Low temperature studies of iron-catalyzed cross-coupling of alkyl Grignard reagents with aryl electrophiles

Article abstract of DOI:10.1002/adsc.201100392

The title reaction has been studied under low temperature conditions. Coupling with active substrates can be done even at dry ice temperature. Initial rate studies at -25 °C indicate that high concentrations of any reagent can lead to either complete or partial catalyst deactivation. Under strongly reducing conditions, iron seems to form less active complexes that only slowly re-enter the catalytic cycle, possibly through bimolecular coupling of iron(II) complexes. Computational studies support the experimental observations, and indicate that oxidation states below +I cannot be reached by reductive elimination. Copyright

Full text of DOI:10.1002/adsc.201100392

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DOI: 10.1002/adsc.201100392
Low Temperature Studies of Iron-Catalyzed Cross-Coupling of
Alkyl Grignard Reagents with Aryl Electrophiles
Jonatan Kleimark,a Per-Fredrik Larsson,a Parisa Emamy,a Anna Hedstrçm,a
and Per-Ola Norrbya,*
a
University of Gothenburg, Department of Chemistry, Kemigꢀrden 4, SE-412 96 Gçteborg, Sweden
Fax : (+46)-31-772-1394; phone: (+46)-31-786-9034; e-mail: pon@chem.gu.se
Received: May 16, 2011; Revised: September 26, 2011; Published online: January 19, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100392.
Abstract: The title reaction has been studied under cycle, possibly through bimolecular coupling of
low temperature conditions. Coupling with active iron(II) complexes. Computational studies support
substrates can be done even at dry ice temperature. the experimental observations, and indicate that oxi-
Initial rate studies at À258C indicate that high con- dation states below +I cannot be reached by reduc-
centrations of any reagent can lead to either com- tive elimination.
plete or partial catalyst deactivation. Under strongly
reducing conditions, iron seems to form less active Keywords: cross-coupling; density functional calcula-
complexes that only slowly re-enter the catalytic tions; iron; kinetics; reaction mechanism
Introduction
anism.[6] One important and useful feature of iron cat-
alysis is the ability to catalyze couplings with alkyl
Metal-catalyzed cross-coupling reactions have been substrates without significant b-elimination, a task
some of the most important classes of reactions in or- that can be problematic within the nickel triad of cat-
ganic synthesis for decades. Reactions such as the alysts.[7] Despite substantial recent progress,[8] we still
Suzuki, Heck, Negishi and Ullmann are today widely need to increase our knowledge of the mechanism of
used tools in synthetic laboratories and constitute es- iron-catalyzed couplings, in order to enable a rational
sential steps in the synthesis of drugs and other fine selection of reaction conditions and ligands.
chemicals.[1] The most prominent example of these re-
In the 1970s, Kochi et al. performed kinetic studies
actions are the Pd-catalyzed cross-couplings, which on the iron-catalyzed coupling between Grignard re-
can be performed under mild conditions and tolerate agents and organic halides.[5a] The reaction showed
many functional groups.[2] Among the potential draw- first-order dependence in both iron catalyst and alkyl
backs can be mentioned the high price of noble halide, and was virtually independent of the concen-
metals and their ligands, potential leaching of the cat- tration of the Grignard reagent. With support of the
alyst to the environment or the product, and in some by-product profile and EPR measurements,[9] Kochi
cases (e.g., the Stille reaction) production of toxic proposed an Fe(I) [or possibly Fe(0)] active catalyst
waste. Investigations into alternative catalysts can po- and suggested a Kumada–Tamao–Corriu[4] type cata-
tentially alleviate these problems while at the same lytic cycle.[10] This view was later challenged when it
time providing interesting differences in scope and re- was discovered that Fe
activity. pre-catalysts in the iron-catalyzed couplings, and the
G
Iron salts have been utilized in cross-coupling reac- dominating view in the last decade has been that iron
tions since the 1940s,[3] but the Pd- and Ni-catalyzed cycles between oxidations states ÀII and 0 in the cata-
versions have come to dominate the area since their lytic cycle.[11][12]
introduction in the 1970s,[4] with only occasional re-
We recently studied the title reaction by a combina-
ports on the use of iron.[5] Since the mid-1990s, the in- tion of reaction monitoring, competitive Hammett
terest in the environmentally friendly iron-catalyzed studies, and DFT modelling.[13] We found strong sup-
reactions has increased, and several groups have con- port for the Fe(I)-Fe
ACHTUNGTRNE(NUNG III) cycle, with oxidative addi-
tributed to broaden the scope and elucidate the mech- tion as rate-limiting step. Interestingly, our computa-
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Low Temperature Studies of Iron-Catalyzed Cross-Coupling of Alkyl Grignard Reagents
Scheme 1. The title reaction, iron-catalyzed cross-coupling
between alkyl Grignard reagent and aryl electrophile.
