Mechanism of alkoxy groups substitution by Grignard reagents on aromatic rings and experimental verification of theoretical predictions of anomalous reactions

Article abstract of DOI:10.1021/ja4015937

The mechanism of direct displacement of alkoxy groups in vinylogous and aromatic esters by Grignard reagents, a reaction that is not observed with expectedly better tosyloxy leaving groups, is elucidated computationally. The mechanism of this reaction has been determined to proceed through the inner-sphere attack of nucleophilic alkyl groups from magnesium to the reacting carbons via a metalaoxetane transition state. The formation of a strong magnesium chelate with the reacting alkoxy and carbonyl groups dictates the observed reactivity and selectivity. The influence of ester, ketone, and aldehyde substituents was investigated. In some cases, the calculations predicted the formation of products different than those previously reported; these predictions were then verified experimentally. The importance of studying the actual system, and not simplified models as computational systems, is demonstrated.

Full text of DOI:10.1021/ja4015937

Article
pubs.acs.org/JACS
Mechanism of Alkoxy Groups Substitution by Grignard Reagents on
Aromatic Rings and Experimental Verification of Theoretical
Predictions of Anomalous Reactions
Gonzalo Jimenez-Oses,† Anthony J. Brockway,‡ Jared T. Shaw,*,‡ and K. N. Houk*,†
́
́
†Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1569, United
States
‡Department of Chemistry, One Shields Ave, University of California, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: The mechanism of direct displacement of alkoxy groups in
vinylogous and aromatic esters by Grignard reagents, a reaction that is not
observed with expectedly better tosyloxy leaving groups, is elucidated
computationally. The mechanism of this reaction has been determined to
proceed through the inner-sphere attack of nucleophilic alkyl groups from
magnesium to the reacting carbons via a metalaoxetane transition state.
The formation of a strong magnesium chelate with the reacting alkoxy and
carbonyl groups dictates the observed reactivity and selectivity. The
influence of ester, ketone, and aldehyde substituents was investigated. In
some cases, the calculations predicted the formation of products different
than those previously reported; these predictions were then verified experimentally. The importance of studying the actual
system, and not simplified models as computational systems, is demonstrated.
originally assigned, and these predictions have been verified
experimentally.
INTRODUCTION
■
The substitution of alkoxy groups on aromatics (SNAr)
activated by ortho-carbonyl substitution1 has been known for
a number of early examples in the literature,2−21 but this
reaction has been shown to be quite general in recent studies by
our group. A general example with 1-methoxynaphthalenes is
shown in Scheme 1a. Related reactions are found in
RESULTS AND DISCUSSION
■
Reaction Mechanism. While metallic chelates of 1,3 and
1,4-alkoxycarbonyl compounds have been detected by NMR
spectroscopy,22−24 we were unable to identify these complexes
in solution using magnesium halides as chelating agents, due to
their insolubility in the deuterated reaction solvents. Instead, we
have performed a computational study of all conceivable
bidentate complexation modes of CH3MgCl to methyl 1-
methoxy-2-naphthoate 1a. Although most experiments were
performed with ethyl or larger Grignards, our initial calculations
involved methyl Grignard reagents for simplicity. The well-
known μ-dichloro dimer form of Grignard reagent25−28
including two solvent molecules (dimethyl ether, DME, in
our model) was selected as the starting material, and several
dimer and monomer isomers of the reactant complex, denoted
as 1a•CH3MgCl (a-m), were calculated. Figure 1 shows the
geometries and formation energies of the most significant
structures for these complexes (see Figure S1 in Supporting
Information for further details). The Schlenk equilibrium29 (i.e.,
formation of dialkyl magnesium compounds and magnesium
halide salts) was not considered to take place significantly
under the experimental conditions. The monomeric magne-
sium chelate 1a•CH3MgCl (a) formed after scission of two
Scheme 1. Displacement of Alkoxy Groups by Grignard
Reagents in (a) Aromatic and (b) Nonaromatic Substrates
nonaromatic systems (Scheme 1b). While the reactions
shown are tolerant to other alkoxy groups, the normally better
leaving group tosyloxy is not displaced. In addition, while many
Grignard reagents are effective, organolithium and organozinc
reagents give poor yields at best. We report a computational
study of this reaction that provides a thorough mechanistic
rationale of these facts. Furthermore, in some cases, theory
predicts the formation of different products from those
Received: February 15, 2013
© XXXX American Chemical Society
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Figure 1. (a) Proposed coordination of Grignard reagents to vinylogous 1,2-alkoxy carbonyl compounds leading to 1:1 and 2:1 complexes (eq. 1 and
eq. 2, respectively). Additional coordination modes are described in the Supporting Information. (b) Structures and complexation free energies
(ΔGcomplex) calculated at the PCM(THF)/B3LYP/6-31G(d) level. Energies are in kcal mol−1 and distances are in Angstroms.
Figure 2. (a) Proposed mechanisms for the reaction of vinylogous 1,2-alkoxy carbonyl compounds with Grignard reagents through six-membered
(TS′) and four-membered (TS) cyclic transition states. (b) Most relevant transition structures and activation free energies (ΔG⧧) calculated at the
PCM(THF)/B3LYP/6-31G(d) level. Energies are in kcal mol−1 and distances are in Angstroms.
