Coumarin synthesis on π-acidic surfaces

Article abstract of DOI:10.1080/10610278.2014.959013

Catalysis with anion-π interactions is emerging as an important topic in supramolecular chemistry. Among the reactions explored so far on π-acidic surfaces, coumarin synthesis stands out as a cascade process with several coupled anionic transition states. Increasing π-acidity has been shown in a different context to increase transition-state stabilisation and thus catalytic activity. In this report, we explore the possible use of macrocycles to accelerate coumarin synthesis between two π-acidic surfaces. To our disappointment, we found that compared to monomeric π-acids, coumarin synthesis within divalent macrocycles is clearly slower. Hindered access to an overly confined active site within the macrocycles could possibly account for this loss in activity, but several other explanations are certainly possible. However, operational coumarin synthesis on monomeric π-acidic surfaces is shown to tolerate structural modifications. Best results are obtained with structures that aim for proximity without obstructing transition-state stabilisation on the π-acidic surface.

Full text of DOI:10.1080/10610278.2014.959013

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Coumarin synthesis on π-acidic surfaces
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François N. Miros , Guangxi Huang , Yingjie Zhao , Naomi Sakai & Stefan Matile
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Supramolecular Chemistry, 2014
http://dx.doi.org/10.1080/10610278.2014.959013
Coumarin synthesis on p-acidic surfaces
Fran cꢀ ois N. Miros, Guangxi Huang, Yingjie Zhao, Naomi Sakai and Stefan Matile*
Department of Organic Chemistry, University of Geneva, Geneva, Switzerland
(
Received 13 June 2014; accepted 17 August 2014)
Catalysis with anion–p interactions is emerging as an important topic in supramolecular chemistry. Among the reactions
explored so far on p-acidic surfaces, coumarin synthesis stands out as a cascade process with several coupled anionic
transition states. Increasing p-acidity has been shown in a different context to increase transition-state stabilisation and thus
catalytic activity. In this report, we explore the possible use of macrocycles to accelerate coumarin synthesis between two
p-acidic surfaces. To our disappointment, we found that compared to monomeric p-acids, coumarin synthesis within
divalent macrocycles is clearly slower. Hindered access to an overly confined active site within the macrocycles could
possibly account for this loss in activity, but several other explanations are certainly possible. However, operational
coumarin synthesis on monomeric p-acidic surfaces is shown to tolerate structural modifications. Best results are obtained
with structures that aim for proximity without obstructing transition-state stabilisation on the p-acidic surface.
Keywords: anion–p interactions; catalysis; anionic transition states; enolates; naphthalenediimides; macrocycles
Introduction
Their existence has been explicitly proposed first in 2002
in a series of computational studies (9–11). For anion–p
interactions to occur, electrons have to be moved from the
aromatic core to the periphery until the axial quadrupole
The idea to accelerate reactions with anionic transition
states on the p-acidic surfaces is intriguing because it is
essentially unexplored (1–3). The complementary cation–
p interactions have been brought to scientific attention in
the late 1980s and early 1990s, mainly by work from the
Dougherty group (4). Today, cation–p interactions are
established as a central force to control interactions
between and within molecules (5). They are routinely
evoked together with hydrogen bonds, ion pairing,
hydrophobic contacts and p–p interactions, and numer-
ous examples have accumulated to testify for their central
role in chemistry and biology. The importance of cation–p
interactions in catalysis is best understood in the context of
the biosynthesis of terpenoid natural products (6).
Particularly impressive is the extended p-basic surface
that stabilises the multiple carbocation intermediates
during the enzymatic cascade cyclisation of terpenes into
steroids. In chemistry, the introduction of cation–p
interactions to stabilise cationic transition states has been
comparably slow despite early evidence from p-basic
macrocycles that the possibility exists (4). Today, catalysis
with cation–p interactions is receiving increased atten-
tion. Examples for carbocation-based cascade cyclisation
similar to steroid biosynthesis have been reported (7) as
well as the stabilisation of several iminium, pyridinium,
imidazolium and thiazolium intermediates in organocata-
lysis (8).
moment Q inverts (9–35). This is possible with electron-
zz
withdrawing substituents, which at the same time expose
the nuclear charge of the ring and introduce strong local
dipole moments in the aromatic plane that could further
support the binding of anions above and below this plane
(Figure 1). The best-known p-acid arguably is hexafluor-
obenzene with Q ¼ þ9.0 B (for Buckinghams) as
zz
compared to Q ¼ 28.5 B for benzene. With possible
zz
contributions from many parameters (Q quadrupole
zz
moments, local in-plane dipoles, polarisability, p*
orbitals, s orbitals, nuclei) and other overlapping
processes (in-plane CZH bonding, charge transfer,
electron transfer), nature and boundaries of the attraction
of anions to the surface of electron-deficient aromatic
planes remain vividly debated in the community (13–20).
