Gaining Insight Into Reactivity Differences Between Malonic Acid Half Thioesters (MAHT) and Malonic Acid Half Oxyesters (MAHO)

Article abstract of DOI:10.1002/chem.201605148

An efficient two-step synthesis of structurally and functionally diverse thiophenol- and (cyclo)alkyl-derived malonic acid half thioesters (MAHTs) and phenol-derived malonic acid half oxyesters (MAHOs) has been achieved using cheap, readily available and easily handled starting materials. The synthesis of the MAHTs and MAHOs (the majority of which have not been previously reported) is readily scalable to afford gram quantities of product. In a hydrogen→deuterium exchange, an interesting stereoelectronic effect was observed when different aryl groups were incorporated. Significant changes in the rates of hydrogen→deuterium exchange and levels of isotope incorporation were observed. By way of example, using [²H]methanol and 4-bromophenol-derived MAHO afforded only 14 % [²H]-incorporation (9 min, k=31) whereas the corresponding 4-bromothiophenol-derived MAHT afforded 97 % [²H]-incorporation (9 min, k=208). In a benchmark procedure and comprehensive DFT study, 54 ester and thioester configurations and conformations were characterized. In the MAHT series, a sulfur-containing molecular orbital provides a path for increased delocalisation of electron density into the enol that is unavailable in MAHOs. This facilitates keto–enol tautomerisation and consequently enhances the rate and percentage of hydrogen→deuterium exchange.

Full text of DOI:10.1002/chem.201605148

A Journal of
Accepted Article
Title: Gaining Insight Into Reactivity Differences Between Malonic Acid
Half Thioester (MAHT) and Malonic Acid Half Oxyesters (MAHO)
Authors: Sean P. Bew, richard stephenson, jacques rouden, jeremy
godemert, haseena seylani, and Luis A Martinez-lozano
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To be cited as: Chem. Eur. J. 10.1002/chem.201605148
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10.1002/chem.201605148
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Gaining Insight Into Reactivity Differences Between Malonic Acid
Half Thioester (MAHT) and Malonic Acid Half Oxyesters (MAHO)
Sean P. Bew,[a]* G. Richard Stephenson,[a]* Jacques Rouden,[b] Jeremey Godemert,[a] Haseena
Seylani[a] and Luis A. Martinez-Lozano[a]
Abstract: An efficient two-step synthesis of structure- and
function-diverse thiophenol- and (cyclo)alkyl-derived malonic acid
half thioesters (MAHTs) and phenol-derived malonic acid half
oxyesters (MAHOs) has been achieved using cheap, readily
available and easily handled starting materials. The synthesis of
the MAHTs and MAHOs (majority of which have not been
previously reported) is readily scalable affording gram quantities of
proceed via similar but ‘inverted’ mechanistic routes either
‘addition-decarboxylation’ pathway i.e. A (Scheme 1) or a
‘decarboxylation-addition’ pathway i.e. B. Depending on where
the MAHO or MAHT reactions take place can influence which
of these pathways is followed. For example, reacting a MAHO
with a pyruvate ester in a ‘reaction flask’, current mechanistic
understanding favors ‘Pathway A’.[ 5 ] In contrast, utilizing a
polyketide synthase (PKS) and a MAHT, the commonly
accepted mechanism[6] involves decarboxylation, generating a
thioester enolate (3, Scheme 1), with subsequent addition to
an aldehyde affording a b-hydroxythioester e.g. 4, ‘Pathway B’.
As a consequence of MAHT-enhanced reactivity, there is
increasing interest in developing novel activation pathways for
MAHTs; organocatalysis (vida infra) and metal-mediated
catalysis are leading examples.[7]
product. In a hydrogen
stereoelectronic effect was observed when different aryl groups
were incorporated. Significant changes in the rates of hydrogen
®
deuterium exchange, an interesting
®
deuterium exchange and levels of isotope incorporation were
observed. By way of example, using [2H]methanol and 4-
bromophenol-derived MAHO afforded only 14% [2H]-incorporation
(9 minutes, k = 31) whereas the corresponding 4-bromothiophenol-
derived MAHT afforded 97% [2H]-incorporation (9 minutes, k =
208). In a benchmarked procedure and comprehensive DFT study
54 ester and thioester configurations and conformations where
characterised. This established in the MAHT series a sulfur-
Detailed studies on the reactivity differences of MAHTs
and MAHOs have not been conducted. We propose these are
related to their ease of keto-enol tautomerization. Probing the
ability of MAHTs and MAHOs to tautomerization we report here
containing molecular orbital provides
a path for increased
delocalisation of electron-density into the enol which is unavailable
in MAHOs, which facilitates keto-enol tautomerisation and
insight into their reactivities using 1H-NMR and a hydrogen
®
deuterium exchange protocol using structure- and function-
diverse substrates based on and 2. subsequent
consequently enhances the rate and percentage of hydrogen
deuterium exchange.
®
1
A
computational study afforded a better understanding of how
changing the substituents on the aryl group in sulfur-stabilized
MAHTs e.g. cisoid-5 (Z = S, Scheme 1) and enol-stabilized
MAHOs e.g. cisoid-6 (Z = O) can enhance or decrease their
reactivity.
Introduction
Malonic acid half thioesters (MAHTs) and oxyesters (MAHOs)
are frequently employed as key starting materials in C-C bond
forming reactions e.g. Claisen couplings,[1] aldol[2], Mannich[3]
and Michael[4] reactions.
The utility of MAHTs (1) and MAHOs (2, Scheme 1) in
Nature and the ‘reaction flask’ resides in the reactivity
associated with the b-carbonyl carboxylic acid group (red
bonds in 1 and 2) and its reaction with different electrophiles.
Typical examples include aldehydes, N-tosylimines, trans-b-
nitrostyrenes, azodicarboxylates and ketones. The reactions
S
OH
O
OH
β-carbonyl
carboxylic acid
Ar
Ar
O
O
O
O
MAHT, 1
MAHO, 2
Addition-decarboxylation,
OH
O-
Ar'
- CO2
Pathway A
O
RX
OH
RX
+
X = O, S
Ar'
H
O
O
O
O
RS
Ar'
4
Decarboxylation-addition,
Pathway B
O
OH
X = S
- CO2
O
RS
+
O-
enzyme
Ar'
Ar
H
3
thioester enolate
LESS reactive MAHO
MORE reactive MAHT
H
H
[a]
Dr S. P. Bew, G. R. Stephenson, J. Godemert, H. Seylani, L. A.
Martinez-Lozano
X
Z = O
X
O
O
O
O
O
O
Ar
Ar
Z = S
Z
OH
Z
OH
Z
OH
School of Chemistry
Norwich Research Park
cisoid-6 (X = Br)
cisoid-5 (X = Br)
University of East Anglia
NR4 7TJ, UK
Scheme 1. ‘Addition-decarboxylation’ and ‘decarboxylation-addition’
reaction pathways associated with MAHTs and MAHOs.
