoxy) group using Pd-phosphine systems (Scheme 3) [48,49]. It
is not yet known whether this would be also the case using phosphine-free Pd
catalysts. Hartwig and co-workers have found that in the presence of an added base,
the oxidative addition of aryl iodide (step II in Scheme 2) can be considered as the
rate determining step and it is zero order in kinetics in most of the Pd-catalyzed
carbonylation reaction due to the presence of a reactive nucleophile. [50]. It is also
known that CO insertion into a phosphine-ligated Pd-alkyl (step IV) or into a
phosphine-ligated Pd–OMe (step III) bond is frequently undetectably fast similar to
the reaction of an acyl group with an alkoxide nucleophile [49, 51]. Similar findings
were made for the insertion of CO into ligated Pd-aryl bonds and somewhat indirectly
into a ligated Pd–OEt bond [47]. In another study, the reaction of a specific
arylcarbonyl complex, p-CH3-C6H4(CO)Pd(PPh3)2I with aryl-substituted phenols was
found to be a pseudo first order in rate and the ester formation from the approriate
Pd-benzoyl complex was proposed as rate determining [17]. However, in this case, a
tertiary amine (Bu3N) was used instead of a stronger base, possibly limiting the
formation aryloxy nucleophiles. Thus, perhaps the rate of aryloxy nucleophile
formation was determined in the study instead of the phenolysis of a benzoyl-Pd, (p-
CH3-C6H4(CO)Pd) compound. The importance of the nucleophile formation, thereby
also its crucial effect on the overall rate was emphasized by comparing the much
better rates achieved with NaOEt than with Et3N and EtOH as bases in the
alkoxycarbonylation of substituted aryl iodides using a Pd–PPh3 catalyst system [52].
However, as mentioned above, the mechanisms of analogous carbonylations using
phosphine-free Pd-systems have scarcely been studied compared to those of the
traditional Pd-triphenylphosphine systems, probably due to instability of the Pd-
species involved and the difficulties in the adequate analyses. What well-established
is that Pd(OAc)2, which can be present in different coordination modes [53, 54],
undergoes reduction to zevovalent Pd-carbonyls (step I, Scheme 2) at higher
temperatures under CO-pressure in the presence of water [53], alcohols [52] or
phenols [55].
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Scheme 3. CO-pressure and the coordination of CO to Pd retards the coordination of alkoxide or an
attack of the alkoxy nucleophile on the carbonyl resulting in the formation of a phosphine-ligated Pd-
alkyl-alkoxycarbonyl complex, thus turning reaction path from A to the acyl route B [49]. The question
is whether is this also the case with phosphine-free Pd-complexes.
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In order to extend the knowledge about aryloxy- and alkoxycarbonation of aryl
iodide using such phosphine-free systems, particularly the effect of substituents on the
reagents, which could limit or influence the yields of products, were further
investigated in this study. For the sake of comparison all of these reactions were done
under similar reaction conditions and ratios using 0.25 mol% of Pd-loading at 100 °C
for 3 hours of reaction time.
First, the effect of aryl substituents of aryl iodide was studied on the yield and
rate, by using numerous aryl iodides bearing various electron donating or withdrawing
functional groups (Table 3). If the reaction is indeed zero order for the aryl iodide
concentration, turnover frequencies (TOF) can be used for the direct comparison of
reaction rates. However, the TOF values are meaningless when calculated from full or
very close to full conversions as it is not known when they were reached. Also, in the
absence of strong stabilizing ligands, homogenous zerovalent Pd-complexes tend to
coagulate to various extents under the applied carbonylation conditions [53]. For this
reason, only the turnover numbers (TON), (which can otherwise readily be calculated
to TOF values) are given below in the Tables for the comparison of catalyst
effectivity.