Figure 1. Two feasible catalytic cycles for the coupling reac-
tion.[13]
tional study indicated the feasibility of two similar
cycles, where the transmetallation can precede or
follow the oxidative addition (Figure 1).
During the course of our further research in this
area, we could verify something that already had
been proposed in the literature – that the title reac-
tion could be performed at significantly lower temper-
atures than the standard cross-coupling reaction.
Figure 2. Competent substrates at different temperatures.
Some of the couplings could even be carried out at lished protocol of adding the Grignard reagent in
À788C, a feature that may be utilized to achieve small portions at intervals (ca. 15 min), to avoid the
better regio- or enantioselectivity and higher func- precipitation of catalyst that had been observed at
tional group tolerance. Ability to perform couplings high concentrations of Grignard reagent.[13] Reactions
at decreased temperatures is rare in the metal-cata- were monitored by GC, and judged successful if a sig-
lyzed cross-coupling family, with only a few examples nificant amount (>50%) of product could be detected
reported in the literature.[6j,7,11a,14] Therefore, we decid- after complete addition.
ed to investigate the catalytic behavior at low temper-
ature in more detail.
The tested substrates are depicted in Figure 2. As
can be seen, only aryl chlorides with a strongly elec-
In the current study we present our examination of tron-withdrawing group were competent coupling
the low-temperature iron-catalyzed cross-coupling re- partners at À788C. Other substrates showed no con-
action, noting in particular differences from the be- version at this low temperature. Chloropyridine was
havior at ambient temperature. The scope and reac- successfully coupled at À208C. At this temperature,
tivity for the reaction at low temperatures is investi- unsubstituted chlorobenzene was still unreactive, but
gated. Furthermore, a kinetic investigation to reveal phenyl triflate reacted well, showing that triflate is a
the influence of all the reacting species in the title re- better leaving group than chloride in these reactions.
action is presented. The experiments are supported Unactivated chlorobenzene required ambient temper-
by computational investigations. The results from the ature for significant coupling activity. These results
experiments and calculations allow us to reach several are well in line with the earlier reported, strongly pos-
new and exciting conclusions concerning the reaction itive 1-value in
a room temperature Hammett
conditions and the mechanism of the reaction. Inter- study,[13] and also agree well with the hypothesis of a
estingly, the conditions from the kinetic investigation rate-limiting oxidative addition.
give us the opportunity to understand, in detail, the
different pathways to catalyst deactivation and how to
avoid them.
Computational Study of the Oxidative Addition
A computational investigation was performed in
order to give an explanation to the results from the
substrate screen. Since the rate-limiting step for this
reaction is the oxidative addition, we therefore calcu-
lated barriers for oxidative addition of Fe(I) to select-
Results and Discussion
Reactivity at Low Temperatures
A
selection of different aryl electrophiles was ed substrates (Table 1). We can see that the calculated
screened for their ability to couple with an alkyl barriers agree reasonably well with the experimental
Grignard reagent at three different temperatures: results in Figure 2. The highest barrier is found for
À788C, À208C, and ambient temperature (Scheme 1). the only substrate requiring room temperature,
For all reactions, we followed the previously estab- chloroACHTNUTRGNEbNUG enzene. Phenyl triflate has a lower barrier,
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Table 1. Calculated barriers to oxidative addition for select-
ed substrates.