Mg−Cl bonds upon substrate coordination was by far the most
stable complex in solution (ΔGcomplex = −7.2 kcal mol−1),
whereas the formation of complexes with Grignard dimer
species was always endergonic (ΔGcomplex = +2.4 to +10.9 kcal
mol−1). This complex was considered the reference minimum
for the estimation of the free energy barriers calculated here.
The classical mechanism of Grignard reagent addition to
carbonyl compounds, especially ketones, was first proposed by
Ashby.25−28,30 This mechanism involves the participation of a
μ-chloro organomagnesium dimer in which one Mg is
coordinated to the carbonyl oxygen, and the other Mg delivers
the alkyl or aryl nucleophile to the carbonyl carbon through a
concerted six-membered cyclic transition state (TS) (Figure 2).
When we calculated this mechanism starting from complex
1a•CH3MgCl (d), it was first necessary to cleave one Mg−Cl
bond and coordinate one ether molecule to provide a
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reasonable coordination environment for the Mg transferring
the nucleophile. This rearrangement barely stabilized the new
reactant complex 1a•CH3MgCl(DME) (d′) by 0.4 kcal mol−1
over the unsolvated μ-dichloro species. In the proposed six-
membered TS geometry, both for the addition to the carbonyl
or the alkoxy displacement, the alkyl group suffers pyramidal
inversion at the reacting carbon during the C−C bond
formation, at a significant energy cost. Accordingly, quite high
energy barriers for the addition to ipso position in the
naphthalene ring and 1,2-addition to the ester carbonyl were
tionally. In good agreement with experimental results1 (Scheme
1), the simple substitution of MeMgCl (yielding 2a) by
EtMgCl as a closer model to n-BuMgCl (yielding 2b) had a
quite beneficial effect on both the calculated reactivity and
chemoselectivity, providing lower activation energies and
shifting to a 98:2 ratio toward methoxy group displacement
(lowest energy barriers: ΔG⧧
= +22.1 for 1a-TSOMe and
OMe
ΔG⧧
= +23.7 kcal mol−1 for 1a-TSCO, respectively). We
CO
decided to use EtMgCl as a more appropriate Grignard reagent
model henceforth, since the majority of experiments were
conducted using primary nucleophiles such as n-BuMgCl and i-
BuMgCl.
calculated (ΔG⧧
= +32.7 for 1a-TS′OMe and ΔG⧧
=
CO
+28.2 kcal mol−1OMfoer 1a-TS′CO, respectively). Moreover, the
favored addition to the carbonyl group by 4.5 kcal mol−1
completely disagrees with the experimental observations.
These results prompted us to investigate alternative pathways
for the studied reactions. Looking at the structure of the most
stable magnesium chelate 1a•CH3MgCl (a), in which the
nucleophilic alkyl group is located proximal to both reacting
carbons at the methoxy and ester groups (3.85 and 4.04 Å,
respectively), we envisaged a direct transfer of the methyl group
to either the carbonyl or ipso aromatic carbons through a four-
membered metalaoxetane TS (Figure 2). Despite the
apparently more strained arrangement of these TSs with
respect to the aforementioned six-membered TS, the alkyl
group is transferred from the Grignard reagent without
pyramidal inversion and with minimal rehybridization of the
reacting carbon. This smaller distortion of the reactants in the
TS provides a significantly lower activation barrier for the both
In order to determine the rate-limiting step of each
competing reaction, the whole mechanisms were calculated
for both processes. As depicted in Figure 3, both reactions
follow stepwise mechanisms in which the initial addition to the
carbonyl or alkoxy groups is clearly the rate-limiting step. This
step is moderately exergonic in both cases and leads to quite
stable but very reactive tetrahedral intermediates.
Such intermediates derived from 1,2- and 1,4-conjugate
additions can be visualized as magnesium alkoxides and
enolates, respectively. These transient species evolve through
an almost barrierless second step to cleave the methoxy leaving
group and recover either naphthalene aromaticity or the
carbonyl sp2 hybridization. The restoration of π-delocalization
along the aromatic and carbonyl systems, and the formation of
ionic Mg-alkoxy species after leaving group departure are the
driving forces for such hyper fast and highly exergonic
processes. Interestingly, the formation of a tetrahedral
intermediate at the ipso carbonyl of naphthalene does not
disrupt the aromaticity and π-conjugation with the ortho
carbonyl group significantly, as demonstrated by the
exergonicity of the first reaction step. As will be discussed
below, this is not the case with other position isomers of this
substrate.
alkyl addition processes (ΔG⧧
= +25.2 for 1a-TSOMe and
OMe
ΔG⧧CO = +24.8 kcal mol−1 for 1a-TSCO, respectively). More
importantly, both competitive pathways get much closer to the
observed preferential displacement of the methoxy group
leading to compound 2a.