E-mail: s.bew@uea.ac.uk or g.r.stephenson@uea.ac.uk
Dr J. Rouden
[b]
Laboratoire de Chimie Moleculaire et thio-organique (LCMT)
UMR CNRS 6507, Ensicaen
6 Boulevard du Marechal Juin, 14050 Caen, France.
PKSs are large multi-domain enzymes that use MAHTs
for the biosynthesis of fatty acids and biologically active
Supporting information for this article is given via a link at the end of
the document.
secondary metabolites.[
Examples of some important
8
]
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10.1002/chem.201605148
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secondary metabolites include rifamycin (antibiotic), callystatin
(anticancer), psymberin (anticancer), pridamicin (antifungal)
and 6-deoxyerythrolide (antiviral). ‘Activation’ of the MAHTs in
PKS is via an active site embedded histidine (His) and
asparagine derived CONH2 (Asn, Scheme 2). In this metal-free
environment the CoA thioester malonic carboxylate anion is
hydrogen-bonded (7) to protonated His and Asn. The activated
MAHT eliminates CO2 and generates reactive thioester enolate
8. Due to its reactivity and close proximity to an electrophilic
cysteine thioester it affords CoA bound b-keto thioester 10 via
tetrahedral intermediate 9.[9]
thioesters (20) were produced in 21-79% e.e. and 42 - 84%
yields.[15]
Efforts to build natural or artificial PKS constructs that
mimic the capabilities of CoA-derived malonic thioesters cf 7
are held back by a lack of understanding of the reactivity,
conformation and electronic ‘communication’ within 1 and 2.
Thus developing efficient, mild and sustainable protocols for
structure- and function-diverse MAHO(T)s is important in their
applications in biomimetic and synthetic processes.
Scheme 3. Bae et al. Enantioselective biomimetic Michael addition of MAHT
12 to trans-b-nitrostyrene catalyzed by cinchona-based 14. Nakamura et al.
Enantioselective Michael addition reaction catalyzed by 18 generating
thioester 17. Ricci et al. Synthesis of b-N-tosylamino thioester 20 via
‘addition-decarboxylative’ reaction of a MAHT to 19 catalyzed by 21.
Increasing applications of MAHOs and MAHTs reinforces
the need for straightforward, efficient and scalable syntheses.
Furthermore, there are relatively few syntheses of structure-
and function-diverse aryloxy-derived MAHOs and arylthiol-
derived MAHTs. The majority of MAHOs are generated using
2,2-dimethyl-1,3-dioxane-4,6-dione (22).[
However, its
16
]
thermal instability to elevated temperatures, requirement for
cold storage and, unless freshly bought, recrystallization
before use.[17] Kee et al. reacted phenol with 22 generating
MAHO 23 (Scheme 4).[18] Mase et al. generated 25 (62% yield)
Scheme 2. Biosynthetic acetyl-CoA derived MAHT ‘activation’, thioenolate
formation and aldol condensation to generate acetyl-CoA bound b-
ketothioester.
from malonic acid and 24 using dicyclohexylcarbodiimide
19 ]
(DCC) as the coupling agent.[
However, DCC is not
particularly atom-efficient and although not commented on,
removing trace amounts of dicyclohexylurea (DCU) from
reaction products can be problematic.
Increasing interest in the synthesis applications of
MAHO(T)s can be attributed, in part, to their exploitation in
asymmetric organocatalysis.[ 10 ] However, there are reports
alluding to the difficulty in generating oxyester enolates of 1
that attribute this to the high pKa values of phenoxy esters i.e.
~18 (DMSO).[ 11 ] Therefore, increased emphasis has been
placed on phenylthioesters which, generally, have lower pKa’s
~16-17 (DMSO).[ 12 ] Substituting MAHTs for MAHOs, their
application in organocatalytic protocols becomes viable. By
way of example, Song et al. utilized 12 (Scheme 3) in
conjunction with squaramide-derived organocatalyst 14 for the
enantioselective Michael addition to trans-b-nitrostyrene 11
generating g-amino acid precursors, based on 13 (88 - 99% e.e.
and 15 - 96 yields).[ 13 ] Similarly, using cinchinone-derived
catalyst 18 conjugate addition of 15 to coumarin 16 afforded
thioester 17 in 95% - 99% yields and 84% - 92% e.e.’s.[14]
Finally, Ricci et al. synthesised 20 via an enantioselective
‘addition-decarboxylation’ of aryl- or alkylthio-MAHTs to 19
using cinchona-derived catalyst 21. The b-N-tosylamino
Searching SciFinder for aryl thioester MAHTs generated
32 references, these contained 10 unique MAHTs. Further
analysis revealed, rather surprisingly, only 2 different synthesis
protocols had been utilized. Using Meldrum’s acid, Kee et al.
generated 15 in a 24% yield,[16] unfortunately it also generated
difficult to remove dithiophenylmalonic ester by-product (not
shown) afforded in a near equal percentage i.e. 21%. Imamoto
et al. reported the synthesis of 8 MAHTs. The series comprised
5 alkyl and the 3 aryl thioesters e.g. 15, 29 and 3-(2,4,6-
trimethylphenylthio)-3-oxopropanoic
acid
(not
shown)
generated in 88%, 65% and 88% yields respectively. Potential
problems and limitations reside in the use of 4 equivalents of
malonic acid and not commercially available ethyl
polyphosphate (also used in excess), and the long reaction
time (30 hours). Imamoto probed the requirement for excess
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malonic acid during the synthesis of 15. However, 1 equivalent
of malonic acid afforded a 40% yield, a 44% drop when
relationship (SAR) study sought to exploit their
acidic a-CH2’s and probe the roles of the sulfur /
oxygen in their ability to effect keto-enol
tautomerisation in a hydrogen → deuterium exchange.
3. Part 3 - Computation. DFT studies were deployed to
explain / determine the unusual reactivity displayed by
OH
O
O
90 °C
O
O
PhO
OH
4 hrs
92% yield
O
O
21
20
some MAHTs in the hydrogen
®
deuterium exchange
HO
OH
study (Part 2). Crucial differences in the delocalised
molecular orbitals associated with the enol were
O
DCC
O
O
EtOAc
O
identified and may account for their differing reactivities.
Initiating our work we developed a straightforward
synthesis of malonyl mono-chloride[22] using readily available
malonic acid and thionyl chloride. Stirring a mixture of the
starting materials for 6 hours in ether at reflux, followed by
removal of any volatile compounds (high vacuum), afforded a
product suitable for use ‘as is’ in onward reactions. Without
further purification 50 g batches of malonyl mono-chloride were
readily synthesized and stored at ambient temperature, for at
least 3 months, with no signs of decomposition.
