Active Iron(II) Catalysts toward gem-Specific Dimerization of Terminal Alkynes

Article abstract of DOI:10.1021/acscatal.8b03552

We report the syntheses and catalytic activity of a series of piano-stool iron complexes with the general formula [FeClCp (NHC)] (where NHC = N-heterocyclic carbene) toward the gem-specific dimerization of terminal alkynes. In comparison to our first-gene

Full text of DOI:10.1021/acscatal.8b03552

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Article
Active Iron(II) Catalysts toward gem-Specific Dimerization of Terminal Alkynes
Qiuming Liang, Kai Sheng, Andrew Salmon, Vivian Yue Zhou, and Datong Song
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03552 • Publication Date (Web): 12 Dec 2018
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Active Iron(II) Catalysts toward gem-Specific
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Dimerization of Terminal Alkynes
Qiuming Liang,‡ Kai Sheng,‡ Andrew Salmon, Vivian Yue Zhou and Datong Song*
Davenport Chemical Research Laboratories, Department of Chemistry, University of Toronto, 80
St. George Street, Toronto, Ontario, M5S 3H6, Canada
ABSTRACT We report the syntheses and catalytic activity of a series of piano-stool iron
complexes with a general formula [FeClCp*(NHC)] (where NHC = N-heterocyclic carbene)
toward the gem-specific dimerization of terminal alkynes. Compared to our first-generation
catalyst, the newly synthesized catalyst is more active and features the same geminal specificity.
Both the experimental and computational data are presented herein.
KEYWORDS N-heterocyclic carbene, iron, catalysis, alkyne dimerization, enyne, computation
INTRODUCTION
1,3-Enynes are important synthons for natural products, bioactive molecules, organic materials,
and other complex molecules.1-11 The general synthetic methods include metal-mediated cross-
coupling reactions, Wittig reaction, and dehydration of propargyl alcohols.12-18 The selective
dimerization of terminal alkynes is the ideal route for enyne synthesis owing to its perfect atom
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economy.17-20 The main challenge of alkyne dimerization is the control of regioselectivity due to
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the competing formation of head-to-head (E/Z) and head-to-tail (gem) isomers.1,17,18
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The catalytic dimerization of the terminal alkynes have been extensively established,18,19 mostly
based on precious metals21-36 and f-block elements.37-40 In contrast, iron-based catalysts are rarely
reported.41-47 The first example of iron-catalyzed alkyne dimerization uses a 30 mol% loading of
FeCl3 as the catalyst in the presence of 300 mol% of KOtBu at high temperatures to give E-enyne
products.41,42 Milstein and co-workers reported [Fe(PNPCH2)(H)(2-BH4)] catalyst toward the
dimerization of arylacetylenes, featuring good Z-selectivity, low catalyst loading, and mild
reaction conditions (Chart 1, I).43 Later, Kirchner and co-workers reported a [Fe(PNPNH)(H)2(2-
H2)] catalyst giving high Z-selectivity for the dimerization of arylacetylenes with a remarkable
increase of reaction rates (Chart 1, II).44,45 The Mandal group reported a well-defined iron(0)
complex capable of catalyzing the dimerization of arylacetylenes, but the reactions require a large
excess of KOtBu and 120 °C and give poor to high E selectivity (Chart 1, III).46 Huang, Hor, Zhao
and co-workers reported the iron(II) complex of an N,N,N-tridentate ligand as the catalyst which
requires the use of a large excess of a t-butoxide base and forcing conditions (Chart 1, IV).47
Interestingly, NaOtBu and KOtBu give the opposite E/Z selectivity. The literature of the geminal
selective dimerization of alkynes is dominated by Pd, Rh, Al, and early metal catalysts.49-71 While
the late transition metal catalysts displayed good functional group tolerance,49-60 the early
transition metal and Al catalysts are incompatible with polar functional groups such as NH and
OH.61-71
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Chart 1. Well-defined iron catalysts for the dimerization of terminal alkynes.