It was not trivial to secure direct experimental support
for the functional relevance of anion–p interactions, to
literally ‘catch them at work’. Contributions of anion–p
interactions to the binding (25–34) and transport of anions
across lipid bilayer membranes (33–35) were obtained
first. These examples for anion stabilisation in the ground
state implied that anion–p interactions should also
stabilise anionic transition states and reactive intermedi-
ates (34). The first explicit example for catalysis with
anion–p interactions was reported last year, focusing on
the Kemp elimination as a classical tool to elaborate on
Consistent with their counterintuitive nature, anion–p
interactions are much younger than cation–p interactions.
*Corresponding author. Email: stefan.matile@chiorg.unige.ch
q 2014 Taylor & Francis

2
F.N. Miros et al.
is a classic in organic chemistry (Scheme 1). Resorcy-
–
laldehyde 2 and acetoacetate 3 are the substrates, the
catalyst is a base, usually piperidine. This coumarin
synthesis was attractive to expand enolate chemistry with
anion–p interactions to cascade processes. Consider the
general compound 4 with an acetoacetate substrate placed
covalently on the p-acidic surface of a naphthalenediimide
+
+
+
+
+
–
+
–
–
+
–
–
–
Qzz > 0
Qzz < 0
Figure 1. (Colour online) Cation–p interactions occur in
electron-rich aromatic surfaces with negative Qzz component of
quadrupole moment (left). Anion–p interactions occur on
electron-deficient aromatic planes with positive Qzz, supportive
local in-plane dipoles from electron-withdrawing substituents
and exposed nuclear charges of the ring (right). The precise
origins and boundaries of anion–p interactions are under debate.
(
NDI) (1–3). Addition of the base catalyst should yield
enolate 5 of acetoacetate stabilised on the p-acidic surface.
The stabilisation of enolate intermediates on unoptimised
NDI surfaces has been confirmed experimentally to occur
with a DpK ¼ 1.9, corresponding to DDG ¼ 4.7 -
a
RI
2
1
kJ mol
(3). This enolate intermediate 5 could then
attack substrate 2. In the anionic transition state 6 of this
aldol condensation, the negative charge is flowing over the
p-acidic surface from the enolate to the phenolate in 7.
Driven by increasing conjugation and, perhaps, anion–p
activation of the anionic leaving group, the Knoevenagel
condensation is then completed with an elimination of
water. In the resulting enone 8, the phenolate is perfectly
positioned to initiate the intramolecular transesterification
leading to coumarin 1. In this substitution reaction on a
carbonyl group, the p-acidic surface could help either by
stabilising the classical anionic tetrahedral intermediate in
9, or by activating the unfavourable alcoholate leaving
group. In principle, the released diol 10 could be reloaded
in situ with another acetoacetate to close the catalytic
cycle. However, the specific objective at this point was to
explore the stabilisation of anionic transition states by
anion–p interactions rather than to achieve turnover.
For this purpose, the positioning of the p-acidic surface
as covalent auxiliary is advantageous to minimise
ambiguities.
innovative systems, including theozymes, abzymes,
synzymes, etc. (1, 2). Increasing transition-state stabilis-
ation with increasing p-acidity of the catalyst provided
meaningful support for the existence of operational
anion–p interactions, and computational simulations
were in agreement with this interpretation (1, 2).