In order to test the validity of our model, the reaction of ester
1a with CH3MgCl was assayed experimentally (Scheme 2). In
In our previous study,1 we reported that nonaromatic
vinylogous esters such us Z-ethyl 3-methoxycinnamate 3 and
methyl 1-methoxy-3,4-dihydro-2-naphthoate 5 (Scheme 3)
readily react with Grignard reagents in a similar manner to
the naphthalene counterparts, namely with complete selectivity
toward alkoxy group displacement. However, treatment of the
corresponding 1H-indene analogue 7 with 1 equiv of i-PrMgCl
only yielded starting unreacted starting material after extractive
workup, hence we decided to shed some light onto this
behavior computationally. Our calculations predicted a
complete selectivity toward methoxy group substitution and
activation barriers similar to those obtained for the analogous 1-
Scheme 2. Reaction of Aromatic β-Alkoxy Esters with Methyl
Grignard Reagents
agreement with our calculations, this reaction yields both 1,2-
and 1,4-conjugate addition products together with a small
amount of hydroxylated compound 18. The intermediate
methyl ketone was not observed and tertiary alcohol 15a was
obtained as the minor reaction product. Despite the major
proportion of 2a in the reaction mixture, 2 equiv of Grignard
reagent are consumed in the two successive 1,2-additions per
equiv. consumed in the 1,4-conjugate addition; this limits the
proportion of tertiary alcohol in the final mixture when
stoichiometric amounts of CH3MgI are used and suggests that
the 1,2-addition to the carbonyl group must be competitive
with 1,4-addition. Hence, the formation of tertiary alcohol 15a
with methyl Grignard reagents, not reported previously for
methoxynaphthyl esters, was successfully predicted by our
calculations and demonstrated experimentally.
methoxy-2-naphthoate (lowest energy barriers: ΔG⧧
=
OMe
+19.9 for 7-TSOMe and ΔG⧧
TSCO, respectively).
= +27.1 kcal mol−1 for 7-
CO
On the basis of previous reports,31 we envisaged the possible
in situ formation of indenylmagnesium chloride32 or bis-
(indenyl)magnesium33,34 as the reason for this lack of reactivity
with stoichiometric amount of Grignard reagent (the pKa of
1H-indene is 20.1 in dimethylsulfoxide35). According to this
hypothesis and our predicted reactivity, we were glad to
demonstrate that the treatment of 7 with 3 equiv of i-PrMgCl
cleanly gave displacement of the methoxy group with no
detectable attack to the carbonyl group in excellent yield (90%,
Scheme 3). Interestingly, the activation barriers for the same
reactions starting from the deprotonated and fully aromatic
indenyl anion 7′, are exceedingly high to be overcome at the
reaction temperature (lowest energy barriers: ΔG⧧OMe = +44.5
The influence of the nature of the Grignard reagent on the
rate-limiting step of the reaction was investigated computa-
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Figure 3. Reaction pathways for the addition of Grignard reagents to aromatic 1,2-alkoxy esters calculated at the PCM(THF)/B3LYP/6-31G(d)
level. Free energies (ΔG) relative to the reactant complex are in kcal mol−1.
derived from 1H-indene is longer (2.40 Å) than in the
naphthalene-derived 1a-TSOMe (2.30 Å) whereas the CCO
Scheme 3. Reactivity of Nonaromatic Vinylogous Esters with
Grignard Reagents
−
CEt forming bond distance is slightly shorter in less stable 7-
TSCO than in 1a-TSCO (2.26 and 2.27 Å, respectively).
Functional Groups Effects. The influence of both the
nature and position of the reacting groups was demonstrated in
our previous report.1 Thus, a simple change in the location of
the alkoxy group to provide other ortho isomer, namely methyl
3-methoxy-2-naphthoate 9, disrupted its reactivity as demon-
strated by competition experiments. In the course of our
computational investigations to rationalize this reactivity, we
found that although the methoxy displacement pathway was
clearly disfavored using EtMgCl as Grignard reagent model
(lowest energy barrier: ΔG⧧
= +30.8 for 9-TSOMe), the
reactivity at the carbonyl group remained essentially unchanged
OMe
(lowest energy barrier: ΔG⧧
= +22.1 for 9-TSCO),
OMe
providing a complete chemoselectivity toward 1,2-addition.
The change of primary EtMgCl by secondary i-PrMgCl,
which was the Grignard reagent used experimentally, did not
change this trend (lowest energy barriers: ΔG⧧OMe = +30.4 for
for 7′-TSOMe and ΔG⧧
= +33.9 kcal mol−1 for 7′-TSCO
,
CO
respectively), pointing to the remaining protonated 1H-indene
in solution as the reactive species in this reaction.
9′-TSOMe and ΔG⧧
= +22.4 kcal mol−1 for 9′-TSCO
,
The source of such a great difference between the two
addition pathways in the 1H-indene derivative 7, lies on the
interruption of π-delocalization along the well-defined α,β-
unsaturated system when the addition takes place to the
carbonyl group, an issue that is alleviated in much more
delocalized systems such as naphthalenes. The greater
conjugation with respect to reactants achieved in the ipso-
disubstituted adduct makes the 1,4-addition step more
exergonic (ΔG = −14.7 kcal mol−1) and the 1,2-addition less
exergonic (ΔG = −10.0 kcal mol−1) compared to the aromatic
ester 1a (ΔG = −7.3 and −12.7 kcal mol−1, respectively).