10°C then
o/n at rt
62% yield
H3CO
HO
O
H3CO
OH
OH
22
HO2C
HO2C
1. benzyl malonyl
chloride
H
N
H
N
O
DCM,
pyridine
O
O
O
NH
O
O
NH
2. Reaction
repeated
O
OBn
Our next objective was to generate aryloxy-derived
MAHOs. Currently, within the synthetic chemistry community,
there is considerable interest in the development of solvent-
free protocols.[23] Attempting the synthesis of 23 (Table 1),
malonyl mono-chloride and phenol were mixed at ambient
temperature. After a short period of time a slow coalescence
towards a homogenous solution was observed which, if left for
2 hours, afforded complete dissolution. Stirring the reaction for
a further 4 hours, a small aliquot was removed for analysis after
dissolving in [2H]chloroform. Disappointingly, 1H-NMR (400
MHz) indicated the majority of 30 (Scheme 5) was still present
and only a small amount (~10%) of MAHO 23 had formed.
Although it seemed this approach had merit, the reaction was
incomplete and the time prohibitively long. The most
straightforward way to increase the rate and hopefully generate
23 more efficiently was to raise the reaction temperature. At
100 °C the mixture quickly transformed into a homogeneous
clear pale yellow solution. After 30-minutes it was cooled to
room temperature and dichloromethane (DCM) added. The
white precipitate was filtered, dried under vacuum and a small
portion re-dissolved in [2H]chloroform. Gratifyingly 1H-NMR
analysis confirmed 23 had formed, with minimal decomposition,
in an unoptimized 75% yield.
3
23
24
3
32% yield
HO2C
H
N
Pd / C / H2
25
CH3OH
O
O
95% yield
O
O
NH
(+ 5 - 10%
of 23)
O
OH
3
SH
O
O
90 °C
O
O
+
4 hrs
PhS
OH
O
O
24% yield
13
20
ethyl
O
HO
HO
OCH3
SH
polyphosphate
O
O
S
THF / CHCl3
+
OCH3
30 hrs rt
65% yield
HO
O
26
compared with 4 equivalents.[20]
Scheme 4. Synthesis of MAHOs 23, 25, 28 and MAHTs 15 and 29.
Malonic acid derivatives are, generally, thermally
unstable. For subsequent studies it was important to determine
the rate of reaction between phenol and malonyl mono-chloride
(no solvent) at 100 °C. Probing the synthesis of 23 it was
analyzed at 4-, 9- and 19-minute intervals. 1H-NMR
spectrometry indicated consumption of phenol and, in all cases,
efficient formation of 23. The reaction was repeated, again
without solvent, in a preheated bath (100 °C) and rapidly
cooled (ice-bath) after 2 minutes. 23 was isolated and purified
via flash-column chromatography in a 77% yield. Thus,
employing these conditions the synthesis of MAHO 23 was fast,
efficient and high yielding. As previously noted, it was
important our protocol was scalable affording, if desired, multi-
gram quantities of MAHO(T)s. 10 g of malonyl mono-chloride
was reacted with phenol (100 °C for 2 minutes) followed by
Results and Discussion
Our strategy had 3 components:
1. Part 1 - Synthesis. Our aim was to develop a simple,
versatile, mild and efficient protocol for generating
structure and function diverse thioaryl- and thioalkyl-
derived MAHTs and aryl oxyester-derived MAHOs. It
was important they were readily available from cheap
‘off the shelf’ reagents using an operationally
straightforward protocol.[
essential our protocol was applicable to the synthesis
of sterically encumbered, electron-rich or electron-poor
MAHO(T)s.
Furthermore, it was
21
]
2. Part 2 - Reactivity. Exploring MAHO (1) and MAHT (2)
1
reactivity, a comprehensive H-NMR structure activity
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cooling and addition of DCM. Analysis of the precipitate
confirmed 23 (13 g) had formed cleanly and efficiently in a 77%
yield (Scheme 5).
cyanophenol afforded MAHO 46 with a restored and
considerably higher (than 37 and 40) 61% yield (Table 1).
Table 1. Examples of structure and function diverse MAHOs which are
readily generated using a mild, efficient and straightforward reaction protocol.
No
Name
Yield[a]
Scheme 5. Efficient, multi-gram solvent-free synthesis of 23
23
25
32
37
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
3-oxo-3-(phenoxy)propanoic acid
77%
61%
43%
25%
21%
66%
65%
66%
66%
60%
61%
51%
nd
3-oxo-3-(4-methoxyphenoxy)propanoic acid
3-oxo-3-(2,6-di-tert-butylphenoxy)propanoic acid
3-oxo-3-(2-nitrophenoxy)propanoic acid
3-oxo-3-((2-methoxycarbonyl)phenoxy)propanoic acid
3-oxo-3-(2,6-dimethylphenoxy)propanoic acid
3-oxo-3-(2-tert-butylphenoxy)propanoic acid
3-oxo-3-(2-allylphenoxy)propanoic acid
To facilitate ‘take up’ of our protocol it was important to
demonstrate synthetic versatility. We probed the formation of
sterically encumbered MAHOs by incorporating hindered 2,6-
dimethylphenol, 2-tert-butylphenol as well as the extremely
hindered 2,6-di-tert-butylphenol. Reacting 2,6-dimethylphenol
and malonyl mono-chloride in our standard reaction conditions
(i.e. 100 °C for 2 minutes) afforded after work up a white solid.
Subsequent physicochemical analysis confirmed 41 (Table 1)
had formed, in an unoptimized 66% yield. Increasing the steric
bias further MAHOs derived from 2-tert-butylphenol and 2,6-di-
tert-butylphenol were attempted. Using our standard reaction
conditions afforded the previously unknown 42, and 32
(Scheme 6). Both were isolated as easily handled, stable solids
in 65% and 43% yields respectively. Although 32 was afforded
in slightly lower isolated yield than 41 and 42, the reaction
seems fully amenable to generating highly sterically
encumbered MAHOs. Changing tack, we sought to incorporate
3-oxo-3-(4-nitrophenoxy)propanoic acid
3-oxo-3-(4-cyanophenoxy)propanoic acid
3-oxo-3-(2-cyanophenoxy)propanoic acid
3-oxo-3-((4-methoxycarbonyl)phenoxy)propanoic acid
3-oxo-3-(4-hydroxyphenoxy)propanoic acid
3-oxo-3-(2-hydoxyphenoxy)propanoic acid
3-oxo-3-(2-methoxyphenoxy)propanoic acid
3-oxo-3-(4-chlorophenoxy)propanoic acid
3-oxo-3-(4-bromophenoxy)propanoic acid
3-oxo-3-(4-iodophenoxy)propanoic acid
a
sterically less challenging 2-allyphenol substituent.
nd
Employing standard conditions 43 (Table 1) was afforded with
an embedded allyl group, a versatile chemical handle, in close
proximity to the b-keto carboxylic acid in a pleasing 66% yield.
