Historical Perspective of the Heck Reaction

Dimitra Kovala-Demertzi
Section of Inorganic and Analytical Chemistry, Department of Chemistry, University of
Ioannina, 45110 Ioannina, e-mail:dkovala@cc.uoi.gr
Historical Perspective of the Heck Reaction
The first intermolecular Heck reaction was reported by Heck in 1972
Development of the general intermolecular reaction suffered due to poor
regiocontrol of the addition and elimination steps for electronically neutral
unsymmetrical olefins
Nolley, J.P.; Heck, R.F.; Tetrahedron 1972, 37, 2320
The first intramolecular Heck reaction was reported by Mori and Ban in
1977
Mori, M.; Ban, K.; Tetrahedron 1977, 12, 1037
1

General Catalysis of the Heck Reaction
Cycle is catalytic in palladium with the addition of stoichiometric base to
scavenge HX
Palladium catalysed carbon–carbon and carbon–heteroatom bond forming reactions
are widely used and powerful tools in organic synthesis. Such processes are typified
by the Heck reaction (Schem e 1) and cross-coupling and related reactions where an
aryl halide is coupled with a nucleophilic partner. The Heck reaction (also called the
M izoroki-H eck reaction) is the chem ical reaction of an unsaturated halide (or
triflate) w ith an alkene and a strong base and palladium catalyst to form a substituted
alkene. It is nam ed after the Am erican chem ist Richard F. Heck [1-4]
The halide or triflate is an aryl, benzyl, or vinyl compound and the alkene contains at
least one proton and is often electron-deficient such as acrylate ester or
anacrylonitrile.
Schem e 1. The Heck coupling reaction
2

Aryl and vinyl halides- Aryl and vinyl chlorides are most reluctant to undergo Pdcatalyzed
activa-tion. Heck reactivity - as expected from the C-X bond dissociation
energies (Figure 1) - increases in the order CI « Br < I, with fluorides being
com-pletely unreactive with any of the known catalysts.
The ideal substrates for coupling reactions are aryl chlorides since they tend to be
cheaper and more widely available than their bromide or iodide counterparts.
Unfortunately the high C-Cl bond strength compared with C-Br and C-I bonds
disfavours oxidative addition, the first step in catalytic coupling reactions, making the
coupling of such substrates far more challenging. Therefore, there is currently much
interest in the synthesis of catalysts that are able to activate aryl chloride substrates at
ever lower catalyst loading
The activation of chlorohydrocarbons is of major industrial interest. Progress was
made by introducing a bimetallic Ni/Pd catalyst which converts the aryl-CI in a first
step into the more reactive aryl-Br bond (NiBr2)' followed by Pd-catalyzed C-Ccoupling
(Pd(dbab)2 dba = dibenzylidene-acetone, (C6H5CH=CH)2C=O).
).
Figure 1. C-X bond dissociation energies (X = F, CI, Hr, I) of aryl halides. 1 kcal
mol -1 = 4,184 kJ mol -1 .
3