Arguably the most important anionic reactive inter-
mediate in chemistry and biology is the enolate anion (36–
4
2). In biology, enolate chemistry is most impressive in the
biosynthesis of polyketide natural products, reaching from
fatty acids and lipids to structures as complex and as
important as the epothilones, erythromycins, amphoter-
icins, prostaglandins or taxol (36–40). With the comp-
lementary cation–p interactions playing a central role in
stabilising carbocation intermediates during the biosyn-
thesis of terpenes and steroids (6), it was thus most
intriguing to explore enolate chemistry with anion–p
interactions. Placed covalently on top of an unoptimised
p-acidic surface, the acidity of malonate diesters increased
by DpK ¼ 1.9 (3). This demonstrated that the already
Several aspects of the mechanism of the cascade
process leading to coumarins can be discussed. For
example, the piperidine base could form enamines with
acetoacetate 4 or iminium cations with formaldehyde 2.
Knoevenagel condensations are expected to pass through
activated iminium acceptors. However, intramolecular
hydrogen bonding in resorcylaldehyde substrate 2 is
presumably sufficient to activate the aromatic aldehyde for
aldol condensation with the anion–p stabilised enolate in
6. Successful coumarin synthesis with triethylamine
instead of piperidine as base catalyst suggested that
iminium activation is not essential.
a
unoptimised anion–p interactions stabilise reactive
2
1
enolate intermediates by DDG ¼ 4.7 kJ mol . From
RI
the stabilisation of this central intermediate, the addition of
the enolate to enones and nitroolefines could be
accelerated significantly. Stabilisations of their anionic
2
1
transition states ranged from DDG ¼ 6.2 kJ mol
to
TS
21
DDGTS ¼ 11.0 kJ mol . In this report, we elaborate on
anionic cascade processes (3) and show that they can
accelerate when placed most closely to a fully accessible
p-acidic surface but decelerate when they take place
sandwiched between two p-acidic surfaces within a
macrocycle.
Throughout the entire cascade process, anion–p
interactions should be supported by p–p interactions.
This begins with the delocalisation of the negative charge
over two carbonyl groups in the enolate intermediate 5 and
culminates with extended phenolate intermediate 8,
leading to the intramolecular transesterification 9. p–p
enhanced anion–p interactions and delocalised anions
have been described previously in the context of nitrate–p
interactions (29, 33, 34). In transition states, anions are by
definition delocalised. Applied to catalysis, the concept of
Results and discussion
Coumarins are natural products from the shikimate
pathway. They are most appreciated as multipurpose
fluorescent probes and laser dyes. Their sweet flavour has
been used in perfumes, whereas their bitter taste might
serve plants for self-defence. The synthesis of coumarin 1

Supramolecular Chemistry
3
Scheme 1. (Colour online) The synthesis of coumarin 1 on a p-acidic surface. To stabilise anionic transitions states with anion–p
interactions, an NDI is covalently attached to acetoacetate 3. Deprotonation of conjugate 4 produces enolate anion of the p-acidic surface
in the reactive intermediate 5, which attacks aldehyde 2 to give the phenolate on the p-acidic surface of 7. Dehydration of aldol 7 is
followed by transesterification of the Knoevenagel product 8 with tetrahedral anionic intermediates and activates anionic leaving groups
on the p-acidic surface of 9.
anion–p interactions will thus necessarily have to evolve,
presumably following the development cation–p inter-
actions have made over the past two decades (5, 7, 8).
The acceleration of coumarin synthesis with anion–p
interactions was originally explored with acetoacetate–NDI
conjugate 11 (Figure 2). A rate of enhancement of k ¼ k
This substrate inclusion was expected to maximise the
stabilisation of the anionic transition states by doubled
anion–p interactions.
Anion–p substrate 12 was synthesised from naphtha-
lenedianhydride 14 (Scheme 2). Reaction with amine 15
afforded a mixture of anti-atropisomer 16 and syn-
atropisomer 17. With rotational barriers above
rel
app
(
11)/k (3) ¼ 8.0 was observed (Table 1). This increase in
app
2
1
activity corresponded to a transition-state stabilisation of
100 kJ mol , these atropisomers do not isomerise
spontaneously at room temperature (43, 44). They were
separated by column chromatography, with the syn-
atropisomer 17 having the smaller retention factor on thin-
layer chromatographs. To confirm this empirical assign-
ment, both atropisomers were reacted with heptanoic
diacid chloride 18. The bridged NDI 19 was obtained only
for the compound assigned to the syn-atropisomer 17.