The NHC iron complexes are a versatile class of molecules for synthesis and catalysis.72-78
Piano-stool iron NHC complexes, an important subclass of NHC iron complexes, are well known
in organometallic chemistry.79-86 Although the stoichiometric reactivity of such complexes has
been intensively investigated, the catalytic counterpart remains rare.79 Our group recently has
developed a piano-stool iron catalyst featuring Cp* and picolyl N-heterocyclic carbene (NHC)
ligands for the geminal specific dimerization of terminal alkynes (Chart 1, V).48 This catalytic
system features a broad substrate scope, i.e., both aryl and aliphatic alkynes are compatible and
even substrates possessing an NH or OH group can be tolerated.48 Our experimental and
preliminary computational studies show that the bulky mesityl group on the NHC ligand is crucial
for both the alkyne C–H activation and geminal specificity and that the pyridine group of the ligand
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retards the catalytic activity by coordinating to metal center to generate stable off-cycle 18e
species.48 These results prompted us to replace the picolyl group of the NHC ligand with non-
coordinating substituents. Herein we report the syntheses and structures of a series of half-
sandwich iron complexes and our investigations into their catalytic reactivity toward alkyne
dimerization. The half-sandwich iron complex of IMesBn (NHC with mesityl and benzyl
substituents) turned out to be a highly active catalyst for the dimerization of terminal alkynes to
yield geminal enynes exclusively.
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RESULTS AND DISCUSSION
Synthesis and Characterization of Pre-catalysts. Complexes 1–7 were synthesized from the
reaction of [FeClCp*(TMEDA)] with corresponding free NHC ligands in THF at −80 °C, and
isolated in 70–89% yields (Scheme 1). The 1H NMR spectra of 1–7 in C6D6 at room temperature
show broadened and paramagnetically shifted resonances spanning the range of −25~110 ppm.
The solution magnetic moments of 1–7 at room temperature (measured by Evans’ method) were
determined to be 3.0–3.7 μB, consistent with intermediate spin Fe(II) centers. The solid-state
structures of 1–7 adopt two-legged piano-stool geometry (Figure 1). The Fe(1)−C(1), Fe(1)−Cl(1),
and Fe(1)–Cp*cent distances for complexes 1–6 (Table 1) are comparable to those found in the
closely related half-sandwich chloro NHC iron complexes.82 Interestingly, the tertiary amine group
in complex 7 shows no interaction with the iron center. The Fe(1)−C(1) (2.133(2) Å) and
Fe(1)−Cl(1) (2.133(2) Å) bond lengths in complex 7 are slightly longer than those in complexes
1–6, and the C(1)–Fe(1)–Cl(1) (106.50(5)º) bond angle is wider (Table 1). The Fe(1)–Cpcent
distance of 1.986(1) Å significantly longer than those in complexes 1–6 (Table 1). At room
temperature, complexes 1–7 slowly decompose into [FeCl2(NHC)2] and FeCp*2 in both solution
and the solid state. They can be stored at −35 °C for months without significant decomposition.
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Scheme 1. Syntheses of complexes 1–7.
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Figure 1. X-ray structures of 5. Ellipsoids are
shown at 50% probability. Hydrogen atoms
have been omitted for clarity.
Table 1. Bond Lengths (Å) and Angles (deg) for 1–8.