Catalysts-The reaction is performed in the presence of an organopalladium catalyst.
Palladium is one of the most versatile and efficient catalyst metals in organic synthesis,
be it in elemental forms (palladium black and palladium colloids in heterogeneous
hydrogenation) or as palladium salts and complexes. Both the renaissance of
organometallic chemistry in the 1960s and the subsequent breakthrough of
homogeneous organometallic catalysis in laboratory-scale and industrial syntheses have
received a major stimulus from palladium coordination chemistry.
Typical catalysts are Pd°-phosphine complexes. The catalyst can be
tetrakis(triphenylphosphine)palladium(0) {Pd[P(C6H5)3]4}, palladium chloride or , or in-situ
catalysts such as palladium(II) acetate Pd(OAc)2 / n P(C6H5)3, with n = 2...4 (OAc =
acetate). The most frequently used catalyst is an in-situ combination of Pd(OAc)2 and
P(C6H5)3. Palla-dium is practically the only catalyst metal used, in the form of certain
Pd° and salts or complexes; normally 1-5 mol% of catalyst is administered.
Unfortunately, whilst useful these ‘classical’ catalyst systems suffer from two major
limitations. Generally, they need to be used in high loadings — typically a few mol%
Pd and they show little or no activity with aryl chloride substrates. For a reaction to be
attractive for application in the industrial sector, such as in the fine chemical or
pharmaceutical industries, then palladium contamination of the product must be in the
low ppm region, often necessitating expensive product clean-up. This, coupled with the
high price of not only the palladium but often the ligands, can make the whole process
prohibitively expensive
Ligands-The ligand is triphenylphosphine or BINAP. Heck and Spencer noticed
that phosphines are necessary to somehow "stabilize" the catalysts. Phosphine
ligands are expensive, toxic, and unrecoverable. In large-scale applications on
industrial and semi-industrial scale, the phosphines might be a more serious
economical burden than even palladium itself, which can be recovered at any
stage of production or from wastes. The chemical reason is lower reactivity of
fully ligated complexes of palladium, the main result of which is the need for
higher loads of catalyst to achieve appropriate rates of reaction and therefore
further aggravation of procedure cost.
Bases-The base is triethylamine (e.g., N(C2H5)3), potassium carbonate
K2CO3,or sodium acetate NaOAc
4

Solvents-Heck reactions are conducted in polar aprotic, σ-donor-type
solvents such as acetonitrile, dimethyl sulfoxide, or dimethylacetamide.
Reaction temperatures and times largely depend on the nature of the
organic halide to be activated and on the catalyst's stability limit. Iodo
derivatives are much more reactive (

Reaction mechanism
The catalytic cycle for the Heck reaction involves a series of transformations around the
palladium catalyst. The palladium(0) compound required in this cycle is generally
prepared in situ from a palladium(II) precursor [3]. For instance, palladium(II) acetate is
reduced by triphenylphosphine to di(triphenylphosphine)palladium(0) and
triphenylphosphine is oxidized to triphenylphosphine oxide in step 1.
Step 2 is an oxidative addition in which palladium inserts itself in the aryl to bromide
bond.
In step 3, palladium forms a π complex with the alkene and in step 4 the alkene inserts
itself in the palladium - carbon bond in a syn addition step.
Step 5 is a torsional strain relieving rotation and step 6 is a Beta-hydride elimination
step with the formation of a new palladium - alkene π complex.
This complex is destroyed in step 7. T
he palladium(0) compound is regenerated by reductive elimination of the palladium(II)
compound by potassium carbonate in the final step 8.
In the course of the reaction the carbonate is stoichiometrically consumed and
palladium is truly a catalyst and used in catalytic amounts.
6

Oxidative addition is often the rate-determining step in a catalytic cycle.
The relative reactivity decreases in the order of I > OTf > Br >> C1. Aryl
and 1-alkenyl halides activated by the proximity of electron-withdrawing
groups are more reactive to the oxidative addition than those with donating
groups, thus allowing the use of chlorides such as 3-chloroenone for the
cross-coupling reaction
Reductive elimination of organic partners reproduces the palladium(0)
complex. The reaction takes place directly from cis-complex, and the transcomplex
reacts after its isomerization to the corresponding cis-complex (eqs
1 and 2). The order of reactivity is diaryl- > (alky1)aryl- > dipropyl- >
diethyl- > dimethylpalladium(II), suggesting participation by the n-orbital
of aryl group during the bond formation (eq 1) [3].
• A general catalytic cycle for cross-coupling Heck reaction
7

Ionic liquid Heck reaction
In the presence of an ionic liquid a Heck reaction proceeds in absence of a
phosphorus ligand. In one modification palladium acetate and the ionic liquid
(bmim)PF6 are immobilized inside the cavities of reversed-phase silica gel
[4a]. In this way the reaction proceeds in water and the catalyst is re-usable.
Heck oxyarylation
In the Heck oxyarylation modification the palladium substituent in the synaddition
intermediate is displaced by a hydroxyl group and the reaction product
contains a tetrahydrofuran ring.[4b]
8

