Catalytic SNAr of unactivated aryl chlorides

Article abstract of DOI:10.1039/c4cc07116f

We present nucleophilic aromatic substitution of unsubstituted aryl chlorides via a mechanism that is catalytic in [CpRu(p-cymene)]PF₆ and involves a Ru(η⁶-arylchloride) intermediate. From the spectroscopic evidence we infer that are

Full text of DOI:10.1039/c4cc07116f

Volume 51 Number 14 18 February 2015 Pages 2737–3004
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James W. Walton and Jonathan M. J. Williams
Catalytic SNAr of unactivated aryl chlorides

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Catalytic SNAr of unactivated aryl chlorides†
James W. Walton*ab and Jonathan M. J. Williamsa
Cite this: Chem. Commun., 2015,
51, 2786
Received 9th September 2014,
Accepted 6th October 2014
DOI: 10.1039/c4cc07116f
www.rsc.org/chemcomm
We present nucleophilic aromatic substitution of unsubstituted aryl
chlorides via a mechanism that is catalytic in [CpRu(p-cymene)]PF6
and involves a Ru(g6-arylchloride) intermediate. From the spectro-
scopic evidence we infer that arene exchange is the rate limiting
step in this process and develop several new Ru(II) complexes that
lower the activation barrier to arene exchange.
Nucleophilic aromatic substitution (SNAr) is one of the building
blocks of synthetic chemistry, and is used far and wide in industry
and academia. However, limitations restrict the use of SNAr to
certain substrates. Activated arenes are required (incorporating an
electron withdrawing group to stabilise the negatively charged
intermediate, Scheme 1A) and the C–X bond must be polarised;
the rate of reaction follows the order X = F 4 Cl c Br. Alternative
arylation methods include metal1a,b and non-metal1c catalysed
coupling reactions of Ar–X and Ar–H.
Scheme 1
Fluorobenzene can undergo SNAr with strong alkoxide nucleo-
philes2 but chlorobenzene does not undergo SNAr (Scheme 1B).
One method by which unactivated aryl halides (i.e. those with-
out an electron withdrawing group) can undergo SNAr is via
Z6-coordination to a transition metal (e.g. Ru(II),3 Cr(0),4 Fe(II),5
Mn(I),6 Scheme 1C). It is well established that p-complexation
of an arene to a transition metal increases its reactivity towards
nucleophilic attack7 and deprotonation.8 More recently, activa-
tion of a Cr(0) Z6-aryl C–H bond towards Pd insertion and
Scheme 2
subsequent arylation has been achieved.9 The drawback to takes place, completing the catalytic cycle (Scheme 2).12 Despite
these reactions is that the Z6-arene–metal bond is strong and demonstrating an increase in the rate limiting step (arene
stoichiometric metal is required; liberation of the aryl product exchange), no catalytic SNAr was reported.