As a general trend observed here, the lower energy TSs for
methoxy group displacement are earlier (i.e., close in geometry
and energy to the reactants), in good agreement with
Hammond’s postulate36 for exergonic processes. Thus, the
COMe−CEt forming bond distance in the more stable 7-TSOMe
CO
respectively). These theoretical results were not in accordance
with the reported reactivity for this substrate, since a slower but
still complete chemoselectivity toward methoxy group displace-
ment was previously published.1 Intrigued by these observa-
tions, we repeated the same reactions and re-examined the
NMR data of the isolated compounds carefully. Thereafter, we
concluded that our previous assessment of reactivity for this
compound was wrong, and the ester carbonyl group indeed
reacts exclusively to provide the corresponding isopropyl
ketone 10 in good yield (85%, Scheme 4), which did not
undergo further 1,2-addition.
These new results predicted by the computations gave rise to
a correction of the original manuscript and stress the great
benefits of integrating experiments and calculations.
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Additionally, and as can be seen in Figure 4, the contribution of
the ipso carbon bearing the methoxy group to the LUMO of 3-
methoxy-2-naphthoate 9 is almost negligible in opposition to 1-
methoxy isomer 1a, justifying the complete selectivity toward
1,2-carbonyl addition with Grignard reagents of the former.
As described in our previous study,1 the presence of a
theoretically better leaving group than alkoxide (such as
tosylate) completely inhibits the displacement reaction at low
temperature, even with primary nucleophiles like n-BuMgCl
and i-BuMgCl. This apparently counterintuitive result was
rationalized computationally by a higher calculated activation
barrier for mesylate (simpler model of tosylate) displacement
using EtMgCl as Grignard model (lowest energy barrier:
Scheme 4. Structural Revision of the Reaction Product
between Naphthyl Ester 9 and Grignard Reagents
a
ΔG⧧
= +25.6 for 11-TSOMe) with respect to methoxy
OMe
substitution in analogous compounds. Reversing the trend
calculated for similar alkoxy derivatives, the nucleophilic
addition of the same reactant to the carbonyl group is now
ca. 4 kcal mol−1 lower in energy (lowest energy barrier:
a
As predicted computationally, 1,2-addition to the carbonyl group
takes place exclusively.
The reduced reactivity of the methoxy group at the 3
position in compound 9 is again reflected by the late character
(structurally close to the product) of the corresponding 1,4-
addition TS illustrated by the short COMe−Calkyl forming bond
distance (2.17 Å with EtMgCl and 2.23 Å with i-PrMgCl,
Figure 4). Moreover, this methoxy group displacement
ΔG⧧
= +21.8 for 11-TSCO), which provides complete
CO
chemoselectivity toward this pathway. To our delight, when the
reaction mixture was allowed to reach room temperature
overnight, only addition to the ester carbonyl group of 11
toward the corresponding tertiary alcohol 12 was observed, as
predicted by our calculations, albeit with low conversion and in
low yield (20%, Scheme 5).
Scheme 5. Reactivity of (Tosyl)naphthyl Esters with
Grignard Reagents
The decreased propensity of tosylate group to be displaced
lies in its inability to form a stable six-membered chelate
involving the oxygen attached to the ipso carbon (11•EtMg-
Cl_a) as in the methoxy-substituted analogues. Instead, the
carbonyl oxygen and a sulfonyl oxygen form an eight-
membered chelate (11•EtMgCl_b), which promotes the
activation of only the ester group toward nucleophilic addition
(Figure 5). Due to the weaker coordinating character of
sulfonate esters compared to ethers, these chelates are
significantly less stable (ΔGcomplex = +7.5 and −0.2 kcal
mol−1, respectively) than the 1-methoxy-substitued analogue.
Although ketones are generally viewed as incompatible with
the high nucleophilicity of Grignard reagents, we have shown
that the displacement reaction is facile at temperatures below
which the ester or ketone products will undergo addition
(Table 1, entries 2−5).1 As an exception, MeMgI in CH2Cl2
undergoes complete addition to the carbonyl group as
previously reported31 and confirmed in our lab (Table 1,
entry 1). In this sense, computations on the reaction of
methylketone 13a with EtMgCl reproduced this trend
quantitatively by estimating a 77:23 ratio favoring the
displacement of the methoxy group with EtMgCl (lowest
Figure 4. (a) Lowest-energy transition structures and activation free
energies (ΔG⧧) for the reaction of naphthyl ester 9 and EtMgCl
calculated at the PCM(THF)/B3LYP/6-31G(d) level. Energies are in
kcal mol−1 and distances are in Angstroms. (b) Isosurface
representation of LUMO of reactant complexes of isomers 1a and 9.