Amino-Heck reaction
In the amino-Heck reaction a nitrogen to carbon bond is formed. In one example,[4c]
an oxime with a strongly electron withdrawing group reacts intramolecularly with the
terminal end of a diene to a pyridine compound. The catalyst is
tetrakis(triphenylphosphine)palladium(0) and the base is triethylamine
3. Recent Developments on Heck reaction
3.1. Palladacycles: Efficient Catalyst Precursors for Homogeneous Catalysis for
Heck reaction
Palladacycles are a popular and thoroughly investigated class of organopalladium
compounds. The vast majority of these complexes possess anionic four-electron
(bidentate) or six-electron (tridentate) donor ligands, with five-membered nitrogencontaining
rings being the most common. Such systems have been known since the
1960s [6].
Examples of palladacycles
Their synthesis is facile and it is possible to modulate their electronic and steric properties simply
by changing (i) the size of the metallacyclic ring (ii) the nature of the metallated carbon atom
(aliphatic, aromatic, vinylic, etc.), (iii) the type of donor group (N-, P-, S-, O containing group,
etc.) and its substituents (alkyl, aryl, etc.), or (iv) the nature of the X ligands (halide, triflate, or
solvent, e.g. THF, H2O). These factors determine whether the complex is dimeric, monomeric,
neutral, or cationic.However, as already mentioned, palladacycles offer a much wider variety of
catalytic applications and several new and efficient complexes based on different ligand
backbones have since been reported
9

Phosphorus-, nitrogen-, and sulfur-containing palladacycles are among the most active
catalyst precursors for the promotion of such reactions reported to date. All of the
palladacycles shown in this scheme promote the Heck reaction of aryl iodides with
acrylic esters (Table 1).
10

All of the palladacycles shown in the Scheme promote the Heck reaction of aryl
iodides with acrylic esters (Table 1). In this reaction, the highest catalytic activity
observed to date was achieved with the palladacycle 6 (Table 1, Entry 9). It is
interesting to note that this palladacycle only promotes the Heck reaction between aryl
iodides and acrylic esters.
Only a few palladacycles are active catalyst precursors for electron-rich aryl bromides
(Table 1). Moreover, in the case of aryl chlorides, complexes 1, 7, 8, and 11 were
found to be the only active palladacycles (Entries 24-30, Table 1).
In particular, 7 promotes the Heck reaction of electron-rich aryl chlorides, such as 4-
chloroanisole (Entry 29, Table 1).
In contrast with the other catalyst systems presented in Table 1, the PCP-pincer complex 7 does
not require the use of additives to show good activity, even with electronically, deactivated aryl
chlorides. This may imply that here the active catalyst is not colloidal palladium but rather is a
well defined molecular species, and currently it is not possible to rule out a Pd(II)/Pd(IV)
catalytic manifold. It was proposed a catalytic cycle that proceeds via the C- H activation of the
olefin at a Pd(II) centre(s) followed by oxidative addition.
Complex 7
Proposed mechanism for Heck
coupling catalysed by complex
7.
11

3.2. Palladium coordination compounds as Catalysts for the Heck reaction
The complexes used as catalysts are usually based on phosphorus ligands. These
catalysts are often water- and air-sensitive.
Therefore, catalysis under phosphane-free conditions is a challenge of high importance,
and a number of phosphane-free ligands as well as ligand-free palladium catalysts for
the Heck reaction have been reported up to now.
We have tried to evaluate phosphane-free systems in the Heck reaction, a substituted
salicylaldehyde thiosemicarbazone was chosen for this purpose.
The chemistry of thiosemicarbazones has been an extremely active area of research
primarily because of the beneficial biological (viz. antiviral and antitumor) activities of
their transition-metal complexes. Salicylaldehyde thiosemicarbazone is a multidentate
ligand with five potential coordination sites: three N, one O and one S atoms. Usually, it
is bonded to a transition-metal leaving some potential donor sites unused, and it could
be play a constructive role for specific purposes, e.g. the construction of
heteropolynuclear complexes.
This phosphane-free system attracted our attention due to the presence of additional
potential N-donors, since it is known that an additional coordination site as stabilizing
group during the course of a metal-mediated reaction could improve the catalytic
efficiency of the complex.
The synthesis of the palladium complex 3 is outlined in Scheme 1. 2-Salicylaldehyde-N(4)ethylthiosemicarbazone
(H2Sal4Et) (2) was prepared by treatment of salicylaldehyde (1) with
N-ethylthiosemicarbazide in ethanol. The synthesis of complex 3 was achieved by the reaction
of ligand 2 with Li2PdCl4, prepared in situ from PdCl2 and LiCl. The microanalytical data are
consistent with the formula C10H14ClN3O2PdS which indicates the structure
[Pd(HSal4Et)Cl] H2O
12