Grignard Reagent
Starting from the lowest concentration of Grignard
reagent, 0.025M, the reaction rate increases when the
concentration is doubled (Figure 3), indicating partici-
pation of the Grignard reagent in the rate-limiting
step. The curvatures of both plots show that the cata-
lyst is slowly deteriorating. At higher concentrations
of Grignard reagent, the catalytic performance is de-
creasing, reaching a minimum at 0.4M and then stay-
Substrate
DE° (kJmolÀ1)
phenyl-Cl
65
52
49
40
phenyl-OTf
p-CF3-phenyl-Cl
2-Cl-pyridine
and that for CF3-substituted chlorobenzene is even ing constant when the loading is increased to 0.5M.
lower, as expected. Somewhat surprisingly, the lowest After the first minute at these two highest concentra-
barrier overall was found for 2-chloropyridine, a sub- tions, the reaction rate seems to be constant, and in-
strate that was only active at À208C. We speculate dependent of the concentration of Grignard. Compa-
that the moderate observed reactivity of this substrate rative F-tests for the series at 0.5M shows that the
could be due to complexation of the nitrogen lone most significant line is obtained by dropping the first
pair, to magnesium or iron, in a geometry that retards point only, starting the analysis 60 s into the experi-
the oxidative addition. We also note that this was the ment. From this point, the data is a straight line with
only substrate that would give coupling product with- r2 >0.998, showing that the rate is constant, independ-
out iron catalyst at room temperature, presumably ent of Grignard reagent, and that the catalyst is not
through an SNAr reaction.
further deactivated after the first minute. The behav-
ior at 0.4M is virtually identical, whereas the catalyst
deactivation is less significant at the lower concentra-
tions of Grignard reagent (the plots at 0.3M and
below show curvature throughout). Overall, the be-
Low Temperature Kinetic Study
The kinetic investigation was designed as an initial- havior is consistent with a dual catalyst activity, where
rate study at À258C, of the reaction between octyl- the initially formed, highly active catalyst is converted
magnesium chloride and phenyl triflate, with by excess Grignard reagent into a less active form.
FeACHTUNGTRENNUNG(acac)3 as catalyst (Scheme 1). The standard reac- The higher the Grignard concentration, the faster the
tion employed 0.5 mmol each of substrate and catalyst deteriorates to the less active form. Taking
Grignard reagent, with 0.025 mmol (5 mol%) of iron into account the strongly reducing power of Grignard
catalyst. The total reaction volume was adjusted to reagents, we can speculate that iron in lower oxida-
20 mL in all cases. The initial concentration of each tion states gives less efficient catalytic cycles. We will
reagent was varied systematically. Reaction progress return to this point later, in connection with our com-
was followed by GC monitoring of product formation putational studies (vide infra). We also note minor
up to ca. 10% conversion. This method ensures that formation of biphenyl at the two lowest Grignard
plots should be linear unless changes in the reaction
mechanism occur in the course of the experiment.
Non-linearity in the plots under conditions where all
concentrations are approximately constant must be
interpreted as a significant change in the catalytic spe-
cies.
From the previously suggested mechanism with a
rate-limiting oxidative addition (Figure 1), we would
expect the reaction to be first order in substrate and
catalyst, whereas the reaction order in Grignard re-
agent could vary between 0 and 1 depending on
whether transmetallation occurs before or after the
oxidative addition step. Our earlier study left this
question unresolved;[13] indeed, both paths could well
be followed in parallel.
The active Fe(I) catalyst is formed from the FeACTHNUGTRNEUNG(III)
precursor by two transmetallations followed by reduc-
tive elimination. Consistent with this, hexadecane was
detected in all reaction mixtures, roughly proportional
to the amount of iron used in each reaction.
Figure 3. GC monitoring of product formation at different
Grignard concentrations.
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Low Temperature Studies of Iron-Catalyzed Cross-Coupling of Alkyl Grignard Reagents
concentrations, but this is suppressed to insignificant
levels at higher concentrations.