is carried out by photolysis10 or oxidation.11
Rh(III) catalysed intramolecular SNAr based on this catalytic cycle
Semmelhack et al. propose a catalytic cycle in which an has been reported but is limited to aryl fluorides.13 Intermolecular
unactivated aryl chloride binds Z6 to Cr(0), facilitating SNAr, SNAr of aryl fluorides (Ru(II) catalysed) has also appeared14 but
before exchange between the bound product and free aryl chloride requires a large excess of arene and is unsuccessful with aryl
chlorides. Anti-Markovnikov hydroamination of styrene via catalytic
p-complexation to Ru(II) has also been reported.15
a Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
In this report we present the first example of catalytic SNAr
b Department of Chemistry, Durham University, South Road, Durham, DH1 3LE,
of unactivated aryl chlorides. Experimental evidence suggests
UK. E-mail: james.walton@durham.ac.uk
that our method proceeds via a Z6-coordination mechanism.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc07116f
In an effort to reduce the high reaction temperature and long
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Table 1 SNAr reaction between morpholine and chlorotoluene under a variety of conditions (see ESI for full list of conditions). Conversions were
determined by 1H-NMR. (Cp* = pentamethylcyclopentadienyl, DMI = 1,3-dimethylimidazolinone, DPPPent = 1,5-bis(diphenylphosphino)pentane)
Entry
Catalyst
Solvent
Temp. (1C)
Time
Additive
Conversion (%)
1
2
3
—
—
—
MeCN
Toluene
Cyclohexanone
80
110
150
18 h
18 h
18 h
—
—
—
0
0
0
4
5
6
[CpRu(MeCN)3]PF6
[Cp*Ru(MeCN)3]PF6
[CpRu(p-cymene)]PF6
Cyclohexanone
Cyclohexanone
Cyclohexanone
150
150
150
18 h
18 h
18 h
—
—
—
6
5
10
7
8
9
10
11
[CpRu(p-cymene)]PF6
[CpRu(p-cymene)]PF6
[CpRu(p-cymene)]PF6
[CpRu(p-cymene)]PF6
[CpRu(p-cymene)]PF6
Cyclohexanone
DMI
Cyclohexanol
p-Xylene
180
180
180
180
180
18 h
18 h
18 h
18 h
18 h
—
—
—
—
—
18
17
16
0
1-Octanol
25
12
13
14
15
[CpRu(p-cymene)]PF6
[CpRu(p-cymene)]PF6
[CpRu(p-cymene)]PF6
[Ru(p-cymene)Cl2]2
1-Octanol
1-Octanol
1-Octanol
1-Octanol
180
180
180
180
18 h
18 h
18 h
18 h
Mol. sieves
Et3N
Na2CO3
DPPPent
25
21
11
0
16
17
18
[CpRu(p-cymene)]PF6
[CpRu(p-cymene)]PF6
[CpRu(p-cymene)]PF6
1-Octanol
1-Octanol
1-Octanol
180
180
180
4 d
7 d
14 d
—
—
—
45
75
90
reaction time, several new catalysts were synthesised with a
view to lowering the activation barrier of the rate limiting step.
Our initial investigation focussed on the reaction between
morpholine and chlorotoluene under a variety of reaction condi-
tions (selected results are given in Table 1, see ESI† for a complete
set of reaction conditions). In the absence of a catalyst no product
formed, despite attempts over a range of temperatures and in
several solvents (Table 1, entries 1–3).
Scheme 3
to 1b; no Z6-bound chlorotoluene (1a) was observed by ES-MS+
or 1H-NMR. We postulate, therefore, that the reaction occurs
via the mechanism shown in Scheme 2 and that arene exchange
is the rate limiting step; SNAr is fast so that no bound chloro-
toluene is observed but arene exchange is slow so that bound
product is observed.
The mechanism by which arene exchange takes place in
[Cr(CO)3(Z6-arene)] complexes has been well studied.16 It was
determined that the rate-determining step is an initial change
in arene bonding from Z6 - Z4 (Scheme 4). While similar analysis
has not been carried out for RuII(Z6-arene) complexes, we assume
the same mechanism for arene exchange and propose that the
success found for our catalytic system with 1-octanol as a solvent is due
to coordination of the hydroxyl group during the slow Z6 - Z4 step.
This maintains an 18 eÀ complex and lowers the activation energy.
Based on the work of Woodgate et al.,3a we anticipated that
catalysts incorporating a [CpRu]+ fragment (Cp = cyclopentadienyl)
would expedite the SNAr reaction, via Z6-coordination of chloroto-
luene. A number of catalysts were investigated (Table 1, entries 4–6).
Each catalyst led to conversion into the desired product, providing
that high temperatures were employed, with [CpRu( p-cymene)]PF6
performing best. In a solvent screen at 180 1C, 1-octanol was found
to give the highest conversion (Table 1, entries 7–11). If the reaction
mixture was left for 14 days the product conversion reached 90%
(Table 1, entries 16–18). The effect of additives on the rate of reaction
was examined (Table 1, entries 12–15). No increase in product
conversion was observed for a variety of additives, including base,
molecular sieves and ligands. In summary, catalytic SNAr between
morpholine and chlorotoluene can be achieved with 90% yield
in 1-octanol at 180 1C in 14 days.