Potentially reactive positions are marked with red (methoxy group)
and blue (carbonyl group) arrows.
proceeded in an asynchronous but concerted manner without
the formation of a stable tetrahedral intermediate, as revealed
by intrinsic reaction coordinate (IRC) calculations. The origin
of this lower reactivity is the poorer ability of 3-methoxy-2-
naphthoates to stabilize the formal negative charge generated
after 1,4-addition of the alkyl group with respect to 1-methoxy-
2-naphthoates (Figure S2 in Supporting Information). The lack
of resonance structures preserving the aromaticity of one fused
benzene ring precludes the formation of stable adducts after
1,4-addition and drives the concerted elimination of the
methoxy group in order to recover naphthalene aromaticity.
energy barriers: ΔG⧧
= +19.0 for 13a-TSOMe and ΔG⧧
CO
OMe
= +19.5 kcal mol−1 for 13a-TSCO, respectively). Interestingly,
the simple change of methyl group in the ketone by a n-butyl
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As an exception to the global trend described before, the
more stable TSs for 1,4-addition on 1-methoxy-2-naphthyl
methyl ketone 13a are later as reflected by the COMe−CEt
forming bond distances (2.38 and 2.28 Å with EtMgCl and
MeMgCl, respectively, Figure 6). These results stress the great
Figure 5. (a) Six-membered (left) and eight-membered (right) chelate
reactant complexes of (mesyl)naphthyl ester 11 with EtMgCl together
with their respective complexation free energies (ΔGcomplex). (b)
Lowest-energy transition structures and activation free energies (ΔG⧧)
for the reaction of 11 and EtMgCl calculated at the PCM(CH2Cl2)/
B3LYP/6-31G(d) level. Energies are in kcal mol−1 and distances are in
Angstroms.
Table 1. Comparison of Carbonyl Reactivity toward
Alkoxide Displacement
Figure 6. Lowest-energy transition structures and activation free
energies (ΔG⧧) for the reaction of nahphyl ketone 13a with EtMgCl
(top) and MeMgCl (bottom) calculated at the PCM(THF)/B3LYP/
6-31G(d) level. Energies are in kcal mol−1 and distances are in
Angstroms.
importance of properly choosing the substrate models for the
calculations, because very similar EtMgCl and MeMgCl provide
very different reactivity patterns.
The reaction with more reactive carbonyls such as aldehydes
completely changes the general selectivity trend observed with
less electrophilic vinylogous esters and ketones. According to
the experimental results (Table 1, entry 6),1 the chemo-
selectivity calculated for the addition of EtMgCl (computa-
tional model of n-BuMgCl) to 1-methoxy-2-naphthaldehyde
13c is reversed with respect to analogous ester 1a with a
calculated ratio of 2:98 favoring the attack toward the carbonyl
group. As can be seen in Figure 7, the contribution of the
carbonyl carbon to the LUMO is larger in naphthyl aldehyde
13c than in the analogous methyl ester 1a, justifying the higher
selectivity toward 1,2-carbonyl addition with Grignard reagents
of the former. It is noteworthy that the activation energies for
both competitive pathways decrease significantly in the case of
ratio of 14:15
isolated yield, %
a
b
entry substrate
R2
predict.
exp.
(product)
1
2
3
4
5
6
13a
13a
13a
13b
13b
13c
Me
9:91
<5:>95
73:27
35 (15a)
66 (14a)
n-Bu
i-Pr
77:23
c
>95:<5
>95:<5
>95:<5
<5:>95
61 (14c)
n-Bu
i-Pr
95:5
3:97
85 (14b)
90 (14d)
85 (15c)
n-Bu
a
Calculated through a Maxwell−Boltzmann distribution at −78 °C of
b
1
all computed TS. Determined by H NMR in the reaction mixture.
c
Corresponding secondary alcohol, resulting from carbonyl reduction,
aromatic aldehydes (lowest energy barriers: ΔG⧧
= +16.8
was isolated in 20% yield.
OMe
kcal mol−1 for 13c-TSOMe and ΔG⧧
+15.4 kcal mol−1 for
CO
13c-TSCO, respectively). Interestingly, this decrease in the
activation barriers matches the lower stability of the reactant
complex with weaker coordinating aldehydes (13c•EtMgCl,
ΔGcomplex = +0.1 kcal mol−1), which are essentially
thermoneutral and 6−7 kcal mol−1 less stable that those of
the corresponding vinylogous esters and ketones. The TSs for
both nucleophilic additions in 13c, are the earliest of all
group in 13b, produces an increase in the calculated selectivity,
providing a calculated ratio of 95:5 toward 1,4-conjugate
addition, in very good agreement with experimental observa-
tions (lowest energy barriers: ΔG⧧
= +19.6 for 13b-TSOMe
OMe
and ΔG⧧CO = +20.5 kcal mol−1 for 13b-TSCO, respectively).
Moreover, and somewhat unexpectedly, the computations on
the reaction of methyl ketone 13a with a slightly harder
nucleophile such as MeMgCl also reproduced the experimen-
tally observed inversion of chemoselectivity, providing a
calculated 9:91 ratio toward the formation of the corresponding
calculated species, exhibiting the largest COMe−CEt and CCO
−
CEt forming bonds distances (2.42 and 2.55 Å, respectively).
Role of Magnesium Chelate. In previously reported
reactions similar to those described herein, the formation of
stable transient chelate complexes with organoalkyl reagents
prior to nucleophilic alkyl transfer has been proposed.22−24 The
key role of magnesium in this type of reactivity is reflected by
tertiary alcohol (lowest energy barriers: ΔG⧧
= +22.0 for
OMe
13a-TS′OMe and ΔG⧧CO = +21.1 kcal mol−1 for 13a-TS′CO
,
respectively).