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8
Fe(1)–C(1)
Fe(1)–Cl(1)
1.966(3)
2.272(1)
96.5(1)
1.793(2)
1.964(3)
2.251(1)
94.9(1)
1.793(2)
1.980(4)
2.264(1)
94.4(1)
1.796(2)
1.998(5)
2.265(2)
96.9(1)
1.823(2)
1.980(4)
2.267(1)
94.4(1)
1.808(2)
1.966(3)
2.255(1)
96.41(9)
1.790(2)
2.133(2)
2.2971(7)
106.50(5)
1.986(1)
1.950(3)
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C(1)–Fe(1)–Cl(1)
Fe(1)–Cp*cent
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1.7812(4)
Catalytic Dimerization of Phenylacetylene. We began by examining 1–7 in the catalytic
dimerization of phenylacetylene, with a loading of 3 mol% of [Fe] pre-catalyst and 3 mol% of
LiHMDS in toluene at room temperature as the standard conditions. No conversion was observed
within 3 hours when 1 was used (Table 2, entry 1), presumably due to its instability. The bulkier
2 gives a moderate conversion of phenylacetylene to the gem dimer within 3 hours (Table 2, entry
2). Complex 3, featuring an isopropyl and a mesityl substituents, gives the complete conversion of
phenylacetylene to the geminal dimer within an hour (Table 2, entries 3–4). In contrast, complex
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4, featuring an isopropyl and a 2,6-diisopropylphenyl (Dipp) substituents, only gives a 35%
conversion in 3 hours (Table 2, entry 5). Complex 5 with benzyl and mesityl substituents leads to
the full conversion within 0.5 hour (Table 2, entry 6). Similar to complexes 3 and 4, complex 6
possessing a Dipp substituent displays a much lower activity (Table 2, entry 7) in comparison to
its mesityl analogue 5. Complex 7 possessing a tertiary amine side chain and a mesityl group is
also an efficient catalyst, giving full conversion within 1 hour (Table 2, entry 9). Complex
[FeClCp*(IMes)]82 (IMes = 1,3-dimesitylimidazol-2-ylidene) with mesityl groups as both R
position and the precursor [FeClCp*(TMEDA)] shows no activity (Table 2, entry 10–11), showing
that the asymmetric NHC ligands are crucial for this conversion. The two control experiments, i.e.,
with pre-catalyst 5 only and with base only, show little and no conversion, respectively (Table 2,
entries 12–13).
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Table 2. Testing of Complexes 1-7 for the Dimerization of Phenylacetylenea
Entry
[Fe]
t (h)
3
Conv. (%)
Yield (%)
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2
0
67
82
>99
35
>99
44
92
>99
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0
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FeClCp*(IMes)
FeClCp*(TMEDA)
5 (no base)
base only
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<5
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<5
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a General conditions: phenylacetylene (0.2 mmol), pre-catalyst (3 mol%), LiHMDS (3 mol%), toluene (1.0 mL), room
temperature. The conversions and yields (of gem product) are based on the 1H NMR integrations using mesitylene as
the internal standard.
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Catalytic Dimerization of Terminal Alkynes. Having identified complex 5 as the most
promising pre-catalyst for terminal alkyne dimerization, we examined the substrate scope next.
Pre-catalyst 5 shows high activity and excellent selectivity toward the dimerization of both
aromatic and aliphatic terminal alkynes. The complete conversions of phenylacetylene and p-Me-
, p-OMe-, p-F-, and p-NMe2-substituted phenylacetylenes into the corresponding geminal products
can be achieved within 0.5 h at room temperature (Table 3, entries A1–A5). With p-Bpin (Bpin =
4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl), p-NH2 and m-NH2-substituted phenylacetylenes, the
reactions are slightly slower (Table 3, entries A6–A8). With m-F-phenylacetylene and 3-
ethynylthiophene substrates, a 5 mol% loading of 5 and LiHMDS is needed to achieve full
conversions in 0.5 h (Table 3, entries A9–A10). Ferrocenylacetylene, aliphatic alkynes including
propargyl amines can also be converted into the corresponding gem products in good yields under
the standard conditions (Table 3, entries A11–A21). A 5 mol % loading of 5 and LiHMDS is
required for the unsubstituted propargyl amine (Table 3, entry A22). Furthermore, various oxygen-
containing functional groups, such as acetals (Table 3, entries A23–A25), ether (entry A26), and
tertiary alcohol (entry A27) are tolerated. In contrast to our previous catalytic system V,48
unsubstituted propargyl alcohol shows no conversion (Table 3, entry A28). The catalytic activity
ceased at 23% and 25% conversions with methyl 4-ethynylbenzoate and propargyl benzoate
substrates, respectively (Table 3, entries A29–A30). In contrast, our previous catalytic system V
shows no conversion of substrates containing ester functional groups.48 The bulky
mesitylacetylene and ethynyltributylstannane cannot dimerize under the same conditions (Table 3,
entries A31–A32). The products from entries A11 and A29 were crystallographically characterized
(Figures S25 and S26).