We sought to understand why such long reaction times
and high reaction temperatures were required. Under the
optimised reaction conditions, positive mode electrospray
mass spectrometry (ESI-MS+) showed a peak at m/z = 344 with
the characteristic Ru isotope pattern, corresponding to the
1
Z6-bound product (complex 1b in Scheme 3). H-NMR showed
Scheme 4
a pair of doublets in the range 5.5–5.7 ppm, also corresponding
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Table 2 The percentage of arene exchange for complexes 1–6, using
either cyclohexanone or 1-octanol as the solvent after 3 and 16 h
reaction times
Scheme 5
This theory is supported by the reasonable product conversion in
solvents such as cyclohexanol and DMI (Table 1, entries 8 and 9)
and the lack of conversion in the non-coordinating solvent
p-xylene (Table 1, entry 10). It has previously been noted that
addition of ketones, such as cyclohexanone, lowers the activation
barrier to arene exchange in Cr(0) systems via coordination of
the carbonyl lone pair during the Z6 - Z4 process.17
To test this theory, several new catalysts were synthesised
(2–6), each incorporating a tether, covalently bound to the Cp
ring, capable of coordinating to Ru during the Z6 - Z4 step
(Scheme 4).18 Our expectation was that intramolecular coordi-
nation of the tether to the Ru centre would lower the activation
barrier to arene exchange and, subsequently, increase the rate
of the SNAr reaction.
Arene exchange (%)
Cyclohexanone
1-Octanol
3 h
Complex
3 h
16 h
16 h
1
2
3
4
5
6
6
38
17
92
(6)a
9
(50)a
51
(15)a
13 (18)b
(17)d
36
(84)a
90 (88)b
(85)d
100
c
c
—
—
44
12
100
50
12
65
Values for decarboxylated 2 ([(MeCp)Ru(p-cymene)]+), which forms
a
b
under exchange conditions. Values for the octyl ester of 3, which
c
forms in 1-octanol. Complex 4 reacts with cyclohexanone, leading to
d
invalid results. Values for the octyl ester of 4, which forms under the
exchange conditions.
Each complex was synthesised by reaction between
[Ru( p-cymene)Cl2]2 and the corresponding Cp–tether adduct,
in the presence of Na2CO3 and ethanol (Scheme 5).19 The reaction
mixtures were treated with NH4PF6 to afford complexes 2–6. The
formation of the Cp–tether adducts were specific to the various
tethers. For complex 2, CpNa and BrCH2CO2Me were stirred in
THF at 0 1C to give CpCH2CO2Me in quantitative yield20 before
complexation with [Ru(p-cymene)Cl2]2.21 Similar protocols
were used to synthesise the other Cp–tether compounds. In
certain cases, it was necessary to synthesise the electrophilic
component before reaction with CpNa. For example, in the
synthesis of 5, 2-Py(CH2)2OH (2-Py = 2-pyridine) was converted
into 2-Py(CH2)2OSO2Me, prior to reaction with CpNa. Each
complex 2–6 was purified by column chromatography on silica
and fully characterised. For full Experimental detail see ESI.†
at 3 h and 16 h using ESI-MS+ (Table 2); calibration of the ESI-MS+
measurement was required to allow quantitative assessment (see
ESI†). Relative to the parent complex, [CpRu( p-cymene)]PF6 (1), a
moderate increase in the extent of arene exchange was observed
for 3 and 6 in cyclohexanone after 16 h (51% and 50%, respec-
tively versus 38% for 1). Most notable, however, was the complete
arene exchange in cyclohexanone for complex 5, which incorpo-
rates a pyridyl tether. In the same solvent, 2 appeared to undergo
ester hydrolysis and decarboxylation, giving [(CpMe)Ru( p-cymene)]+,
indicated by a m/z peak at 315. This species underwent a similar
amount of arene exchange to 1. Finally, exchange for 4 in cyclo-
hexanone could not be determined due to a side reaction with the
solvent. Similar exchange behaviour was found when 1-octanol was
used as the solvent. Complex 5 again displayed the greatest amount
of arene exchange. The tether components in 3 and 5 rapidly
reacted with the solvent to form octyl esters, which exchanged
at a similar rate to the parent complex (1). Once again, complex
2 decarboxylated whilst 6 showed a slight reduction in the rate
of exchange compared to 1.