21
DDGTS ¼ 5.2 kJ mol by anion–p interactions (3). This
initial experimental support for the stabilisation of an anionic
cascade process on p-acidic surfaces called for confirmation
and encouraged further development. For this purpose, we
here report design, synthesis and evaluation of anion–p
substrates 12 and 13 (Figure 2).
Compared to the original anion–p substrate 11, the
linker between acetoacetate and NDI in the new anion–p
substrate 12 is shortened by two atoms to afford a
preorganised ‘pseudo’-Leonard linker (2). This compact
positioning of the acetoacetate was expected to liberate
more space for the anions on the p-acidic surface during
the cascade transformation of the acetoacetate in 12 into
coumarin 1, and to increase transition-state stabilisation by
preorganised anion–p interactions. In macrocycle 13, the
acetoacetate substrate is sandwiched between two NDIs.
1
In the H NMR spectrum of macrocycle 19, the central
methylene hydrogens in the middle of the bridge over the
p-acidic surface were upfield shifted to 0.25 ppm. They
coupled to methylenes at 0.97 ppm, which in turn coupled
to the hydrogens in a-position to the carbonyl groups at
1.55 ppm. The anti-atropisomer 16 was reacted with 1
equiv. of acetoacetic acid 20, and the target molecule 12
was isolated from the resulting mixture of diesters,
monoesters and unreacted anti-diol 16.

4
F.N. Miros et al.
included the expanded macrocycle with three NDIs.
Macrocycle 26 was isolated as a mixture of stereoisomers.
Because of the poor performance of the final product (see
below), this mixture was not further analysed. Esterifica-
tion with acetoacetic acid 20 gave the target molecule 13 in
35% yield besides the corresponding diester and unreacted
starting material.
Consistent with the presence of a mixture of
stereoisomers, the acetoacetate part of anion–p substrate
1
3 appeared in two separate sets of signals in the H NMR
1
spectrum. The methyl hydrogens, for example, appeared at
d ¼ 2.05 ppm and d ¼ 1.90 ppm in a nearly 1:1 ratio, the
acidic hydrogens appeared between two carbonyl groups
at d ¼ 3.29 ppm and d ¼ 2.99 ppm. Compared to the
d ¼ 2.25 and 3.41 ppm for the same hydrogens in the ethyl
ester 3, these upfield shifts demonstrated that the
acetoacetates are exposed to the ring current of the NDIs
and thus included in the macrocycle. The same hydrogens
in anion–p substrate 12 appeared at d ¼ 3.31 ppm and
d ¼ 2.12 ppm. These comparably weaker upfield shifts of
Dd , –0.11 suggested that the average location of the
acetoacetate should be near the area where the effect of the
ring current inverts from shielding to deshielding (45), or
that contributions from conformers with acetoacetates that
are rotated away from the p-surface are quite significant.
A more peripheral average location of the acetoacetate
was predicted as ideal to preserve enough free space on
the p-acidic surface to stabilise the anionic cascade
process transforming the acetoacetate into coumarin 1. For
comparison, the firmly fixed hydrogens in the middle of
the alkyl bridge over the p-acidic surface of macrocycle 19
showed upfield shifts up to d ¼ 0.25 ppm, i.e.
Dd ¼ 21.05.
Figure 2. (Colour online) Anion–p systems designed to
explore coumarin synthesis on p-acidic surfaces, with
schematic indication of their envisioned advantages to stabilise
anionic transition states during coumarin synthesis (right,
compare Scheme 1).
The macrocyclic anion–p substrate 13 was syn-
thesised from phenol 21 with a solubilising tert-butyl
group in para-position (Scheme 3). Nitration in ortho-
position was followed by reaction of product 22 with (^)-
epichlorohydrin 23. The dinitro product 24 was reduced to
diamine 25. For macrocyclisation, diamine 25 and
dianhydride 14 were reacted at high dilution in the
presence of base in a microwave reactor. The desired
macrocycle 26 containing two NDIs and two secondary
alcohols could be isolated in maximal 14% yield. Other
components of the quite complex product mixture
Coumarin synthesis is an attractive reaction to probe
cascade processes with anion–p interactions because
product formation can be easily followed by absorption
spectroscopy. In the spectra of the reaction mixture, the
maximum of coumarin 1 appeared at lmax ¼ 435 nm
(Figure 3). This red-shifted maximum was clearly
separated from the absorption of the NDI in anion–p
substrates 12 and 13 at lmax ¼ 379 nm and the
resorcylaldehyde substrate 2 at lmax ¼ 336 nm. To assure
comparability of the results, the kinetic measurements
were conducted under conditions used previously for
substrates 3 and 11 (3). Namely, a 100 mM solution of
a
Table 1. Kinetic data for coumarin synthesis.