45%
64%
69%
77%
68%
71%
55%
59%
3-oxo-3-(2-chlorophenoxy)propanoic acid
3-oxo-3-(2-bromophenoxy)propanoic acid
3-oxo-3-(4-trifluoromethylphenoxy)propanoic acid
3-oxo-3-(3-trifluoromethylphenoxy)propanoic acid
Scheme 6. Synthesis of sterically encumbered MAHO 32
[a]. nd = not determined
We turned our attention to the synthesis of MAHOs
derived from electron-deficient substrates e.g. 2- and 4-
nitrophenol, 2- and 4-cyanophenol as well as methyl 2- and 4-
hydroxybenzoate. In the 4-substituted series, MAHOs 44 (4-
nitrophenol), 45 (4-cyanophenol) and 47 (methyl 4-
hydroxybenzoate) were all readily generated in good 66%,
60% and 51% isolated yields. Seemingly the known propensity
of phenols to undergo intermolecular hydrogen-bond
dimerization does not appear to hinder the formation of the
MAHOs. In contrast, the incorporation of 2-nitrophenol or
methyl 2-hydroxybenzoate resulted in poor isolated yields of
37 and 40 i.e. 25% and 21% respectively. Interestingly 2-
We sought to rationalize the low yields for 37 and 40.
Here we propose an intramolecular hydrogen-bond in 2-
nitrophenol and methyl 2-hydroxybenzoate perturbs, in a
negative sense, their reaction with malonyl mono-chloride. A
substantial body of evidence supports 2-nitrophenol’s
existence in a “closed” i.e. 34 (Scheme 7) or “open” (not
shown) conformation. When “closed” the resulting resonance-
assisted hydrogen bond (RAHB) generates non-esterifiable o-
quinonoid 33. Furthermore, in conformation 34 (“closed”) its
reactivity is significantly curtailed by a strong hydrogen-bond,
which for 2-nitrophenol has been determined using different
experimental techniques to be 25 - 35 kJ mol-1.[24] Interestingly,
ab initio studies predict a considerably higher 45 - 50 kJ mol-
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.
1 [25] Needless to say which ever is considered, the strength of
quantities of the corresponding dicarboxylic acids (not shown)
was straightforward (filtration), their insolubility in a wide range
of solvents made further purification tedious, difficult and
ultimately not possible. The synthesis of analytically pure,
electron-rich aryl-derived MAHOs was, however, an important
milestone. Incorporating the more lipophilic 4-methoxyphenol
and 2-methoxyphenol the desired mono-carboxylic acids 25
and 50 were isolated as easily purified solids in 61% and 45%
yields respectively (Table 1). Once again the 2-regioisomer
(50) was afforded in a slightly lower than anticipated yield (cf.
37 and 40). Presumably, 2-methoxyphenol generates a five-
membered intermediate strength intramolecular hydrogen-
bond (2.11 Å27), similar to 34 and 39, that reduces its reactivity
and results in a lower yield of product (50).
the hydrogen-bond is reflected in the short ca. 1.7 Å OH····O
bond (based on X-ray diffraction[ 26 ]). The net result of the
RAHB and the inductive effect (2-nitro group) is a reduction in
the nucleophilicity of the phenolic hydroxyl of 34 affording it
with poor reactivity towards acyl chloride 30. A similar
argument is proposed for 39. Again, a strong intramolecular
hydrogen bond i.e. OH····O (< 2.0 Å) combined with RAHB (38)
and a strong inductive effect is highly effective at reducing the
nucleophilicity of the phenolic hydroxyl group resulting in a low
21% yield of 40 (Table 1).
As a homogenous reaction it was prudent to consider the
effect (if any) malonyl mono-chloride may have as
a
bifunctional hybrid-like and unconventional malonic acid-
malonyl chloride ‘solvent’ on the poor yields of 37 and 40. As a
potential proton donor, we considered the possibility the
‘malonic acid’ (pKa 2.5) may protonate the phenolic oxygen of
34 generating malonate ion-pair 35 (Scheme 7) on route to 37.
However, the phenolic hydroxyl is poorly nucleophilic and as
such it will be reluctant to undergo protonation by the weakly
acidic carboxylic acid of 30, furthermore once protonated 35 is
no longer able to participate in the desired reaction pathway. It
seems feasible 30 could protonate “closed” 34 via the pink
arrows (Scheme 7) and disrupt the strong intramolecular
Synthesizing aryl halide derived MAHOs was important
because of their applications as easily accessible starting
materials capable of metal-catalyzed chemical manipulation
and elaboration.[
4-Chloro, 4-bromo and 4-iodophenol
28
]
reacted, without solvent, with malonyl mono-chloride (100 °C,
2 minutes) affording 51, 52 and 53 in broadly similar 64%, 69%
and 77% yields respectively. Furthermore, unlike the
incorporation of strong EWGs at the 2-positions of 37 (nitro)
and 40 (methyl ester) the 2-chloro- and 2-bromophenol
adducts afforded 2-chlorophenyl-54 and 2-bromophenyl-55 in
68% and 71% yields respectively. Explaining the relatively
weak ‘ortho-halo effect’ it is known they form only moderately
strong intramolecular X····HO bonds (X = Cl or Br).[ 29 ]
Incorporating substrates equipped with more than one halogen
was explored using the trifluoromethyl group. Both 4-
(trifluoromethyl)phenol and 3-(trifluoromethyl)phenol afforded
56 (55% yield) and 57 (59% yield, Table 1). Clearly incorporting
the trifluoromethyl moiety is not detrimental to a successful
reaction outcome.
hydrogen-bonded complex i.e. 34
→
36. However, as a major
reaction pathway this is unlikely because it requires breaking
the strong OH····O=N(O)- bond. Applying similar RAHB
arguments (i.e. formation of 38) and reasoning, the low yield
for ortho-ester 40 can be rationalized. Thus, it seems 37 and
40 are generated via an inefficient reaction of poorly
nucleophilic 34 or 39 with malonyl mono-chloride i.e. 39
(Scheme 7).
→
40
Confident our protocol was amenable to generating
structure and function diverse aryloxy-derived MAHOs
attention switched to the corresponding MAHTs. Utilizing the
protocol for generating 23 i.e. neat, 100 °C, 2 minutes but with
thiophenol we were surprised 15 was afforded in a poor 25%
yield (cf. 77% yield for MAHO 23, Table 1). Presumably the
greater reactivity of 15 relative to MAHO 23 resulted in
decomposition at the elevated reaction temperature.
Attempting to mitigate this the rapid two-minute reaction time
was maintained whilst the temperature was lowered to 65 °C.
Disappointingly 15 was afforded in a poor yield with the
reaction comprising largely unreacted thiophenol and 30. If,
however, it was increased to two hours whilst maintaining the
temperature at 65 °C 15 was isolated as a white solid after a
simple work-up in a 59% yield. Our slightly modified protocol
proved to be a convenient starting point for the incorporation of
16 commercially available thiophenols. Monocyclic 4-
Scheme 7. Poor reactivity of 34 and 39 is ascribed to RAHB and strong
inductive effects associated with the 2-nitro and 2-carboxymethyl groups.
methylthiophenol,
sterically
encumbered
2,6-di-
methylthiophenol and multicyclic 2-naphthalenethiol all reacted
(individually) with malonyl mono-chloride. The desired MAHTs
58 - 60 were isolated in 59%, 43% and 52% yields respectively
with the reaction appearing to be unaffected by steric bias, thus
2,6-dimethylthiophenol and 4-methylthiophenol afforded,
within experimental error, identical yields. Similar to the
Reacting one equivalent of malonyl mono-chloride with
electron-rich hydroquinone or catechol was at first promising.