Evaluating the results shown in Table 3, it appears that aryl iodides
bearing aryl-substituents with strongly positive electronic parameters (σ+) [56] (1g–
1m) on the phenyl ring (typically electron withdrawing groups in para position)
facilitate the rate of the reaction. Thus, possibly the rate of the crucial oxidative
addition step of R–I (step II in Scheme 2) is increased by the increased polarization of
the C–I bond. To obtain more exact kinetic data, the reactions should be repeated by
using significantly lower Pd-loading in multiple parallel experiments. It should be
noted for these experiments that the reaction of p- and m-bromo iodobenzene (and
also that of p-chloro) leads exclusively to the conversion of iodo functionality, which
allows the use of bromo-substituted esters in subsequent reaction schemes, for
example, involving cross coupling reactions.
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Table 3. Phenoxycarbonylation reaction of iodoaromatic
compounds (1a–1o) and phenol (2a) in GVLa
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Aromatic
iodides
Yield
(%)b
#
Product
3a
σc
TONd
1
2
3
4
5
6
7
8
9
60
77
0
240
1a
H3C
I
–0.17
-0.07
n.a.
308
332
316
336
156
1b
1c
1d
1e
1f
3b
3c
3d
3e
3f
I
83
H3C
79
H3CO
tBu
I
84
–0.27
–0.20
I
39
Cl
I
> 99
> 99
> 99
> 99
> 99
> 99
> 99
79
+0.23 > 396
+0.23 > 396
+0.39 > 396
+0.35 > 396
+0.45 > 396
+0.50 > 396
+0.66 > 396
1g
1h
1i
3g
3h
3i
I
Br
10
11
12
13
14
15
1j
3j
1k
1l
3k
3l
1m
1n
1o
3m
3n
3o
n.a.
n.a.
316
> 99
> 396
a
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284
285
286
287
Reaction conditions: Catalyst precursor: Pd(OAc)2 (0.25 mol%), 0.5
mmol of aryl iodide (1a-1o), 0.625 mmol of phenol (2a), 2.5 equiv. of
K2CO3, pCO = 7 bar, 2.5 mL of GVL, T = 100 °C, t = 3 h. b GC yield.c
d
Hammett electronic parameter [56], TON: Turnover Number =
mmol product/mmol Pd catalyst, n.a.: not applicable or not available.
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291
It was also shown in an already quoted study that the presence of different
substituents of phenols at para position, affected the reaction efficiency in the
presence of tributylamine [17]. Particularly, both +σp and –σp substituents on the
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304
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306
aromatic ring of phenol significantly enhanced the reaction rate compared to
unsubstituted phenol. For this reason, the carbonylation of iodobenzene (1a) was
investigated with various p-substituted phenols (2a–m) but in the presence of K2CO3
as base instead of tributylamine Table 4. As it can be seen, there is no unambiguous
tendency in this case neither way between the electronic parameters (0, negative or
positive σ) of the substituent and the activity. In fact, all the observed activities
(TOF’s between 70–20 h-1) can fall in the range of acceptable experimental errors of
non-stabilized phosphine-free homogeneous Pd-systems. In this sense many parallel
experiments would be required to get statistically reliable data for these systems.
Ultimately, the formation of phenoxy nucleophile is expected to be significantly more
facile using the stronger base K2CO3 than with NBu3 or NEt3 for a plausible
explanation, in addition to that the two catalytic systems are different. As mentioned
above, NaOEt as base also provided much higher rates than Et3N + EtOH in the
alkoxycarbonylation of aryl-substituted aryl iodides using Pd–PPh3 systems [52].
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
Table 4. Phenoxycarbonylation reaction of iodobenzene (1a) and
para-substituted phenols (2b–o) in GVLa
330
12

#
1
O-nucleophile
Product
Yield
(%)b
60
σc
TON
240
2a
0
3a
2
3
2b
2c
76
88
–0.17
–0.27
304
352
4b
4c
4
5
2d
2e
50
87
-0.12
200
348
4d
4e
+0.42
6
7
8
9
2f
2g
2h
2i
91
67
70
86
–0.03
+0.06
+0.23
+0.54
364
268
280
344
4f
4g
4h
4i
10
11
2j
2k
2l
88
84
0
+0.45
n.a.