Phenyl Triflate
The initial concentration of phenyl triflate was varied
in the range 0.025–0.2M. The reaction order was posi-
tive, with a clear increase in initial rate with increas-
ing concentration (Figure 4). Catalyst deactivation oc-
curred in all runs, but especially at the highest con-
centration of phenyl triflate, where the catalyst died
suddenly after 4 min. This is somewhat surprising, as
earlier reports suggest that high substrate concentra-
Scheme 2. Plausible disproportionation paths to multiply
arylated iron species.
tion can protect the integrity of the catalyst.[13] How- should deactivate more rapidly upon increasing the
ever, the experimental set-ups differ substantially. In concentration of the “oxidant”, phenyl triflate. To ra-
the previous study, the Grignard reagent was added in tionalize this behavior, we must postulate that there
small aliquots, ensuring that there was never a large are several mechanisms for deactivating the catalyst.
excess of Grignard reagent with respect to the cata- In addition to the already proposed deactivation
lyst. In the current study, there is sufficient Grignard mode based on reduction of Fe, yielding a less effi-
reagent present to provide a constantly reducing envi- cient but still active catalyst (vide supra), there must
ronment. Still, we did not expect that the catalyst also be a deactivation mode based on reaction with
the arylating reagent.
It has been noted earlier that poly-aryl iron species
are stable enough to isolate,[15] and thus would not be
expected to be effective catalysts. Addition of multi-
ple aryl groups to the same iron center could occur in
exchange reactions between iron centers (Scheme 2),
or by a series of oxidative addition and electron trans-
fer reduction steps. If this is occurring, higher concen-
trations of phenyl triflate should result in significant
production of biphenyl by reductive elimination from
diphenyl FeACTHNUGTRNEUNG(III) complexes in solution. This is indeed
observed; biphenyl production seems to increase
more rapidly than the desired product, octylbenzene,
upon increasing the phenyl triflate concentration, see
Figure 5. Biphenyl production is also terminated
abruptly after 3 min at the highest concentration of
phenyl triflate, indicating complete conversion of all
iron into a catalytically incompetent polyaryl com-
plex. We can only speculate what this could be. It is
plausible that
(III) anion[6e,15]
a symmetric Ph4FeACHTUNTGNRUEGN
would be reluctant to undergo reductive elimination.
However, under the strongly reducing conditions of
the current study, another reasonable candidate for
the inactive state of iron is a neutral Ph2Fe(II) com-
plex (Scheme 2), since we know that Fe(II) has a high
barrier to reductive elimination.[13]
Iron Catalyst
The catalyst loading was varied from 0.25–5 mM, cor-
responding to 1–20 mol%. As with the other reagents,
at low concentrations the reaction order was positive,
with increasing initial rates up to ca. 2 mM (Figure 5).
With the most dilute catalyst, the reaction was close
Figure 4. Formation of octylbenzene and biphenyl at varying
concentrations of phenyl triflate.
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sudden catalyst death was observed, similar to what
was seen in the phenyl triflate series. This is a strong
indication that catalyst deactivation is bimolecular in
nature. It has been shown that reductive elimination
from mono-nuclear Fe(II) is disfavored, but also that
a binuclear mechanism involving two Fe(II) is facile,
albeit with a higher barrier than is observed for the
proposed Fe(I)-Fe/
ACHTUNGTRENNUNG
can be rationalized if Fe(I) and FeAHCUTNGTRENNUNG
reaction mixture comproportionate to Fe(II) com-
plexes that react to products in a slow, bimolecular
step, reforming Fe(I). Catalyst death could then be ra-
tionalized by formation of stable, unreactive PhnFe
complexes through similar processes. As in the case
of high phenyl triflate concentration, increased levels
of biphenyl at higher iron concentration gives support
for the hypothesis that multiply phenylated iron spe-
cies are formed in solution.
Computational Study of the Hypothetical Fe(0)-Fe(II)
Catalytic Cycle
The results from the kinetic investigation suggest that
under strongly reducing conditions, the reaction can
drop out of the highly active Fe(I)-FeACTHNUGRTENUNG(III) cycle, en-
tering a cycle with lower activity. For comparison, we
have here calculated barriers for a hypothetical Fe(0)-
Fe(II) cycle, to investigate whether such a mechanism
could be responsible for the lower activity observed
at high Grignard concentrations. For details of the
calculations, such as the number of explicit solvent
molecules tested, see the Computational Details sec-
tion.