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Table 3. Substrate Scopea
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a
General reaction conditions: substrate (0.2 mmol), 5 (3 mol%), LiHMDS (3 mol%), toluene (1.0 mL), room
temperature, 0.5 h. The yields (of gem product) are based on 1H NMR integration of the product peaks compared to
those of the internal standard mesitylene. Isolated yields for reactions carried out with 1 mmol of the substrate are
given in parentheses. b 1 h. c Reaction carried out with 5 mol% of 5 and 5 mol% of LiHMDS.
Coupling of Alkynes with N,N-Dimethyl-propargylamine. Selectively producing a single
product is even more challenging when coupling two different alkynes, where 12 possible products
may form (Scheme 2). Several strategies have been reported for the selective cross-dimerization
of silyl alkynes with other alkynes.31-35,43 Alkynes bearing an O or N-donor directing group have
also been used as the acceptor alkyne to give high selectivity in cross-dimerizations.48,58-61 The
cross-dimerization of propargyl alcohols and amides with arylacetylene affords 2-en-4-yn-1-ols
and 2-en-4-yn-1-yl amides (E-a, where R1 = aryl and R2 = CH2OH, CH2NPg) in high selectivity
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using a trialkyl phosphine-derived palladacycle catalyst under mild conditions.58 Propargyl
alcohols or amines provide high selectivity in cross-dimerization reactions to give gem-a enynes
in high selectivity, using both late transition metals49,59,60 and Ti(III)61 catalysts.
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Scheme 2. Possible enyne products in alkyne cross-dimerization reactions.
Table 4. Cross-dimerization of N,N-dimethylpropargylamine and other terminal alkynesa
Yield (%)
Entry
B1
a
b
c
d
76 (72)
6
14
61
80 (78)
70 (61)
75 (70)
80 (73)
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B5
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B7
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B8
a
General conditions: substrate (0.5 mmol), N,N-dimethyl-propargylamine (1.0 mmol), pre-catalyst (5 mol%),
LiHMDS (5 mol%), toluene (2.5 mL), room temperature, 4 h. The yields (of gem product) are based on the 1H NMR
integrations using mesitylene as the internal standard. Yields of isolated product are given in parentheses.
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The reaction of phenylacetylene (1 equiv) and N,N-dimethyl-propargyl amine (2 equiv) resulted
in the complete conversion of the starting alkynes into a mixture of the cross-dimerization products
a (76%) and b (6%) and the homo-dimerization products c (14%) and d (61%) (Table 4, entry B1)
at ambient temperature with 4 h with a 5 mol% catalyst loading. Similar yields and selectivity were
observed phenylacetylene was replaced with p-substituted phenylacetylenes (Table 4, entries B2–
B5). Poor selectivity was observed when 1-hexyne and 5-chloro-1-pentyne were used instead of
phenylacetylene (Table 4, entries B6–B7). When the bulky trimethylsilylacetylene was used, the
yield of a was 65% (Table 4, entry B8).
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Mechanistic Investigations. We first investigated the conversion of the pre-catalyst into the active
species. The reaction between 5 and 1 equiv. of LiHMDS is slow and in 24 h gives a mixture where
5 is still the major species (Figure S95). The attempted isolation of the newly formed compounds
was unsuccessful. In contrast, the reaction of 5 and PhC≡C−Li resulted in the clean formation of
1
[FeCp*(C≡CPh)(IMesBn)], 8 instantaneously (Figure 2). The H NMR spectrum of 8 in C6D6
shows paramagnetically broadened and shifted resonances. The magnetic moment of 8 in solution
at room temperature (measured using the Evans’ method) is 3.0 μB, consistent with a triplet spin
state. The molecular structure of 8 was confirmed by X-ray crystallography (Figure 2). The Fe(1)–
C(1) distance of 1.950(3) Å is slightly shorter compared to that in 5.
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Figure 2. Synthesis of catalytic intermediate 8 (Left) and its X-ray structure (Right).