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coordinated nonchelated structures was unsuccessful even if an
alternate ester rotamer was considered. Notably, the reactant
complex in which the magnesium adopts a pentacoordinated
environment by coordinating to both the methoxy and carboxyl
oxygen atoms, is significantly less stable than the tetrahedral
monodentante complex with the carbonyl group (ΔGcomplex
=
+2.9 kcal mol−1 for 1′a•CH3MgCl(DME)), which in turn is
much less stable than the Mg-carbonyl-ether chelated species
discussed above. The energy barrier for methoxy displacement
increases by ca. 13 kcal mol−1 with respect to the unsolvated
chelate, but the activation energy for 1,2-addition to the
carbonyl group remains essentially unperturbed.
Finally, in an attempt to completely dissect the contribution
of the methoxy and ester groups to the observed reactivity, we
calculated the energy profiles starting from monosubstituted 1-
methoxynaphthalene 16 and methyl 2-naphthoate 17, including
again a solvent molecule to provide tetracoordination for
magnesium (Figure 8b). The monodentate complexes of these
species with CH3MgCl resulted to be quite unstable compared
to the chelated ones, specially the methoxy-derived species
(ΔGcomplex = +14.4 kcal mol−1 for 16•CH3MgCl(DME) and
ΔGcomplex = +2.6 kcal mol−1 for 17•CH3MgCl(DME)).
Moreover, the activation barrier for methoxy group displace-
Figure 7. (a) Lowest-energy transition structures and activation free
energies (ΔG⧧) for the reaction of nahphyl aldehyde 13c and EtMgCl
calculated at the PCM(THF)/B3LYP/6-31G(d) level. Energies are in
kcal mol−1 and distances are in Angstroms. (b) Isosurface
representation of LUMO of reactant complex derived from ester 1a
and aldehyde 13c. Potentially reactive positions are marked with red
(methoxy group) and blue (carbonyl group) arrows.
ment is totally unfeasible (ΔG⧧
= +55.9 for 16-TSOMe
OMe
(DME)), and virtually identical to those previously calculated
for 1,2 ester carbonyl attack (ΔG⧧
(DME)).
= +25.1 for 17-TSCO
CO
Altogether, these results clearly indicate that the presence of
a carbonyl group is required to achieve alkoxy group
displacement with Grignard reagents, as ethers themselves are
not able to efficiently coordinate to the Lewis acid. The
presence of a chelate complex does not appear to be mandatory
for carbonyl activation, whereas the methoxy group is
completely unreactive in the absence of the chelate even if
magnesium is (poorly) coordinated to the alkoxy group oxygen.
The true 1,4-conjugate addition character of the initial steps of
methoxy group displacement is revealed through these results.
Thus, the presence of an acyl group in ortho position of the
aromatic system allows both the Lewis acid-enhanced activation
the numerous examples reported, for instance, for the
conversion of esters into ketones in the presence of alkoxy
groups susceptible of displacement.37−41
In our calculations, satisfactory activation barriers and
chemoselectivities were obtained from quite stable complexes
between alkyl Grignards and bidentate ortho-methoxycarbonyl
species. To further investigate the role of these complexes in
the reaction outcome, we calculated the same reaction profiles
starting from alternative monodentate structures with
CH3MgCl, adding a solvent molecule (DME) to achieve a
comparable coordination environment around magnesium and
prevent chelation (Figure 8a). Any attempt to locate methoxy-
Figure 8. (a) Lowest-energy reactant complexes and transition structures for the reaction of nahphyl ester 1a and CH3MgCl(DME). (b) Lowest-
energy reactant complexes and transition structures for the reaction of 1-methoxynaphthalene 16 and methyl 2-naphthoate 17 with
CH3MgCl(DME). Complexation (ΔG) and activation free energies (ΔG⧧) were calculated at the PCM(THF)/B3LYP/6-31G(d) level and are
related to the isolated reactants. Energies are in kcal mol−1 and distances are in Angstroms.
G
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Journal of the American Chemical Society
Article
60−200 mesh) packed in glass columns; the eluting solvent for each
purification was determined by thin layer chromatography (TLC).
Analytical TLC was performed on glass plates coated with 0.25 mm
silica gel using UV for visualization.
of the β position of the α,β-unsaturated carbonyl system, and
the stabilization of the negative charge generated upon alkyl
addition in the form of magnesium enolates, which ultimately
triggers the displacement reaction.
Instrumentation. 1H NMR spectra were obtained on a 300 MHz,
400 MHz or a 600 MHz NMR spectrometer. Chemical shifts (δ) are
reported in parts per million (ppm) relative to residual solvent
(CHCl3, s, δ 7.26). Multiplicities are given as: s (singlet), d (doublet),
t (triplet), q (quartet), dd (doublet of doublets), sep (septuplet), m
(multiplet). Proton-decoupled 13C NMR spectra were obtained on a
75 MHz, 101 MHz, or a 150 MHz NMR spectrometer. 13C chemical
shifts are reported relative to CDCl3 (δ 77.2 ppm). IR frequencies are
given in cm−1 and spectra were obtained on a FT-IR spectrometer
equipped with a DTGS detector and diamond ATR accessory. High-
resolution mass spectra were obtained on an Orbitrap FTMS.