Figure 5. Formation of octylbenzene and biphenyl at varying
concentrations of iron catalyst.
to linear, indicating that in this particular reaction,
Somewhat surprisingly, the results depicted in
catalyst deterioration was largely suppressed. At Figure 6 indicate that all steps in the Fe(0)-Fe(II)
higher concentrations, the curvature became more no- cycle are less efficient than those in the Fe(I)-Fe(III)
ACHTUNGTRENNUNG
ticeable, and at the highest catalyst concentrations, cycle. Common wisdom would indicate that if a free
Figure 6. Free energy surface for the hypothetical Fe(0)-Fe(II) cycle.
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Low Temperature Studies of Iron-Catalyzed Cross-Coupling of Alkyl Grignard Reagents
Fe(0) species existed in solution, it would be more ef- Mechanism under Reducing Conditions
ficient in oxidative addition than the Fe(I) species.
However, this is not observed, possibly because the From the combined results from the kinetic investiga-
oxidative addition is more complex than a pure redox tion and the computational study, we can draw several
reaction, also involving coordination of the aromatic interesting conclusions. Our previous study has shown
p-system to Fe. The barrier is a rather modest that under slow addition conditions, so that the con-
87 kJmolÀ1, higher than for Fe(I), but not incompati- centration of Grignard reagent does not exceed iron
ble with a catalytic cycle even at low temperature. As concentration, the reaction follows a simple FeACHTUNGTRENNUNG(III)-
before, transmetallation has an insignificant barrier, Fe(I) cycle.[13] The current results clearly indicate that
occurring easily in a bimetallic complex. The plateau in the presence of high concentrations of Grignard,
for the bimetallic complex shown in Figure 6 is in fact the catalyst becomes less active (Figure 3). This lower
not a transition state, but an energy minimum. At the activity cannot be simple Grignard addition to either
potential energy surface, this is lower in energy than FeACTHNUGTRNEUNG(III) or Fe(I), since these processes are part of the
the separated species flanking it. The separations, fast catalytic cycle depicted in Figure 1. The most
either forward or backward, are monotonic processes probable remaining option is that the most easily sus-
on the PES, occurring without saddle points, indicat- ceptible complex in the catalytic cycle, ArFeACTHNUGTRENUNG(III)X2, is
ing very low free energy barriers.[16] However, the re- reduced, either by single electron transfer (SET) from
ductive elimination is prohibitive at 204 kJmolÀ1, excess Grignard reagent or, as depicted in Figure 7,
making it completely impossible to reform Fe(0) by by comproportionation with Fe(I) species. This would
reductive elimination from the Fe(II) complex shown lead to Fe(II) complexes that could easily undergo
in Figure 6. Ligands like alkenes (present in the reac- transmetallation, but would be unable to undergo
tion mixture as impurities in the Grignard reagent) direct reductive elimination at these low temperatures
could potentially lower this barrier by stabilizing the (vide supra) and would only slowly return to the
Fe(0) state. To investigate this possibility, we per- “normal” catalytic cycle through a bimetallic coupling
formed a computational study where one or both of process.[13]
the solvent molecules in Figure 6 were replaced by
The side path depicted in Figure 7 is hypothetical,
the simple model alkene ethene (see Computational but it does explain the reduced reactivity at high con-
Details section and the Supporting Information for centrations of iron and/or Grignard, since increased
further details). Replacement of one solvent with Grignard concentration will result in a higher propor-
ethene in the Fe(II) complex resulted in a modest sta- tion of iron in lower oxidation state (here +I). Other
bilization by ca. 6 kJmolÀ1, further replacement re- reaction mechanisms could also explain the observed
sulted in an equally large destabilization, with the di- retardation, but the constraints imposed by our com-
ethene complex showing similar stability as the origi- putational studies seem to exclude iron oxidation
nal solvent complex. The transition states for the sub- states below +I. Thus, the intermediacy of Fe(II)
sequent reductive elimination were identified and the complexes in a slower side cycle seems the most plau-
barriers were found to be 144 and 129 kJmolÀ1, for sible candidate for explaining the activity lowering
the solvato-ethene and diethene complexes, respec- when the Grignard concentration is increased.
tively, giving Fe(0)-alkene complexes. Thus, in the
We note that the mechanism in Figure 7 does not
presence of substantial amounts of alkene, these explain the sudden catalyst death observed at high
paths become feasible at higher temperatures, but im-
probable at the low temperatures examined here.