Although the isolation of the presumed mono-carboxylate 48
and 49 (Table 1) together with what appeared to be small
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synthesis of electron-poor 4-nitrophenyl derived MAHO 44
(66% yield), 4-nitrothiophenol was readily transformed into the
previously unknown 61 in a 52% yield. 2-Nitrothiophenol
afforded the expected MAHT i.e. 62 in a 30% yield. Comparing
37 (25% yield) with the slightly higher yield of 62 can be
accounted for in terms of the thiol group being more
nucleophilic than the hydroxyl and within the 2-nitrothiophenol
the intramolecular hydrogen-bond i.e. –NO2····HS-30 (1.922 Å
and 34.64 kJ mol-1) being longer and weaker than the
hydrogen-bond in 37.
reported; apart from several recent examples from our own
laboratory and Matille et al.[21] only two are known i.e. 2-methyl-
3-oxo-3-(phenylthio)-[2H]propanoic acid and 2-([2H]methyl)-3-
oxo-3-(phenylthio)propanoic acid.[34]
Table 2. Examples of structure and function diverse MAHTs which are
readily generated using a mild, efficient and straightforward reaction protocol.
No
Name
Yield[a]
3-oxo-3-(4-methoxyphenylthio)propanoic acid
Incorporating electron-rich 4-methoxythiophenol and 2-
methoxythiophenol the corresponding 12 and 29 (Scheme 4)
were afforded in 61% and 51% yields respectively. The
identical yields for 4-methoxyphenyl-MAHO 25 and 4-
methoxythiophenyl-MAHT 12 (Table 2) verify the viability of
incorporating EDGs on phenols or thiophenols and their
suitability as starting materials for novel MAHO(T) synthesis.
Similar to the reasons outlined for aryl halide containing
MAHOs 51 - 57 (Table 1), the incorporation of thioaryl halides
and (trifluoromethyl)thiophenols in MAHTs was important.
Employing our ‘standard’ MAHT reaction conditions malonyl
12
15
29
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
61%
59%
51%
59%
43%
52%
52%
30%
50%
58%
45%
41%
65%
50%
2%
3-oxo-3-(3-phenylthio)propanoic acid
3-oxo-3-(2-methoxyphenythio)propanoic acid
3-oxo-3-(4-methylphenylthio)propanoic acid
3-oxo-3-(2,6-dimethylphenylthio)propanoic acid
3-oxo-3-(2-napththylthio)propanoic acid
3-oxo-3-(4-nitrophenylthio)propanoic acid
3-oxo-3-(2-nitrophenylthio)propanoic acid
3-oxo-3-(4-chlorophenylthio)propanoic acid
3-oxo-3-(3-chlorophenylthio)propanoic acid
3-oxo-3-(2-chlorophenylthio)propanoic acid
3-oxo-3-(4-bromophenylthio)propanoic acid
3-oxo-3-(4-fluorophenylthio)propanoic acid
3-oxo-3-(4-trifluoromethylphenylthio)propanoic acid
3-oxo-3-(pentachlorophenylthio)propanoic acid
3-(2-methoxy-2-oxoethylthio)-3-oxopropanoic acid
3-oxo-3-(benzylthio)propanoic acid
mono-chloride
chlorothiophenol, 3-chlorothiophenol, 2-chlorothiophenol, 4-
bromothiophenol, 4-fluorothiophenol and 4-
was
added,
independently,
to
4-
trifluoromethylphenol. The desired MAHTs 63 - 68 were
isolated in 50% (4-chlorophenyl), 58% (3-chlorophenyl), 45%
(2-chlorophenyl), 41% (4-bromophenyl), 65% (4-fluorophenyl)
and 50% (4-trifluorophenyl) yields (Table 2). Reflecting on the
slightly lower yield of 65 it is known, similar to 2-chlorophenol,
an ortho-chlorine atom can generate
a
5-membered
intramolecular hydrogen bond (2.16 Å) with the adjacent thiol
i.e. -Cl····HS-[31] which reduces the nucleophilicity of the thiol,
albeit not to the same extent as a 2-nitro group, and impedes
its capacity to react efficiently with 30. Similar to 56 and 57 4-
(trifluoromethyl)aryl substituted MAHT 68 was readily
generated in a 50% yield and, within experimental error, an
identical yield to 4-(trifluoromethyl)aryl substituted MAHO-56
i.e. 55% yield. Disappointingly, all attempts at generating
pentachlorophenyl-69 failed with, at best, single figure yields
returned. Presumably the five electron-withdrawing chlorine
atoms reduce the nucleophilicity of the thiol to such an extent
it is no longer able to react with acyl chloride 30. Expanding the
substrate scope, we sought to include representative examples
of alkyl thiols. 3-Mercaptopropanoate methyl ester, benzyl
mercaptan and cyclohexanethiol generated 70, 71 and 72 in
30%, 55% and 44% yields respectively (Table 2).
Ultimately it is our intention to develop novel isotope
derived MAHOs and MAHTs as multinuclear NMR[32] and mass
spectrometric (MS) probes.[33] Therefore our focus switched to
generating structure and electronically diverse isotopologues
[2H]-MAHO (73) and [2H]-MAHT (74) (Scheme 8).
MAHOs and MAHTs are important motifs in synthetic and
biological chemistry. (Scheme’s 2 and 3). Similarly, stable
isotopes, especially deuterium, are widely employed in many
different research sectors e.g. pharmaceutical, agrochemical,
biotech, medtech, materials and analytical chemistry. However,
only a handful of deuterated MAHOs and MAHTs have been
30%
55%
44%
3-oxo-3-(cyclohexylthio)propanoic acid
We contemplated the synthesis of entities based on [2H]-
73 and [2H]-74 using [2H]malonic acid ([2H]-75, Scheme 8).
We had reservations however on progressing deuterated
intermediates through multiple procedures and, potentially,
drawn-out flash chromatography purifications using ‘wet’ and
acidic silica gel. With our concerns focused on the product
being produced with reduced levels of [2H]-incorporation
resulting from deuterium → hydrogen exchange (‘washout’) at
the acidic [2H]-methylenes. Opting for an alternative strategy
we took advantage of the facile keto-enol tautomerisation
properties of ‘pre-assembled’ MAHO(T)s and their potential for
hydrogen
®
deuterium exchange. At the outset, it was
important to establish a proof of principal using a simple MAHO
and MAHT. Ester 23 and thioester 15 were dissolved in
[2H]methanol and monitored by 1H-NMR at 4-, 9-, 19- and 29-
minutes. Table 3 outlines the rather surprising results with
significantly divergent levels of [2H]-incorporation for these
very similar compounds.
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MAHOs and MAHTs is the surprising observation with 4-
bromothiophenol-derived 66 which afforded the largest
percentage of [2H]-incorporation, after only 9 minutes (96%).