anion–p substrate 12 in EtOH/CHCl 1:1 was incubated
3
b
21 21 c
s
d
21 e
krel DDGTS (kJ mol )
Entry Cpd
kapp (M
)
with 300 mM resorcylaldehyde 2 and 10 mM piperidine, at
room temperature. At appropriate intervals, an aliquot was
taken and the absorption spectrum was recorded. The
coumarin band at long wavelength increased with
increasing reaction time, whereas that of the aldehyde
substrate at high energy decreased and that of the NDI in
between remained constant, demonstrating that the p-
surface is not modified during the reaction. With anion–p
substrate 12, the coumarin absorption at lmax ¼ 435 nm
2
2
2
2
1
1
1
1
1
2
3
4
3
0.30 ^ 0.02 £ 10
2.39 ^ 0.07 £ 10
4.55 ^ 0.11 £ 10
0.89 ^ 0.04 £ 10
–
–
11
12
13
8.0
15.2
2.6
5.2
6.7
2.7
a
Data for entry 1 and 2 are taken from (3).
Compounds, see Figure 2.
Apparent second order rate constant.
Rate enhancement compared to substrate 3.
Transition-state stabilization compared to substrate 3.
b
c
d
e

Supramolecular Chemistry
5
2
1
kJ mol relative to coumarin synthesis with acetoacetate
was approximated. The same procedure was used to
3
determine rate enhancement and transition-state stabilis-
ation with macrocyclic substrate 13.
(
a)
(
a)
Compared to the original p-acidic substrate 11, rate
enhancements with 12 nearly doubled to krel ¼ 15.2
(
Table 1). These improvements originated from a more
compact structure, with a pseudo-Leonard linker intended
to place the acetoacetate closer to the p-acidic surface.
1
Consistent with pertinent shifts in the H NMR spectra,
(
b)
(c)
the shorter linker between p-surface and acetoacetate in
12 was further expected to preserve more free space on
the surface to accommodate the anions during the cascade
process. The different nature of alcohols used in anion–p
substrates 11 and 12 implied that differences in the nature
of the leaving group in the last step, the basicity of the
enolate stabilised on the p-acidic surface in the first step,
etc, could also contribute to the significant increase in
activity. However, these differences in the nature of the
leaving groups appear too small to cause the observed
differences in reactivity. Moreover, the trends should be
Scheme 2. Synthesis of anion–p substrate 12. (a) TEA, DMF,
408C, 10 h, 65% (25% 16, 40% 17). (b) EDC, DMAP, TEA,
CH Cl , 08C to r.t., 14 h, 20%. (c) CH Cl , TEA, 08C, 60 min,
1%.
1
2
2
2
2
3
increased clearly faster than with control substrate 3
(
reversed, 11 (2-methoxyethanol, pK ¼ 14.8) should be
a
Figure 4, A vs V).
From the coumarin absorption, the increase of product
slightly more reactive than 12 (benzylalcohol,
pK ¼ 15.4) (46) (Figure 2), which is obviously not the
a
concentration with reaction time could be calculated
Figure 4, A). The slope of the obtained plot then gave the
initial velocities v , which gave an apparent second-order
case (Table 1).
(
The presence of a p-basic pyrene surface in control
substrate 27 has been shown previously to have negligible
influence on the velocity of coumarin synthesis (Figure 4,
X) (3). In additional support of operational anion–p
interactions, previous studies have also provided unam-
biguous evidence that covalently positioned enolate bases
ini
2
5
21 21
rate constant kapp ¼ 4.55 £ 10
M
s
for 12 (Table 1).