The monoanionic HSal4Et ligand is coordinated to palladium in a tridentate fashion via the
phenoxy oxygen, the azomethine nitrogen N(1) and the sulfur atom, forming one six- and one fivemembered
chelate rings. The ligand shows a Z, E, Z configuration for the donor centres oxygen,
nitrogen and sulfur, respectively. The S–C(9) bond distance of 1.713(3) Å is consistent with a
double-bond character, while both thioamide C–N distances (N(2)-C(9), 1.338(4) Å; N(3)-C(9),
1.331(4) Å) indicate an increased single bond character, in accordance with a molecule protonated
on N(2).15 The displacement from coplanarity is indicated by the dihedral angle between the
phenol ring, and the plane defined by the five-membered chelate ring Pd-S-C(9)-N(2)-N(1) being
3.45(12)º, and the dihedral angle between the phenol ring and the plane defined by the sixmembered
chelate ring Pd-N(1)-C(8)-C(7)-C(2)-O(1) being 2.21(13)º.
Complex 3 was applied to the Heck reaction of styrene with some representative 4-substituted
aryl bromides (from electron-rich to electron-poor) in DMF at 150ºC for 24 h, using AcONa as
base, and in the absence of any promoting additive (Scheme 2, Table 1).
The reaction was first performed using a 1:1000 catalyst:aryl bromide molar ratio to ensure a
higher yield process, and then by decreasing the ratio to 1:100000. There was good selectivity
towards trans-stilbenes 6, ranging from 92.0 – 96.4%, and it is noteworthy that side-products
were absent or present only in traces. As expected, the catalytic activity depends on the halide,
while electron-withdrawing groups on the aryl ring increase the reaction rate. The activity
follows in the order NO2 > CHO > H > OMe, suggesting that the rate-determining step in the
Heck reaction is the oxidative addition of the aryl bromide to the palladium catalyst. Under
argon, the catalyst is thermally stable and the reaction mixture retains yellow or colorless,
depending of the palladium concentration. A catalyst:substrate ratio of 1:1000 leads to total
yields of 45.8 and 53.9% for the very inactive 4-bromoanisole and the relatively inactive
bromobenzene, respectively. At lower conversions, for these substrates the reaction proceeds
with TONs up to 17100 and 18000, respectively. High activity was observed for the activated 4bromobenzaldehyde
and 1-bromo-4-nitrobenzene. A catalyst:substrate ratio of 1:1000 leads to
high conversion (95%) of the aryl bromide, and with a ratio of 1:100000, the reaction proceeds
with TONs up to 42700.
13

Table 1. Heck reaction of aryl bromides with styrene catalysed by palladium complex 3
aTotal GC yield of all isomers, based on the aryl bromide using decane as internal standard.
bTurnover no. (TON) = fraction of products (6 + 7 + 8) × substrate/Pd ratio.
performed under argon. However, in air and at a very low palladium concentration, for a
catalyst:4-bromobenzaldehyde ratio of 1:100000, the yield was diminished.
This phosphorus-free complex with additional potential N-donors is thermally stable
under argon, and efficiently catalyses the Heck reaction of aryl bromides with
styrene, with good turnover numbers and a good selectivity towards trans-stilbenes.
This system efficiently catalyses the Heck reaction of aryl bromides (from electronrich
to electron-poor) with styrene under argon, with turnover numbers of up to
42700, at 150ºC after 24 h, and with a selectivity towards trans-stilbenes ranging
from 92.0 to 96.4 %. In air, for activated aryl bromides and for a palladium
concentration of 1 mM, the yields are essential the same to those obtained when the
reaction performed under argon.
These phosphine-free catalysts offer the advantage of the successful coupling of aryl
halides and the synthesis of biaryls under aerobic conditions [7].
14