This contrasts sharply with 4-bromophenol-derived 52 which,
as already noted, afforded only 15% [2H]-incorporation - the
only difference between them, a sulfur versus an oxygen atom.
Table 3. Percentage levels of [2H]-incorporation into MAHO 23 and MAHT
15 after 4-, 9-, 19- and 29-minute reaction times.
Time
Phenol MAHO 23
18% [2H]-incorporation
4
9
38% [2H]-incorporation
60% [2H]-incorporation
74% [2H]-incorporation
Thiophenol MAHO 15
72% [2H]-incorporation
90% [2H]-incorporation
97% [2H]-incorporation
98% [2H]-incorporation
19
29
Time
4
Scheme 8. Potential synthesis of MAHT [2H]-77 from [2H]-75
Evidently after only 4 minutes the extent of deuterium
exchange for thiophenol-derived MAHT 15 was significantly
faster and more efficient than the corresponding phenol-
derived 23. Compare, for example, after only 4 minutes 72%
incorporation for 15 with only 18% for 23. Furthermore, after
only 9 minutes 15 had incorporated 90% deuterium, 52% more
than its chalcogen equivalent. After 29 minutes 23 still had not
undergone complete isotope incorporation reaching a level
equivalent to the same afforded by 15 in only 4 minutes! Clearly,
switching phenol for thiophenol has a significant and positive
effect on the enol reactivity of 15. It was important to ascertain
if the increased reactivity was an ‘isolated’ result specific to 15
or if it was a more general and if so more interesting, presumed,
stereoelectronic effect. Using a selection of structure and
function diverse MAHOs (17 examples) and MAHTs (7
9
19
29
Dissecting the data generated from the hydrogen
®
deuterium study (Figure 1) several important observations and
interpretations can be inferred:
1. Using easy to generate 1H-NMR data on MAHOs
and MAHTs it is possible to determine fundamental
reaction rate differences between these two classes
of compounds.
2. Integrating the remaining protons on the acidic a-
methylenes of the MAHOs and MAHTs after 9
minutes afforded a convenient ‘snap-shot’ of the
examples) a comprehensive hydrogen
®
deuterium exchange
study was undertaken. Employing a standard concentration of
MAHO or MAHT (both 70 µM) in excess [2H]methanol (500 µL)
the results are presented in Figure 1. What is immediately
evident is high-levels of [2H]-incorporation can be readily
achieved in the majority of substrates simply by stirring them
at ambient temperature with a deuterated protic solvent.
Furthermore, there are significant rate differences
between thioesters and esters [compare graphs (a) and (b)] but
also within each of the two classes different aryl substituents
have a significant influence on their reactivity and ability to
initial rate of hydrogen
®
deuterium exchange. Here
we determined the percentage of [2H]-incorporation
and the relative rates of reaction (k) associated with
the exchange process.
3.The results (Table 4) clearly show MAHOs derived
with 2- and 4-bromophenol undergo hydrogen
®
deuterium exchange at approximately the same rates
i.e. k = ~31 ±2 and afford almost identical low levels
of [2H]-incorporation i.e. 14% - 15%. In the same
study, 4-methoxyphenol-derived 25 (k = 60), 4-
trifluoromethylphenol-derived 56 (k = 67) and 4-
chlorophenol derived 51 (k = 66) afforded, at similar
rates of reaction, the [2H]-MAHOs with 27%, 30%
undergo hydrogen
®
deuterium exchange. See, for example,
the clear ‘gap’ between the majority of examples and the four
electron-poor arenes (Figure 1). Our observation is further
reinforced by comparing 4-bromothiophenol-derived MAHO 52
with 4-cyanophenol-derived MAHO 45. Not only is there a
noticeable difference in the rate of exchange but also a
significant difference in the percentage of [2H]-incorporation.
Compare 2,6-dimethylphenol-derived 59 which has nearly
and 31% [2H]-incorporation. Clearly, hydrogen
®
deuterium exchange in these MAHOs is faster and
more efficient than the bromoaryl-substituted MAHOs.
4. Strong electron-withdrawing para- and ortho-
substituted aryl groups on MAHOs increase (see
50% [2H]-incorporation after only
9
minutes with 4-
bromophenol-derived 52 which is less than 10%. Further
Table 4) the rate of hydrogen
®
deuterium exchange,
highlighting the reactivity differences between almost identical
see for example 44 (4-nitrophenyl), 37 (2-nitrophenyl)
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and 47 (4-carboxyphenyl methyl ester). For example,
4-cyanophenol-derived 45 affords 79% [2H]-
incorporation with a rate k = 171 whereas phenol-
derived 23 affords 38% [2H]-incorporation with a
reduced rate i.e. k = 83.
Figure 1. Rates of hydrogen
®
deuterium exchange for a variety of structure and function diverse MAHO and MAHOs.
and para-substituted MAHO(T)s seem dependent on
steric congestion at the ortho-substituents.
5. Within the confines of our study the overall rate of
hydrogen
®
deuterium exchange is significantly
8.The distributions of the hydrogen deuterium
®
faster in the majority of MAHTs than MAHOs.
6. Increasing the steric bulk either side of the phenolic
ester alcohol increases the rate of hydrogen
deuterium exchange but with only moderate
increases (after 9 minutes) of [2H]-incorporation.
Compare for example phenol-derived 23 (k = 83) with
2,6-dimethylphenol-derived 41 (k = 101).
exchange reaction rates are smaller, within the 9-
minute window (see Table 4), for the MAHTs i.e. k =
102 ® 208 than for the MAHOs i.e. k = 30 ® 171.
These results suggest, in general, the rate of
exchange for MAHTs is less dependent on the aryl
substitution than the MAHOs.
9. In nearly all examples the initial rate of hydrogen ®
deuterium exchange for the MAHTs were
substantially faster than the majority of MAHOs. The
only exceptions were when MAHOs were appended
with strong electron-withdrawing groups i.e. 44 (4-
nitrophenol), 37 (2-nitrophenol), 45 (4-cyanophenol)
and 47 (4-carboxyphenyl methyl ester).
®
7. In like-for-like comparisons incorporating specific
ortho-substituents
a decrease in the rate and
percentage of [2H]-incorporation with respect a para-
substituent was observed. For example, methyl
ortho-ester-derived MAHO 40 returned 24% [2H]-
incorporation (k
= 53) and ortho-cyano-derived
MAHO 46 38% [2H]-incorporation (k = 85). Whilst the
analogous para-methyl ester-derived 47 returned
72% [2H]-incorporation (k = 157) and para-cyano-
derived 45 afforded 79% [2H]-incorporation (k = 171).