Comparing to the barrier calculated earlier for reduc-
tive elimination from a bis-Fe(II) complex giving two
Fe(I) complexes, 85 kJmolÀ1,[13] we can conclude that
the reaction giving Fe(I) should be strongly favored
over pathways leading to Fe(0).
It should be noted that heterogeneous Fe(0) can be
formed from the reaction of Grignard reagents with
simple iron salts.[17] However, the current results indi-
cate that in the presence of substrates like phenyl tri-
flate, oxidative addition will outcompete Fe(0) forma-
tion.
Figure 7. Plausible catalytic cycles under reducing condi-
tions.
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composites obtained from adding the gas phase thermody-
namic adjustment (including ZPE) to the final energies in
solvent calculated with the continuum model at the con-
verged gas phase geometries. All structures are inspected
for interactions that may invalidate the use of gas phase ge-
ometries. We note that the approximations used here are
usually valid for energy minima, but may be problematic for
transition states if the reaction coordinate is coupled to a
major electrostatic change.
concentrations of PhOTf. However, transmetallation
among iron complexes could presumably produce in-
active Ar2Fe or more highly arylated species.[6e,15]
Conclusions
À
The title reaction shows extreme reactivity in C C
couplings, with facile reactions even at dry ice temper-
atures. However, the scope at this low temperature is
limited. Only aryl chlorides with strongly electron-
withdrawing groups are competent substrates. The re-
action scope was wider at À208C, but still required
electron deficient substrates, or the triflate leaving
Experimental Details
All reactions were performed under a nitrogen atmosphere
using standard Schlenk techniques. The glassware was pre-
dried at 1508C overnight before use. THF was distilled from
sodium benzophenone ketyl. Dodecane, NMP, and phenyl
triflate were distilled from calcium hydride under a nitrogen
atmosphere. The kinetic study was performed in a Dewar
flask and the temperature was held constant with a Lauda
Compact Low-Temperature Thermostat RL 6 CP using eth-
anol as cooling liquid. Analysis was performed on a gas
chromatograph with a flame ionization detector and a
30 mꢂ0.25 mmꢂ0.25 mm EQUITYTM-5 fused silica capil-
lary column, with nitrogen as carrier gas. General tempera-
ture program: 708C for 2 min, then up to 3008C at 188C
minÀ1. Dodecane was used as an internal standard. NMR
spectroscopic analysis was carried out on a Varian 400 MHz
instrument using CDCl3 as solvent, with shifts measured
against TMS.
À
group. The low temperature protocol allows C C cou-
pling with Grignard reagents even in the presence of
moderately sensitive functional groups like esters.
Kinetic investigations at À258C were in agreement
with the previously proposed Fe(I)-FeACTHNUGRTENUNG(III) catalytic
cycle when all reactants were diluted. Potentially
problematic catalyst deactivations pathways were
identified. Most importantly, excess Grignard reagent
produced reduced iron complexes with low activity,
explaining the observed benefit of slow addition pro-
tocols. Completely inactive complexes were produced
when the concentration of either iron or phenyl tri-
flate was high.
Computational investigations have shown good
agreement between observed reactivity of different
substrates and calculated barriers for oxidative addi-
tion to Fe(I). It could also be shown that formation of
Fe(0) has a prohibitively high barrier, but that Fe(II)
complexes can re-enter the catalytic cycle in a slow,
Low Temperature Reactivity
A 100-mL round-bottomed flask was charged with with
FeACTHNUGTRENNG(U acac)3 (89 mg, 0.25 mmol), sealed with a rubber septum,
then evacuated and refilled with nitrogen four times. The
substrate (5 mmol), dodecane (1.14 mL, 5 mmol), NMP
(1.1 mL) and THF (50 mL) were added at room tempera-
taure and the mixture was cooled to À208C or À788C. A so-
lution of n-octylmagnesium bromide (3 mL, 2M in diethyl
ether, 6 mmol) was added dropwise via syringe to the reac-
tion flask (À208C), or in portions (0.3 mL every 20 min,
À788C), causing a color change from red-orange to dark
brown. After 30 min or 200 min, respectively, a small
amount (1 mL) of the mixture was quenched with saturated
ammonium chloride (1 mL) or brine (1 mL, used for the N-
heterocycles), filtered through a small silica plug, diluted
with diethyl ether (1 mL) and analyzed by GC. The concen-
tration of all components was determined using dodecane as
an internal standard.