When 8 was used at a 3 mol% loading without the addition of LiHMDS, the catalytic performance
toward the dimerization of phenylacetylene is comparable to that of the combination of 5 and
LiHMDS under identical conditions (Figure 2). Complex 8 was used to study the mechanism
further. The consumption of phenylacetylene follows a first-order decay curve (Figure S96),
suggesting that the transition state of either the isomerization of an η2-alkyne complex to an η2-C–
H σ-complex or alkyne C–H cleavage is turnover-determining. We observed a slightly slower rate
for the dimerization of PhC≡C−D compared to that of PhC≡C−H using 3 mol% of 8 as the catalyst,
with a secondary kinetic isotope effect (KIE) of kH/kD = 1.29 (Figure 3). This result is comparable
to the value we previously observed for catalyst V, suggesting that the turnover-determining
transition state is not associated with the alkyne C–H bond cleavage step. In the literature, such a
normal secondary KIE was attributed to the isomerization of an η2-alkyne complex to an η2-C–H
σ-complex being the rate-determining step, where the C–H bond is weakened in the transition
state.87 Our experimental results also suggest that the turnover-determining transition state is
associated with the isomerization of an η2-alkyne complex to an η2-C–H σ-complex.
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y = 2.6788x
R² = 0.9964
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y = 2.0727x
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Time (min)
Figure 3. Left: Reaction profiles of the dimerization of phenylacetylene vs phenylacetylene-D
catalyzed by 3 mol % of 8 (based on 1H NMR integrations against mesitylene internal standard);
Right: Linear regression of initial rates.
One possible mechanism is shown in Scheme 3. To enter the catalytic cycle, the pre-catalyst 5
reacts with in situ generated PhC≡C−Li to form 8. The facile coordination of the alkyne substrate
affords A, followed by a migratory insertion to give B. The subsequent σ-bond metathesis releases
the enyne product and generates the cyclometallated intermediate C, which is converted into D via
the facile coordination of the alkyne substrate in an η2 fashion. The subsequent turnover-
determining isomerization of D forms the σ-complex E, which undergoes another σ-bond
metathesis to regenerate 8.88
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Scheme 3. Proposed catalytic cycle for
phenylacetylene dimerization.
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Figure 4. Computed singlet-state energetics: the proposed catalytic cycle in this work (in red) vs
the catalytic cycle of catalyst V (in blue). NOTE: for the structure of each species in the catalytic
cycle of catalyst V, replace the benzyl group on the NHC ligand of the corresponding species in
Scheme 2 with a picolyl group.
Based on the mechanistic proposal above, the mechanism of the reaction has been
computed using Gaussian 16, Revision A.03,89 with PBEPBE90 exchange-correlation functional.
The TZVP91 basis set was used for all elements. All structures were optimized with PCM solvent
correction (solvent = toluene) and the D3 version of Grimme’s dispersion correction with the
original D3 damping function.92 Frequency analysis was then performed to confirm that the
structure is a ground state or a transition state as appropriate and to obtain the thermodynamic data.
The 16e species (i.e., 8, B, and C) in the catalytic cycle (Scheme 3) have triplet ground states with
low lying singlet excited states, whereas the 18e species (i.e., A, D, and E) have single ground
states. Although 8, B, and C have triplet ground state, the facile alkyne binding would
instantaneously convert C and 8 to the singlet D and A, respectively. Therefore, the reaction
mechanism along the singlet surface was computed using the spin-restricted method and the
energetics are plotted in a sequence starting with the cyclometallated intermediate C, where no
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alkyne substrate is associated with the metal center for convenience (Figure 4). The free energy
span of the catalytic cycle is 14.0 kcal·mol−1, which is associated with the turnover-limiting
isomerization of the η2-alkyne complex D into the σ-complex E. The catalytic cycle of catalyst V
was computed using the same method for comparison. As shown in Figure 4, the energetics of the
two catalytic cycles are quite similar. However, for catalyst V the coordination of the dangling
pyridine N-donor of the 16e intermediates produces the corresponding off-cycle 18e species, which
are thermodynamically much more stable than the corresponding in-cycle species. For example,
in the catalytic cycle of V, the off-cycle species related to intermediates C and 8 are 21.6 and 13.9
kcal·mol−1 more stable than C and 8, respectively, in terms of free energy. Effectively, the off-
cycle species are the dominant Fe-containing species in the reaction mixture and there is only a
trace amount of the active species performing the catalysis. Consequently, catalyst V requires
elevated temperatures to achieve moderate activity (i.e., TOF of 88 h−1 at 80 °C), whereas our new
catalytic system is much more active (i.e., TOF of 800 h−1 at 25 °C).