10. All the MAHTs afforded 95% [2H]-incorporation
after less than 39 minutes. Indeed, excellent levels of
deuterium were installed in many MAHTs in less than
20 minutes. Further highlighting the reactivity
differences between MAHTs and MAHOs similar
levels of [2H]-incorporation were only achieved for
MAHOs 37, 45 and 47 after stirring for 94 minutes
(Figure 1). On the other hand MAHOs 23 (phenyl), 40
(2-carboxymethyl ester), 25 (4-methoxyphenyl), 51
(4-chlorophenyl), 52 (4-bromophenyl), 55 (2-
Similarly,
ortho-methoxythiophenol-derived
29
afforded lower [2H]-incorporation (46%) and at a
slower rate (k = 102) than para-methoxythiophenol
12 with 74% [2H]-incorporation (k = 161). Differences
in the levels of [2H]-incorporation in between ortho-
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bromophenyl) and 56 (4-trifluoromethylphenyl) all
afforded reduced levels of [2H]-incorporation i.e. 77%
- 94% even after extended reaction times.
11. Further underlying the fundamental difference in
reactivity between the oxygen- and sulfur-derived
esters was the difference in the observed rates of
exchange. In nearly all cases, the aryl thioester motifs
p
q
r
methyl-4-hydroxybenzoate / 72%
k = 157
k = 161
k = 170
k = 171
k = 178
k = 191
k = 195
k = 208
4-methoxyphenol / 74%
2-nitrophenol / 78%
s
t
4-cyanophenol / 79%
underwent hydrogen
®
deuterium exchange at
4-chlorothiophenol / 81%
4-trifluoromethylthiophenol / 88%
thiophenol / 90%
significantly faster rates than their oxygen
counterparts when compared like-for-like e.g.
u
v
w
A.
phenol derived 23 i.e. k = 195 versus 83.
B. 4-bromothiophenol-derived 66 faster
thiophenol derived 15 faster than
4-bromothiophenol / 96%
than 4-bromophenol-derived 52 i.e. k = 208
versus 31.
An explanation for the unusual MAHT reactivity
enhancement was required. Initiating a computational study we
sought to gain a comprehensive understanding of the reactivity
differences. The electronic communication between the aryl
ether and aryl thioether functionality and the enol was probed
by DFT calculations. First, for the parent MAHO i.e.
PhOCH(OH)=CHCO2H, and MAHT i.e. PhSCH(OH)=CHCO2H
the E- and Z-enols were compared in two representative
conformations: (i) the enol-carboxylic acid section was close to
co-planarity and (ii) the plane of the arene was orthogonal
(~90°) to the enol-carboxylic acid section.[35]
C.
4-trifluoromethylthiophenol-derived 68
faster than 4-trifluoromethylphenol-derived 56
i.e. k = 191 versus 67.
D.
chlorophenol 51 i.e. k = 178 versus 66.
E. 4-methoxythiophenol 12 faster than 4-
methoxyphenol 25 i.e. k = 161 versus 60.
4-chlorothiophenol 63 faster than 4-
Entry
Name / [2H]-incorporation
Rate
4-bromophenol / 14%
a
b
c
d
e
f
k = 31
k = 33
k = 53
k = 60
k = 67
k = 66
k = 83
k = 84
k = 85
k = 96
k = 96
k = 101
k = 102
k = 150
k = 156
In view of the similarity of the results obtained with the
relatively rapid calculations possible with B3LYP/6-31G(d) or
M06-2X/6-31+31G(d,p) compared with MO6-2X/def-QZVP we
choose to employ B3LYP/6-31G(d) and M06-2X/6-
31+31G(d,p) in the work described here as it would allow us to
considerably extend our computational ‘reach’ examining the
influence the substituents within the arene have on the
conformations and molecular orbitals of the MAHO and
MAHTs.[36] Initiating our study on MAHOs twenty-five distinct
phenyl MAHO configurations / conformations were identified
(see Table S3, SI) the most stable (–648.67222 Ha) retained
the phenyl ring at about 92° (dihedral angle –92.14°) relative to
the enol-carboxylic acid section which had an almost planar
conformation. The enol was in the E-configuration, and the
orientation of the carboxylic acid relative to the OPh group was
transoid. The H-O-C-C, C-C-C-O and C-C-O-H sections of
MAHO 23 and MAHT 15 were “e-z-z”. A frequency calculation,
however, indicated the –648.67222 Ha structure was a
transition point not a true minimum. Further investigation
identified two similar more stable forms (–648.67244 Ha),
again corresponding to “E-transoid-e-z-z” structures, but now
the phenyl ring was displaced from a perpendicular orientation
to –62.3° (Figure 2) and –122.7° (Figure 3).
2-bromophenol / 15%
methyl-2-hydroxybenzoate / 24%
4-methoxyphenol / 27%
4-trifluoromethylphenol / 30%
4-chlorophenol / 31%
g
h
i
phenol / 38%
2-methoxyphenol / 38%
2-cyanophenol / 38%
j
3-trifluoromethylphenol / 44%
hexafluoroisopropanol / 43%
2,6-dimethylphenol / 46%
2-methoxythiophenol / 46%
4-nitrophenol / 68%
k
l
m
n
o
2-chlorothiophenol / 71%
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Figure 2. Minimum energy B3LYP/6-31G(d) structures for phenyl ester 23 in –62° dihedral angle form: (A): side view of the enol form of MAHO 23; (B): top view of
enol form of MAHO 2
Figure 3. Minimum energy B3LYP/6-31G(d) structures for phenyl ester 23 in –123° dihedral angle form: (A): side view of the enol form of MAHO 23; (B): top view
of enol form of MAHO 2
Figure 4. Minimum energy B3LYP/6-31G(d) structures for thioester 15 in –92° dihedral angle form: (A) side view of enol form of MAHT 15; (B): top view of enol form
of MAHT 15
These two independently optimized structures had
identical energies as well as almost identical bond lengths and
angles. The structure at –648.67222 Ha corresponds to the
transition between these conformers. As expected, the energy
barrier for interconversion was very low i.e. 0.000215 Ha; <1
kJ mol–1.[37] Applying the same computational procedure to the
analogous MAHT (15) identified (Table S4, SI) a true minimum
at –971.63728 Ha [B3LYP/6-31G(d) data] as the most stable
form. In contrast to the data in Table S5 (SI), the cisoid form
was observed, and although a minimum, it had a dihedral angle
of –91.67° between PhS and -SC(OH)CHCO2H (Figure 4). An
E-transoid MAHT conformation was identified (at –971.63648
Ha) and established to be a transition structure with –91.93°
between the PhS and -SC(OH)=CHCO2H. A true E-transoid
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minimum was found at an almost identical energy with the PhS
tilted at –103.3°. As expected, the central bond angle for the
MAHTs (~ 103°, see Figure 4) was smaller than the MAHOs (~
121°, see Figures 2 and 3) and the Ph-S and Ph-O bond
lengths (1.80 Å and 1.40 Å respectively) were longer than the
PhS-C and PhO-C bond lengths into the enol (1.78 Å and 1.34
Å). The preference for cisoid or transoid forms (for examples,
see Figures 2 - 4) in these structures is finely balanced. The
calculations were repeated with the highly recommended[38]
M06-2X functional[39] using the 6-31+G(d,p) basis set[40] which
has been identified[41] as one affording a good balance between
performance and computing time for structures with non-
covalent or H-bonding interactions. The cisoid conformation
was the most stable in both MAHO and MAHT series.