Synthesis of Methyl 1-Methyl-2-naphthoate (2a). To a cooled
solution (−78 °C) of 1a (1.55 g, 7.19 mmol) in 36 mL of CH2Cl2 was
added a solution of CH3MgI in Et2O (3.0 M, 2.4 mL). The reaction
was monitored until complete by TLC and quenched with saturated
ammonium chloride (5 mL). The resulting layers were separated, and
the aqueous layer was extracted with 2 × 10 mL of EtOAc. The
combined organic layers were washed with 20 mL of brine, dried
(MgSO4), and concentrated in vacuo to afford the crude product
mixture. Integration of the crude NMR indicated a 83:17 ratio of 2a to
15a. The product was purified by flash chromatography (5:95 EtOAc/
hexanes) to afford the product 2a as a white solid (0.72 g, 50%): mp =
CONCLUSIONS
■
An inner-sphere mechanism through metalaoxetane-like TS has
been determined computationally for the displacement of
alkoxy groups of vinylogous esters and ketones by Grignard
reagents. The formation of a stable organomagnesium chelate
between both oxygenated groups allows this reaction to take
place, which is otherwise inaccessible, even in the presence of
expectedly better leaving groups such as tosylate. The
calculated chemoselectivities toward 1,4-conjugate (with esters
and ketones) or 1,2-addition (with aldehydes) are in excellent
agreement with the experimental results and rationalize the
influence of the nature and position of both the leaving alkoxy
and adjacent carbonyl groups. The reasons behind the different
reactivities are the modification of the substrate LUMO by the
ortho carbonyl group, and the ability of the substrates to
stabilize the negative charge by π-delocalization after
nucleophilic addition. Our computational predictions were
verified experimentally, leading in some cases to the
reinterpretation of previous experimental results as in the
reaction of two position isomers of the same methyl
alkoxynaphthanoate.42
1
55−56 °C; H NMR (600 MHz, CDCl3) δ 8.19 (d, J = 9.0 Hz, 1H),
7.84 (m, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.57 (m, 2H), 3.97 (s, 3H),
2.95 (s, 3H); 13C NMR (151 MHz, CDCl3) 169.2, 137.1, 134.6, 132.8,
128.5, 127.8, 127.3, 126.5, 126.1, 125.8, 125.3, 52.1, 15.8; HRMS
(ammonia CI) m/z calcd for C13H16NO2 (M + NH4)+ 218.1181,
found 218.1183; IR (thin film) 3090, 2954, 1685 and demethylated
EXPERIMENTAL SECTION
■
1
byproduct methyl 1-hydroxy-2-naphthoate 18 (0.07 g, 5%) H NMR
Computational Details. All calculations were carried out with the
B3LYP hybrid functional43,44 and 6-31G(d) basis set. Full geometry
optimizations and transition structure (TS) searches were carried out
with the Gaussian 09 package.45 The possibility of different
conformations was taken into account for all structures. The
theoretical ratio of reaction products was obtained through the energy
of the different transition states using a Maxwell−Boltzmann
distribution at −78 °C, temperature at which thermal and entropic
corrections to energy were calculated. Frequency analyses were carried
out at the same level used in the geometry optimizations, and the
nature of the stationary points was determined in each case according
to the appropriate number of negative eigenvalues of the Hessian
matrix. The harmonic oscillator approximation in the calculation of
vibration frequencies was replaced by the quasiharmonic approx-
imation developed by Cramer and Truhlar.46 Scaled frequencies were
not considered since significant errors in the calculated thermody-
namic properties are not found at this theoretical level.47,48 Where
necessary, mass-weighted intrinsic reaction coordinate (IRC) calcu-
lations were carried out by using the Gonzalez and Schlegel
scheme49,50 in order to ensure that the TSs indeed connected the
appropriate reactants and products. Bulk solvent effects were
considered implicitly by performing single-point energy calculations
on the gas-phase optimized geometries, through the SMD polarizable
continuum model of Cramer and Thrular51 as implemented in
Gaussian 09. The internally stored parameters for tetrahydrofuran
were used to calculate solvation free energies (ΔGsolv). Gibbs free
energies (ΔG) were used for the discussion on the relative stabilities of
the considered structures. Cartesian coordinates, electronic energies,
entropies, enthalpies, Gibbs free energies, lowest frequencies of the
different conformations of all structures considered are available as
Supporting Information.
values matched those previously reported. The tertiary alcohol 15a was
unable to be chromatographically separated from a small amount of
residual starting material. An analytically pure sample used a reference
for integration of the crude NMR was prepared from the
corresponding ketone 13a.
Synthesis of Methyl 3-Isopropyl-1H-indene-2-carboxylate
(8). To a cooled solution (−78 °C) of 7 (1.14 g, 5.58 mmol) in 28 mL
of THF was added a solution of i-PrMgCl in Et2O (2.0 M, 8.37 mL)
The reaction was monitored until complete by TLC and quenched
with saturated ammonium chloride (5 mL). The resulting layers were
separated, and the aqueous layer was extracted with 2 × 10 mL of
EtOAc. The combined organic layers were washed with 20 mL of
brine, dried (MgSO4), and concentrated in vacuo to afford the crude
displacement product. The product was purified by flash chromatog-
raphy (5:95 EtOAc/hexanes) to afford the product 8 as a yellow solid
(1.08 g, 90%): mp = 79−80 °C; 1H NMR (600 MHz, CDCl3) δ 7.78
(m, 1H), 7.50 (m, 1H), 7.33 (m, 2H), 4.31(m, 1H), 3.84 (s, 3H), 3.66
(s, 2H), 1.45 (d, J = 7.2 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ
166.3, 161.2, 144.4, 143.0, 128.3, 127.2, 126.1, 124.4, 123.7, 51.2, 39.2,
26.7, 20.9; HRMS (ammonia CI) m/z calcd for C14H17O2 (M + H)+
217.1223, found 217.1233; IR (thin film) 3075, 2975, 1710.