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Scheme 4. The cis and trans-H/D conversion used herein and the fate of exchangeable H.
For the dimerization of PhC≡C−D catalyzed by 8, each molecule of 8 has six exchangeable
protons (i.e., two ortho CH3 groups of mesityl). With a 3 mol% catalyst loading, there is 18 mol%
of exchangeable proton from the catalyst. In addition, the PhC≡C−D substrate has a 99%
deuteration level, providing an additional 1 mol% of exchangeable proton. Therefore, the total
amount of exchangeable proton is 19 mol%. At the initial stage of the catalysis, when the catalyst
is almost fully protio, only the signal of the cis-proton (with respect to the alkynyl group, Scheme
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3) of the enyne product grows in intensity (Figure S97), indicating that the product release through
cyclometallation is operational. The signal of the trans-proton (with respect to the alkynyl group,
Scheme 4) of the enyne product starts to grow in intensity at 20 min (i.e. at ~90% yield of the
enyne products), accompanied by the slow intensity decrease of the cis-proton. Such a
phenomenon suggests the scrambling of the cis-H and trans-D of the enyne product, similar to that
observed for the reaction catalyzed by V. Distinct from the reaction catalyzed by V, where the cis-
H and trans-H signals become 1:1 ratio in intensity within 4 h under the conditions for catalysis,
the reaction catalyzed by 8 showed much slower scrambling under the conditions for catalysis, i.e.,
after 48 h the cis-H signal is still slightly more intense (Figure S97). The scrambling of the cis-H
and trans-D rate depends on the concentration of phenylacetylene but not the concentration of 8
(Table S3). It appears that the catalyst is not responsible for the scrambling between the cis-H and
trans-D of the enyne product. Our attempt to isolate the D-labelled enyne product for further study
by passing the reaction mixture through a short silica gel column (i.e., removing the catalyst) at 1
h gave an enyne sample with the cis- and trans-H signals of nearly equal intensity (Figure S98).
The sum of the cis- and trans-H is ~16 mol% (Figure S98), ruling out the exchange between the
enyne trans-D and the acidic protons from silica or moisture.
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CONCLUSION
A series of NHCs ligand varying steric properties have been used to prepare piano-stool iron
complexes [FeClCp*(NHC)], 1–7, among which 5 with mesityl and benzyl group on the NHC
ligand showed the highest catalytic activity toward terminal alkyne dimerization. Compared to our
previous catalyst V, possessing a picolyl-NHC ligand, the new catalyst displays a much higher
activity due to the lack of the stable off-cycle species. We tentatively attribute the normal
secondary KIE to the turnover-limiting isomerization of an η2-alkyne complex into a σ-complex,
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which is further supported by our computational results. The scrambling between the cis-H and
trans-D of the enyne product is not fully understood and will be studied further.
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AUTHOR INFORMATION
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Corresponding Author
* E-mail: dsong@chem.utoronto.ca
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free of charge on the ACS
Publications website at DOI:
Experimental procedures, selected crystallographic data tables, NMR and IR spectra
(PDF), and details of computational studies.
Accession Codes
CCDC 1865872-1865880 contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
ACKNOWLEDGMENT
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We thank Natural Sciences and Engineering Research Council (NSERC) of Canada for funding.
Q.L. thanks the Ontario government for an Ontario Graduate Scholarship. We also acknowledge
the Canadian Foundation for Innovation Project #19119, and the Ontario Research Fund for
funding the CSICOMP NMR lab at the University of Toronto enabling the purchase of several
new spectrometers.
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We report an iron-catalyzed geminal-specific dimerization of terminal alkynes at ambient
temperature.
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