binuclear step. The resulting Fe(I)-FeACTHNUTRGNE(NUG III)-Fe(II) cycle
is currently the most plausible proposal for the slower
reaction observed at the later stages of the monitoring
in the reducing environment when high concentra-
tions of Grignard reagents are employed.
Experimental Section
Computational Details
As model for the Grignard reagent we use ethylmagnesium
chloride (C2H5MgCl). The THF solvent is modelled by a
variable number of directly coordinated dimethyl ether mol-
ecules (CH3OCH3). All possible spin configurations have
been considered. The actual number of explicit solvent mol-
ecules for each complex is determined by the final free
energy (vide infra). With this explicit solvation, geometries
are determined in vacuum using the Jaguar program[18] but
final energies are determined in conjunction with a continu-
um solvation model with parameters suitable for THF.[19] All
calculations employ the B3LYP functional[20] in conjunction
with the LACVP* basis set.[21] Stationary point validation
and thermodynamic contributions are obtained from gas
phase vibrational calculations. The final energies (DG) are
Initial-Rate Measurement
The kinetic investigation was carried out by varying the con-
centration of one component at a time and keeping the rest
of the components constant at standard reaction conditions;
THF (19.5 mL), dodecane (114 mL, 0.5 mmol), NMP
(0.5 mL), phenyl triflate (81 mL, 0.5 mmol), n-octylmagnesi-
um chloride (250 mL, 0.5 mmol, 2M in THF) and Fe
(250 mL, 0.025 mmol, 0.1M in THF).
A round-bottomed flask fitted with a rubber septum and
magnetic stirring bar was placed in Dewar flask at À258C.
To the round-bottomed flask was added THF, dodecane,
NMP, phenyl triflate and n-octylmagnesium chloride. The
ACHTUNGTRENNUNG(acac)3
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Low Temperature Studies of Iron-Catalyzed Cross-Coupling of Alkyl Grignard Reagents
total THF volume was adjusted to 20 mL for each run. The
reaction mixture was left to equilibrate for 20 min at the
given temperature. A calibration sample was taken from the
reaction mixture (100 mL), quenched in ammonium chloride
(aqueous) (1 mL), diluted in diethyl ether and analyzed by
gas chromatography using dodecane as internal standard.
The reaction was initiated by adding FeACTHNUTRGENUG(N acac)3 (0.1M in
THF). Samples were withdrawn from the reaction mixture
and treated as detailed above.
Rahn, D. C. Shubert, S. E. Bonde, Tetrahedron Lett.
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1H NMR (400 MHz, CDCl3) Spectroscopic Data
Methyl 4-octylbenzoate: d=0.86–0.89 (t, 3H), 1.25–1.31 (m,
10H), 1.58–1.61 (m, 2H), 2.63–2.67 (t, 2H), 3.90 (s, 3H),
7.23–7.25 (d, 2H), 7.93–7.96 ppm (d, 2H).
p-Trifluoromethyloctylbenzene: d=0.88 (t, 3H), 1.21–1.39
(m, 10H), 1.57–1.64 (m, 2H), 2.65 (t, 2H), 7.27 (d, 2H),
7.52 ppm (d, 2H).
2-Octylpyridine: d=0.88 ppm (t, 3H), 1.29ACTHNURGTNE(NUG m, 10H), 1.7
(m, 2H), 2.77 (t, 2H), 7.25 (m, 2H), 7.58 (t, 1H), 8.5 (d,
1H)
Acknowledgements
The current project is supported by the Swedish Research
Council. The computations were performed on C3SE com-
puting resources in Gothenburg. We are grateful to AstraZe-
neca for generous support and to Dr. Sten Nilsson Lill for
helpful discussions regarding the calculations.
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