In summary, with such finely balanced conformational
preferences identified using B3LYP and MO6-2X and the small
energy differences between both the cisoid and transoid series
we have established both need to be considered when
studying substituent effects on the aromatic ring and
interpreting [2H]-incorporation results. In practice, the two
conformers easily interconvert and both will be present in
solution. It was decided to concentrate initially on the
characterization of the more stable E-enols. The “E-cisoid-e-z-
z” and “E-transoid-e-z-z” MAHO and MAHT structures (see the
Tables S3 and S4 in SI) were now used as the basis to perform
calculations on 4-methoxy, 4-chloro and 4-bromo aryl
substituted MAHOs and MAHTs. In both the MAHO and MAHT
series, cisoid and transoid minimum energy conformations
were identified for the E-enols. Consistently in these structures
(Table 7), in which hydrogen-bonding between the enol OH
and the C=O of the carboxylic acid was apparent (illustrated in
Figures 2 - 4 for the parent phenyl examples), the hydrogen
bonding O···H separation was 1.63 - 1.66 Å. The O-H bond of
the enol was lengthened to 1.01 - 1.02 Å compared to the
carboxylic acid O-H at 0.98 Å and in all cases, the enol and
carboxylic acid sections of the structure were essentially
coplanar (dihedral angles +0.6 - –0.6°), and the C-C bond
lengths within the C=CHCO2H section shorter for C=CH than
for CH-CO2H (1.37 - 1.38 Å and 1.43 - 1.44 Å, respectively) but
none-the-less these are both significantly shorter than a typical
C-C bond, as expected because of the extended conjugation.
The molecular orbitals of the gas phase optimised structures
were examined from the LUMO down to the lowest p-orbital of
the MAHO(T). Figures 5 - 10 illustrate well the flat delocalised
p-systems associated with their structures. In general, the
patterns of the orbitals were similar for all the MAHOs and
MAHTs examined. The p-donation from the oxygen or sulfur
atoms of the PhO / PhS groups[42] into the enol is clearly visible
in the slightly higher energy E-cisoid HOMO-11[ 43 ] (ester,
Figure 7) and E-cisoid HOMO-12 (thioester, Figure 8)
molecular orbitals. Similarly, E-transoid HOMO-8 and E-
transoid HOMO-10 show the delocalisation between the
heteroatom link and the arene (Figure 9), especially in the
thioester case. In Figures 5B, 7B and 9B, the tilted geometry
of the MAHO distorts these orbitals.
Figure 5. Low lying E-cisoid and E-transoid MOs in the ester structures with p-overlap across the enol and carboxylic acid (A: structure cisoid-23; B: structure
transoid-23
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Figure 6. Low lying E-cisoid and E-transoid MOs in the thioester structures with p-overlap across the enol and carboxylic acid (A: structure cisoid-15; B: structure
transoid-15)
Figure 7. Typical examples of p-delocalisation in the parent MAHO 23 with p-overlap across the enol and carboxylic acid (A: structure cisoid-23; B: structure transoid-23)
Figure 8. Typical examples of p-delocalisation in the parent MAHT 15 with p-overlap across the enol and carboxylic acid (A: structure cisoid-15; B: structure transoid-
15).
Figure 9. Orbitals illustrating p-overlap between the heteroatom and the arene (A: structure cisoid-15; B: structure transoid-15)
Figure 10. Orbitals illustrating p-overlap between the heteroatom and the arene (A: structure cisoid-15; B: structure transoid-15)
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Figure 11. Orbitals illustrating p-overall between the heteroatom and the arene (A: structure cisoid-15; B: structure transoid-15)
These archetypal p-symmetry orbitals are observed
across the whole series of MAHO and MAHT structures (see
SI) with only minor variations in the sequence of relative
All are easily prepared using a quick and efficient protocol.
Whilst the yields in most cases are good, the inclusion of a
strong EWG i.e. nitro or ester at the ortho-position on the aryl
ring of the phenol or thiophenol starting materials affords the
products, but with reduced yields. This is attributed to the
formation of a strong intramolecular hydrogen-bond (cf. RAHB)
between the hydroxyl or thiol group and the ortho-EWG.
Overall, the formation of a resonance-assisted hydrogen bond
and the inductive effect reduces nucleophilicity and reactivity
towards the malonyl mono-chloride. Whilst probing the
reactivity of the MAHO and MAHTs, as measured by hydrogen
energies.
A significant difference between MAHOs and
MAHTs, however, was identified from the presence of an
additional frontier orbital (HOMO-3) in the thioesters (see Table
8, and Figure 11) which is delocalized between sulfur atom and
the enol. In other aspects, the geometries and molecular
orbitals of the MAHOs and MAHTs are very similar and
consistently showing the same key features.[44] The significant
HOMO-3 MAHT orbital, however, which was consistently
present in all MAHT conformers examined in our study was not
present in the MAHOs and provides for increased p-overlap in
the MAHT series. This may account for the much easier
enolisation and much faster deuterium incorporation observed
in the NMR experiments for the parent phenol and thiophenol
MAHO and MAHT structures.
®
deuterium exchange, we identified an unexpectedly rapid
enolisation in the MAHT series. We ascribed the increased
reactivity to the presence of an additional sulfur-centred frontier
orbital which increases p-delocalisation between the
heteroatom and the enol. The exceptional ease of enolisation
in the MAHT series suggests these nucleophiles should offer
new prospects for the efficient C-C bond formation under mild
conditions. Ultimately, our work will help develop a better
understanding of how Nature employs MAHTs for metabolite
biosynthesis and with the two slightly different protocols now
well established, we have the capability to synthesize either
electron-rich, or electron-poor or sterically hindered aryl
derived MAHOs or MAHTs.
Conclusions
In summary, we detail the synthesis of 39, mostly
unknown, structure- and function-diverse MAHOs and MAHTs.
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10.1002/chem.201605148
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and the EPSRC Mass Spectrometry Service for generating
HRMS data.
Acknowledgements
Keywords: thioester • isotope exchange • DFT • reaction rate
• hydrogen bond • p-delocalisation
The authors acknowledge the EPSRC, UEA, and INTERREG
IVA (IS:CE chem project 4061) for financial support, the UEA
high-performance cluster “Grace” for computational resources,
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Chemistry - A European Journal
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MAHTS are the best. Three comprehensive studies on the
synthesis, reactivity ([2H]-exchange) and conformational
properties of aryl (thio)ester-derived MAHOs and MAHTs are
reported. Using ‘off the shelf’ starting materials and a solvent-
free protocol 39 structure and function diverse MAHOs and
MAHTs are readily generated. These are the fastest, easiest
and most environmentally friendly routes to MAHO(T)s. The
synthetically valuable ease of enolisation of the MAHTs is
accounted for by the computationally established presence of
an additional frontier orbital unique to the MAHT series which
provides enhanced p-delocalisation between the sulfur and the
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