3.3 Palladium nanoparticles as catalysts for Heck reaction
A palladium-nanoparticle-cored G-3 dendrimer, characterized by TEM, TGA,
absorption, and IR spectroscopies, has approximately 300 Pd atoms in the metallic core
and an average diameter of 2.0 nm, to which are attached fourteen G-3 dendrons.
Nearly 90% of the metal nanoparticle surface is unpassivated and available for
catalysis. The dendrons inhibit metal agglomeration without adversely affecting
chemical reactivity. Thus, investigations have shown that Pd-G-3 can efficiently
catalyze Heck and Suzuki reactions [8]
Synthesis of Pd-G-3, in Which Seven of the Fourteen G-3 Wedges Are Shown (see
text)
Pd-G-3 was prepared by the Brust reaction
(K2PdCl4 was phase transferred into toluene using
tetraoctylammonium bromide (TOAB). Fre´chettype
dendritic polyaryl ether disulfide3 of
generation 3 (G-3S) was then used. The mixture
was cooled in ice (0-2 °C) and excess of NaBH4
was added. The Pd-G-3 thus obtained was a black
powder, freely soluble in methylene chloride,
chloroform, toluene and THF, but insoluble in
ether and alcohol. Pd-G-3 was stable for several
months both as a powder and as a dilute solution
in CH2Cl2. FT-IR and TGA experiments showed
that Pd-G-3 incorporated some amount of TOAB
and this could not be removed by the standard
purification procedure. Figure 5 shows a highresolution
TEM image of Pd-G-3 and the
corresponding core-size histogram. It can be seen
from Figure 1 that the particles exhibit a relatively
wide size distribution (1-5 nm). The mean core
diameter obtained from the histogram plot was 2.0
nm
TEM image and core-size histogram of
Pd-G-3.
15

It was used Pd-G-3 [8,9] as catalyst in the Heck reactions shown in Scheme 2. Typically, 10
mM each of the reactants and 20 mM triethylamine were taken up in toluene and the mixture was
heated to reflux for 24 h in the presence of 10 mg (2- 10-3 mol %) Pd-G-3. Pd-G-3 is soluble in
toluene and, hence, reactions 1 and 2 occur under homogeneous catalytic conditions. After the
reaction, toluene was removed in a rotavapor and the residue extracted with ether.
The turnover numbers (TON ) mol product/mol catalyst) and turnover frequencies (TOF ) mol
product/mol catalyst/hour) given in Scheme 2 were calculated from isolated product yields. The
reaction with ethyl acrylate proceeded with good yield, although that with styrene was low. The
TON and TOF, however, are very high for both reactions. This, coupled with the absence of side
products, indicates that the yields could be improved by using slightly higher amounts of Pd-G-3.
In most Pd catalyzed reactions, 0.5-2 mol % catalyst is generally used and this is 100-1000 times
higher than what we have employed here.
The catalytic properties of the Pd nanoparticles dispersed in BMI. PF6 were tested in
the coupling of aryl halides with n-butylacrylate at different temperatures (Table 1).
First, we tested different bases (NaOAc, NEt(iPr)2, DABCO, and Na2CO3) in the
reaction of iodobenzene with n-butylacrylate at 80 oC ([PhI]/[Pd] ) 1000). A mixture of
the aryl halide (1.0 mmol) and n-butyl acrylate (1.2 mmol) with the Pd nanoparticles
dispersed in 0.5 mL of ionic liquid gave a light-yellow solution in the presence of
NEt(iPr)2 and suspensions in the presence of the other bases.
16

Figure 2. Possible pathways involved in the Heck reaction promoted by Pd nanoparticles
dispersed in imidazolium ionic liquids.
Almost complete iodobenzene conversion was observed in the reaction experiment performed
with NEt(iPr)2, whereas only 60%). A similar trend was recently observed in Heck reactions promoted by a
heterogeneous catalyst precursor where it was proposed that Pd dissolution and
reprecipitation are inherent parts of the catalytic cycle.
References
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