Having established that arene exchange could be accelerated by
the presence of a coordinating tether, we proceeded to calculate half
lives (t1/2) for the initial p-cymene complexes of 1, 3, 5 and 6 under
the exchange conditions described in Table 2, with cyclohexanone
as the solvent. The results confirm that the pyridyl complex 5
exchanges an order of magnitude faster than the parent complex,
1 (t1/2 = 2.2 Æ 0.1 h versus 34 Æ 0.7 h, see ESI† for details). Complexes
3 and 6 each have shorter t1/2 than 1 (23 Æ 0.3 h and 28 Æ 0.4 h,
respectively), confirming that the rate of arene exchange is
To investigate whether the presence of the various tethers accelerated by the coordinating tether.
would decrease the energy barrier for the Z6 - Z4 process,
Our hypothesis stated that faster arene exchange will lead to
exchange experiments were carried out. Each complex was higher conversion in the SNAr reaction between morpholine and
heated in either 1-octanol or cyclohexanone in the presence chlorotoluene. To test this, we carried out the SNAr reaction with
of 100 equivalents of hexamethylbenzene (C6Me6) for 16 h. The three of the new potential catalysts, 1, 3 and 5 (Table 3). As a
extent of exchange between p-cymene and C6Me6 was measured comparison, 1 with an equivalent of free pyridine was also tested.
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Z6-arene exchange is realised, we envisage many applications in
efficient organic synthesis.
Table 3 SNAr reaction between morpholine and chlorotoluene with
catalysts 1, 3 and 5. Conversions were determined by 1H-NMR
Notes and references
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Conversion (%)
Catalyst
1 d
4 d
7 d
1
3
5
25
25
26
24
45
59
55
59
75
72
54
65
1 + Py
After 24 h, each catalyst gave a similar conversion. After 4 d,
the catalysts incorporating a tether showed a small improve-
ment in conversion but after 7 d the parent compound returned
the highest value, due, in the case of 5, to degradation of the
catalytic species (indicated by loss of Ru species in the mass
spectrum). Once again, mass spectrometric analysis after 24 h
shows a m/z peak corresponding to the Z6-bound product in
each of the reactions. Ultimately, it appears that although the
rate of arene exchange is accelerated in the p-cymene - C6Me6
experiment described above, this acceleration does not translate
into a higher conversion in the SNAr reaction. Two explanations
present themselves: (1) the Z6-bound product is more kinetically
inert than [CpRu(p-cymene)]+, so that arene exchange is slower, (2)
the Z6-bound product is more thermodynamically stable than
[CpRu(Z6-chlorotoluene)]+, leading to the build-up of the product
bound complex and long reaction times. Of course, a combination
of both factors may be present. [(Z6-Dimethylaniline)Cr(CO)3] is
known to be more thermodynamically stable than the chloro-
benzene analogue16a,17 and a similar trend is likely in the case
of [CpRu(Z6-arene)]+ – the aryl ring in the product (e.g. 1b in
Scheme 3) is more electron rich than p-cymene. In an attempt to
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with long reaction times. In an attempt to move to milder reaction
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21 Transesterification to form the ethyl ester took place under the
our test reactions. Once an efficient catalytic system based on
reaction conditions.
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