352
336
0
4j
4k
4l
12
+0.45
a
331
332
333
334
335
Reaction conditions: Catalyst precursor: Pd(OAc)2 (0.25 mol%), 0.5
mmol iodobenzene (1a), 0.625 mmol of substituted phenol (2a-2o),
2.5 equiv. of K2CO3, pCO = 7 bar, 2.5 mL GVL, T = 100 °C, t = 3 h. c
d
Hammett electronic parameter, TON: Turnover Number = mmol
product/mmol Pd catalyst, n.a.: not applicable or not available.
336
337
338
In general, an increased concentration and nucleophile attack of the corresponding
phenoxide anion on the benzoylpalladium complexes [Ph(C=O)Pd(II)I (CO)n], (n=1,2)
is very important for a fast ester formation [52]. The effect of increased concentration
of anionic nucleophile on the esterification reaction was also demonstrated for Co-
catalyzed system, which was optimized for production of methyl-3-pentenoate in
methanol [57].
339
340
341
342
343
344
345
346
347
348
349
3.2 Alkoxycarbonylation reactions
350
351
The GVL-based carbonylation protocol was further explored for the
alkoxycarbonylation of aryl iodides with aliphatic alcohols to form the corresponding
13

352
353
354
esters. The conversion of iodobenzene (1a) with CO in the presence of MeOH (5a) to
methyl-benzoate (6a) was selected as model reaction (Scheme 4).
355
356
357
Scheme 4. Methoxycarbonylation of iodobenzene (1a) in the presence of palladium catalyst
358
359
360
361
362
363
364
The solvent screening (Table 5) gave similar effectivities compared to those obtained
for phenoxycarbonylation of 1a in polar, aprotic solvents using Et3N as base. The
formation of the methyl ester, 6a was only slightly faster than that of the phenyl ester,
3a in GVL (Table 1 entry 6). Similarly, lowering the CO pressure from 14 to 7 bar did
not affected the yield of 6a, however, by applying 3.5 bar, the product yield dropped
by ca. 10% (91%).
365
366
Table 5. Methoxycarbonylation reaction of
iodobenzene (1a) in different solventsa
Yield 6a
#
Solvent
TONc
(%)b
< 5
52
1
3
4
5
n-octane
N,N-dimethylformamide
dimethyl sufloxide
GVL
20
208
244
316
61
79
367
368
369
370
371
372
a Reaction conditions: 0.5 mmol of iodobenzene (1a), 0.625
mmol of methanol (5a), 0.25 mol% of Pd(OAc)2, 2.5 equiv.
of Et3N, pCO = 14 bar, 2.5 mL of GVL, T = 100 °C, t = 3 h;
RPM = 400 min–1; b GC yield. c TON: Turnover Number =
mmol product/mmol Pd catalyst.
373
374
375
376
377
378
As above with phenol (2a), the effect of aryl substituents of aryl iodide was also
studied on the yield and rate, by using numerous aryl iodides bearing various electron
donating or withdrawing functional groups with MeOH under the standard reaction
conditions (Table 6).
379
380
Table 6. Alkoxycarbonylation reaction of iodoaromatic compounds
(1a–o) and methanol (5a) in GVLa
14

381
#
Iodoaromatic compounds
Base
Product Yield (%)b
σc
TONd
316
1
Et3N
79
0
1a
6a
6a
2
K2CO3
> 99
0
> 396
1a
H3C
I
I
3
4
Et3N
71
82
–0.17
–0.17
284
328
1b
6b
6b
H3C
K2CO3
1b
5
Et3N
83
n.a.