Synthesis of 2-(4-Hydroxy-2,6-dimethylheptan-4-yl)-
naphthalen-1-yl 4-methylbenzenesulfonate (12). To a cooled
solution (−78 °C) of tosylate 11 (0.23 g, 0.63 mmol) in 3.15 mL of
CH2Cl2 was added a solution of i-BuMgCl in Et2O (2.0 M, 0.32 mL)
The reaction was then stirred for 18 h during which time the solution
was allowed to warm to room temperature. The reaction was
quenched with saturated ammonium chloride (10 mL). The resulting
layers were separated, and the aqueous layer was extracted with 2 × 10
mL of CH2Cl2. The combined organic layers were washed with 20 mL
of brine, dried (MgSO4), and concentrated in vacuo to afford the crude
product. The product was purified by flash chromatography (5:95
EtOAc/hexanes) to afford the product 12 as a colorless oil (0.056 g,
20%). 1H NMR (600 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.80−
7.76 (m, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.44
(ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.34 (ddd, J =
8.3, 6.8, 1.2 Hz, 1H), 2.51 (s, 3H), 2.10 (dd, J = 14.5, 5.2 Hz, 2H),
Materials. Unless otherwise specified, all commercially available
reagents were used as received. All reactions using dried solvents were
carried out under an atmosphere of argon in flame-dried glassware
with magnetic stirring. Dry solvent was dispensed from a solvent
purification system that passes solvent through two columns of dry
neutral alumina. Silica gel chromatographic purifications were
performed by flash chromatography with silica gel (Sigma, grade 62,
H
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Journal of the American Chemical Society
Article
1.78 (dd, J = 14.5, 6.6 Hz, 2H), 1.69 (m, 2H), 0.94 (d, J = 6.6 Hz, 6H),
0.75 (d, J = 6.6 Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 145.4, 142.5,
137.1, 134.0, 133.6, 129.9, 128.9, 128.3, 127.3, 126.8, 126.6, 126.3,
123.2, 79.8, 51.9, 24.5, 24.3, 21.8, 18.6; HRMS (ESI) m/z calcd for
C26H32NaO4S (M + Na)+ 463.1919, found 463.1921; IR (thin film)
3415, 3065, 2950, 1580.
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(15a). To a cooled solution (−78 °C) of 13a (1.86 g, 9.30 mmol)
in 50 mL of CH2Cl2 was added a solution of MeMgI in Et2O (3.0 M,
3.1 mL). The reaction was monitored until complete by TLC and
quenched with saturated ammonium chloride (5 mL). The resulting
layers were separated, and the aqueous layer was extracted with 2 × 10
mL of EtOAc. The combined organic layers were washed with 20 mL
of brine, dried (MgSO4), and concentrated in vacuo to afford the crude
product mixture. The product was purified by flash chromatography
(5:95 EtOAc/hexanes) to afford the product 15a as a clear oil (0.71 g,
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1
35%): H NMR (600 MHz, CDCl3) δ 8.07 (d, J = 8.3 Hz, 1H), 7.83
(d, J = 8.1 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.51 (m, 3H), 4.07 (s,
3H), 1.73 (s, 6H); (600 MHz, CDCl3) δ 152.7, 136.1, 134.3, 128.1,
127.9, 126.0, 125.9, 124.6, 124.2, 122.1, 73.6, 63.3, 31.8; HRMS
(ammonia CI) m/z calcd for C14H15O (M + H − H2O)+ 199.1123,
found 199.1132; IR (thin film) 3420, 3066, 2957, 1586.
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ASSOCIATED CONTENT
* Supporting Information
■
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ChemInform 1999, 30, 1−1.
Additional figures, Cartesian coordinates, electronic energies,
entropies, enthalpies, Gibbs free energies, lowest frequencies of
the different conformations of all structures considered. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
houk@chem.ucla.edu; jtshaw@ucdavis.edu
Notes
■
4370.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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This research was supported by National Science Fundation
(CHE-1059084 to K.N.H.) the Petroleum Research Fund
(administered by the American Chemical Society) and by the
National Institutes of Health (R56AI80931-01 and
R01AI080931-01 to J.T.S.). G.J.O acknowledges Ministerio
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́
de Economia y Competitividad (EX2010-1063 postdoctoral
grant) and A.J.B for support in the form of a Bradford Borge
Graduate Research Fellowship from UC Davis. Calculations
were performed on the Hoffman2 cluster at UCLA and the
Extreme Science and Engineering Discovery Environment
(XSEDE), which is supported by the National Science
́
Foundation (OCI-1053575). We thank Dr. Jesus Garcia-
́
Lop
́
ez for useful discussions.
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