A rate enhancement k ¼ 15.2 was calculated in
rel
2
6
21 21
s
comparison with the kapp ¼ 3.00 ^ 0.16 £ 10
M
obtained for acetoacetate 3 (3). From the rate enhance-
ment, a transition-state stabilisation DDGTS ¼ 6.7 -
are stabilised on the same NDI surfaces by DpK ¼ 1.9 (3),
a
anion binding has been demonstrated experimentally (34),
theoretically (34) and in crystal structures (31), and the
(
a)
(c)
(
b)
(
d)
(
e)
Figure 3. (Colour online) Changes in the absorption spectra
during the synthesis of coumarin 1 (lmax ¼ 435 nm) from
aldehyde 2 (300 mM, lmax ¼ 336 nm), NDI–acetoacetate 12
(100 mM, lmax ¼ 379 nm) and piperidine (10 mM) in EtOH/
Scheme 3. Synthesis of anion–p substrate 13. (a) AcOH,
HNO , 93%. (b) H O, NaOH, N , 608C, 25%. (c) H , Pd/C,
3
2
2
2
MeOH, r.t., 97%. (d) TEA, DMF, mW, 1408C, 14%. (e) EDC,
DMAP, TEA, CH Cl 08C to r.t., 14 h, 30%.
3
CHCl 1:1, room temperature. Spectra were taken at 0, 0.9, 3.0
and 4.2 h (with increasing absorption at 435 nm).
2
2

6
F.N. Miros et al.
interactions are further supported by the inability of
p-basic pyrene surfaces to significantly accelerate
coumarin synthesis (3), by the stabilisation of enolate
anions by DpK ¼ 1.9 (3) together with extensive
a
experimental and theoretical evidence for the recognition,
translocation and transformation of various anions on the
same NDI surfaces, increasing with increasing p-acidity,
and even by crystal structures (1, 2, 31, 34). However,
further significant efforts will be needed to fully work out
the role of anion–p interactions in coumarin synthesis and
their ability to catalyse chemical reactions in general.
Studies in this direction are ongoing and will be reported in
due course.
Figure 4. (Colour online) Product concentration c as a function
of reaction time t for 3 (V), 13 (j), 11 (†), 12 (A) and 27 (X)
with linear curve fit. Conditions: 100 mM substrates, 300 mM of
Supporting information
2
, 10 mM piperidine, EtOH/CHCl
changes in absorption, see Figure 3. For data analysis, see Table
. Data for 3, 11 and 27 are from (3).
3
1:1, room temperature. For
Experimental details can be found here: http://dx.doi.
org/10.1080/10610278.2014.959013
1
role of p–p interactions has been elaborated in the context
of nitrate–p recognition (29, 33, 34).
Acknowledgements
We thank the NMR and the Sciences Mass Spectrometry (SMS)
platforms for services.
To further increase the impact of anion–p interactions
on coumarin synthesis, either the p-acidity of a
monomeric surface or the number of p-surfaces could be
increased. Increasing p-acidity of monomeric surfaces has
been shown previously to increase the transition-state
stabilisation of the Kemp elimination (1, 2). The impact of
an increasing number of p-acidic surfaces around the
acetoacetate substrate was explored with macrocycle
Funding
We thank the University of Geneva, the European Research
Council (ERC Advanced Investigator), the National Centre of
Competence in Research (NCCR) Chemical Biology and the
Swiss NSF for financial support.
1
3. Clearly slower coumarin synthesis than the operational
p-acidic substrates 11 and 12 was found (Figure 4, j,
Table 1, entry 4). Different reasons can be imagined to
explain the disappointing performance of the divalent
macrocycle 13. Various forms of hindered access of base
or substrate to the p-surfaces or an enolate anion
sandwiched between them would be among the nicest.
Too strong anion binding within a p-acidic macrocycle has
been evoked previously to account for poor anion transport
activity (34). Alternative explanations could consider poor
solubility, topological mismatches, interference from p–p
interactions, leaving group properties (46) and so on.
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Conclusions
The general objective of this study was to explore the
possible acceleration of anionic cascade processes on
p-acidic surfaces. The reported results indicate that
increasing proximity to single p-acidic NDI surfaces
increasingly accelerates coumarin synthesis, whereas
inclusion within p-acidic macrocycles decelerates cou-
marin synthesis. The latter could be explained by steric
hindrance and the former by operational anion–p
interactions. These possible contributions from anion–p
7
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8
F.N. Miros et al.
Fran cꢀ ois N. Miros, Guangxi Huang, Yingjie Zhao, Naomi Sakai
and Stefan Matile
Coumarin synthesis on p-acidic surfaces
1–8