332
1d
6d
H3CO
I
I
6
7
8
Et3N
K2CO3
Et3N
84
86
13
–0.27
–0.27
–0.20
336
344
52
1e
6e
6e
6f
H3CO
1e
tBu
tBu
Cl
I
I
1f
1f
9
K2CO3
Et3N
36
74
–0.20
+0.23
+0.23
144
296
6f
6g
6g
I
10
11
1g
1g
Cl
I
K2CO3
> 99
> 396
12
K2CO3
> 99
+0.37
> 396
1p
6p
13
14
K2CO3
Et3N
> 99
58
+0.23
+0.78
> 396
232
1q
1r
6q
6r
a
382
383
384
385
Reaction conditions: Catalyst precursor: Pd(OAc)2 (0.25 mol%), 0.5 mmol of aryliodides
(1a-1j), 0.625 mmol methanol (5a), 2.5 equiv of base, pCO = 7 bar, 2.5 mL of GVL, T = 100
°C, t = 3 h. b GC yield, c Hammett electronic parameter, d mmol product/mmol Pd catalyst, .
n.a.: not applicable or not available.
386
387
388
389
390
391
392
393
394
395
When the yields or TON’s of the carbonylation of iodobenzene are compared in the
presence of phenol (Table 3, entry 1) and of methanol (Table 6, entry 2), it occurs that
phenol gives significantly lower yield than methanol. This is not unexpected as
phenoxide is much worse nucleophile than methoxide, regardless that its formation is
about 5 magnitudes more favorable from K2CO3 than that of the methoxide in the
equilibria based on known pKa values. It is also worthwhile to compare the results of
the methoxycarbonylation of iodobenzene using trimethylamine (Table 6, entry 1) and
K2CO3 (Table 6, entry 2) as bases in the reactions. The inorganic base gives
significantly higher rate than Et3N, parallel with its higher basicity (pKa ~ 12 vs.
15

396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
10.8), i.e. parallel with its higher effectivity in the formation of methoxide
nucleophile. This is again in agreement with the already quoted study by Hu et al.
[52]. Regarding the influence of the electronic parameters of the aromatic substituents
using K2CO3 as base in Table 6, similar conclusions can be drawn as above in the
analogous phenoxycarbonylation experiments (Table 3). Thus, possibly the rate of the
crucial oxidative addition step of R–I (step II) is increased by the increased
polarization of the ipso-C-I bond, as the rate of CO insertion and the nucleophilic
attack on the arylcarbonyl-Pd (steps IV in Scheme 2) should be very fast under these
conditions. In agreement with this reasoning electron donating, -σ substituents retard
the rates compared to the unsubstituted derivative. However, when a similar trend is
sought by the use of Et3N as base in Table 6, there is no unambiguous correlations is
found between σ and the rate. Apparently, the presence of MeOH and Et3N as base
levels off the differences in the oxidative addition aryl iodides indicating that in these
particular systems not the oxidative addition but probably the nucleophilic attack of
the methoxide (step IV) should be the rate determining step (see also the results
below). Interestingly, the presence of p-t-butyl groups as aryl substituent is also
disadvantageous in the methoxycarbonylation of aryl iodide in the presence of neither
base, seemingly not for an electronic reason (see also Table 3).
Finally, the effects of the alkyl groups of several lower alcohols were
investigated in the alkoxycarbonylation of iodobenzene under the standard conditions
(Table 7). Among the used alcohols, methanol was found to be the most effective,
which points again to the importance of the strength and concentration of
nucleophiles. Methoxide is the strongest nucleophile among the other alkoxides or
aryloxides, which can be formed from alcohols or phenols. Other than the strength of
the nucleophile, its concentration is certainly also important as discussed above.
Phenoxide is weaker nucleophile than methoxide but its formation is magnitudes
faster and very favorable from K2CO3 as compared to that of methoxide. Thus,
possibly the high concentration of the phenoxide facilitates high yields and also
prevents the nucleophile attack (step IV) to be the rate limiting step in the
phenoxycarbonylations above (Table 3). Although the methoxide formation is not
favorable using K2CO3, and even less by using Et3N as base in the equilibria based on
pKa’s, the formation of higher or branched alkoxides is even more suppressed. Beside
the weaker strength of nucleophiles from higher alkoxides, their lower concentration
can also contribute to their observed lower effectivity in the alkoxycarbonylations as
16

430
431
432
433
compared to that of MeOH (Table 7). The lower effectivity of the branched
propoxide as sterically hindered nucleophile is also in line with this representation.
Thus, in these systems, with the exception of methanol, the nucleophile attack on the
benzoyl-Pd complex (step IV) is plausibly also involved in rate-limitation.
434
435
436
Table 7 Alkoxycarbonylation reaction of iodobenzene (1a)
with lower alcohols (5b–5o) in GVLa
437
#
Alcohol
Product
Yield
(%)b
>99
TONc
1
2
3
>396
200
5a
5b
5c
6a
7b
7c
50
48
192
4
5
5d
5e
46
51
184
204
7d
7e
a
438
439
440
441
Reaction conditions: Catalyst precursor: Pd(OAc)2 (0.25
mol%), 0.5 mmol of iodobenzene (1a), 0.625 mmol of alcohol
(5a-5e), 2.5 equiv. of K2CO3, pCO = 7 bar, 2.5 mL of GVL, T =
100 °C, t = 3 h. c mmol product/mmol Pd catalyst.
442
443
444
445
3. Conclusion
Fossil-based solvents and triethylamine as toxic and volatile base were successfully
replaced with γ-valerolactone as non-volatile solvent and K2CO3 as also non-volatile
base in the alkoxy- and aryloxycarbonylation of aryl iodides using phosphine-free Pd
catalysts system. By this, the traditional systems were not simply replaced but also
significantly improved. In fact, the applied Pd-loading could be substantially
decreased as the typically applied relatively low, 0.25 mol% loading proved to be
unnecessary too high in many cases. In the study, the effects of different reaction
parameters, i.e. the use of several other solvents, the temperature, the carbon
monoxide pressure, the base and the catalyst concentrations, were evaluated in details
striving for the highest efficiency in the carbonylations. In order to collect some
information on the mechanism of these reactions, the effects of electronic parameters
(σ) of various aromatic substituents of the aryl iodides as well as the influence of
para-substitution of phenol were investigated on the activity. For a comparison, the
aryl-substituted aryl iodides were also reacted with methanol and aryl iodide was also
446
447
448
449
450
451
452
453
454
455
456
457
458
17

459
460
461
462
463
464
465
alkoxycarbonylated using several different lower alcohols. From the observed
correlations between the electronic parameters of the aromatic substituents and the
rates, furthermore excluding the expectedly very fast CO-insertion from the
competition, it appears that the rate determining step is the oxidative addition of Ar–I
to Pd0, provided that sufficient amounts of nucleophiles are present for the ester
formation. If this is not the case, the rate of nucleophile attack might determine the
overall rate.
466
467
468
469
Acknowledgment
This work was funded by National Research, Development and Innovation Office
under projects KH 129508 as well as Higher Education Excellence Program of the
Ministry of Human Capacities in the frame of Biotechnology research area of
Budapest University of Technology and Economics (BME FIKP-BIO).
470
471
472
473
474
475
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24

Palladium-catalyzed aryloxy- and alkoxycarbonylation of
aromatic iodides in γ-valerolactone as bio-based solvent
József M. Tukacs,a Bálint Marton,a Eszter Albert,a Imre Tóthb and László T. Mikaa*
a
Department of Chemical and Environmental Process Engineering, Budapest University of
Technology and Economics, Műegyetem rkp. 3., H–1111, Budapest, Hungary.
b Institute of Chemistry, University of Pannonia, Egyetem u. 10, H–8200 Veszprém, Hungary.
Highlights
• A green protocol for Pd-catalyzed aryloxycarbonylation aryl iodides were
developed.
• A green protocol for Pd-catalyzed alkoxycarbonylation aryl iodides were
developed.
• Fossil-based solvent was replaced by a biomass-originated alternative one.

BUDAPEST UNIVERSITY OF TECHNOLOGY AND ECONOMICS
DEPARTMENT OF CHEMICAL AND ENVIRONMENTAL PROCESS ENGINEERING
Dr. László T. Mika
Assoc. Professor and Head
laszlo.t.mika@mail.bme.hu
May 29, 2020
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as
potential competing interests:
László T. Mika
Corresponding author