A theoretical study of the Duff reaction: Insights into its selectivity

Article abstract of DOI:10.1039/c6ob01887d

The Duff reaction is one of the most employed methods for the ortho-formylation of phenols; however, not much is truly known about its mechanism. Using DFT calculations, we disclose the first theoretical study regarding the selectivity-determining step of the reaction. We have found that this stage is governed by a hydrogen bond, that gives rise to a cyclohexa-2,4-dienone intermediate and establishes the position where the formylation will take place. These findings were evaluated by analysis of the reaction outcome of several non-symmetrically substituted phenols.

Full text of DOI:10.1039/c6ob01887d

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DOI: 10.1039/C6OB01887D
Organic & Biomolecular Chemistry
ARTICLE
A Theoretical study of the Duff reaction: Insights into its
selectivity
Received 00th January 20xx,
Accepted 00th January 20xx
Nicolás Grimblat,*, Ariel M. Sarotti, Teodoro S. Kaufman and Sebastian O. Simonetti*
DOI: 10.1039/x0xx00000x
The Duff reaction is one of the most employed methods for the ortho-formylation of phenols; however, not much is truly
known about its mechanism. Using DFT calculations, we disclose the first theoretical study regarding the selectivity-
determining step of the reaction. We have found that this stage is governed by a hydrogen bond, that gives rise to a
cyclohexa-2,4-dienone intermediate and establishes the position where the formylation will take place. These findings
were evaluated by analysis of the reaction outcome of several non-symmetrically substituted phenols.
www.rsc.org/
the setup of the Duff reaction, except for the employment of
trifluoroacetic acid (TFA) as solvent, to enable or enhance the
Introduction
The synthesis of salicylaldehyde derivatives often entails the
installation of a formyl moiety ortho to a phenol. This can be
9
formylation of the less activated aromatic rings and the novel use
10
of Cu O to upgrade the yields of the reaction. In addition, an
1
2
efficient methodology for the synthesis of lactams based on the
accomplished through different classical approaches, such as the
11
Duff formylation was recently developed by Moreau et al.
2
3
Duff, 4Reimer-Tiemann and Vilsmeier-Haack reactions, among
As a result, the most demanding applications of the Duff
formylation, which involve the elaboration of advanced
intermediates in multistep synthesis, are currently limited to only
specific examples. Among them, in the recent syntheses of (–)-
kendomycin, parvistemin A and the structure originally assigned to
aspergillitine, the Duff formylation played a key role in order to
others.
The Duff formylation involves the treatment of a phenol with
HMTA in acidic media followed by hydrolysis in order to afford the
desired salicylaldehyde (Scheme 1). Compared to the other
approaches, the Duff formylation is advantageous in many synthetic
scenarios, because it combines the use of inexpensive and easily
available reagents and tolerance to traces of moisture, with its
great operational simplicity and compatibility with a wide variety of
functional groups.
12
install the required formyl moieties.
Most probably, the reaction complexity and the lack of a better
understanding of its mechanism have discouraged its wider
application toward complex products. In consequence, its use was
mainly applied to the preparation of differently substituted
OH
OH
N
13
salicylaldehydes, which usually served as starting materials.
CHO
6
5
2
3
+ N
N
1) AcOH or TFA
2) HCl or H SO
The Duff formylation is a Mannich-type reaction, where a phenol
acts as the carbonyl component, which is initially subjected to an
ortho-aminomethylation with hexamethylenetetramine (HMTA),
which in turn serves as the needed amino component and a latent
source of the formyl moiety. The reaction, which requires acid
catalysis, is usually carried out in hot acetic acid or TFA and involves
a complex series of steps. Finally, a mineral acid or water-mediated
treatment is employed to hydrolyze the late stage intermediates,
leading to the final product.
N
2
4
4
HMTA
R
R
Scheme 1. The Duff reaction.
However, in order to be still more synthetically useful, it faces
5
,6
the same challenges that the other approaches. These defiance
include the need of increasing product yields and reaction
robustness, as well as to have a handy means to predict its
regioselectivity when applied to non-symmetrically substituted
From a mechanistic point of view, the Duff formylation was
postulated as a C-C bond formation process, between a phenol (i)
7
phenolic substrates.
+
and the iminium species HMTA (ii), resulting from protonation and
Despite its importance, in nearly one century after its first
8
ring opening of HMTA), which acts as the Mannich acceptor. This
gives rise to a β-aminoketone-type Mannich base (iii) as the main
intermediate, which carries a protonated oxygen atom (Scheme 2).
This intermediate, which defines the reaction selectivity, undergoes
further oxidation, followed by rearomatization to afford the
intermediate iv, and a final hydrolysis to furnish the desired
salicyladehyde product (v).
description no major studies nor improvements have been made in
Instituto de Química Rosario (IQUIR, CONICET-UNR), Facultad de Ciencias Bioquímicas y
Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, Rosario (2000),
Argentina
E-mail: grimblat@iquir-conicet.gov.ar; simonetti@iquir-conicet.gov.ar
Although the same picture of the first step of this reaction is
widely accepted in order to obtain the intermediate iii, several
postulates may be found through the literature, explaining how the
This journal is © The Royal Society of Chemistry 2016
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ARTICLE
Org. Biomol. Chem.
iminium intermediate iv could be formed. Mainly, these deal with formation and breaking, under or without the assiVsiteawnAcreticloe fOntlhinee
how the different structural changes take place in the more solvent. In addition, a rearomatization 4D seOqIu: 1e0n.1c0e3,9/fCo6llOowB0e1d887bDy
1
advanced intermediates. These modifications most commonly dehydrogenation, has also been proposed.
include intra-molecular system rearrangements, with C-N bond
Scheme 2. The reaction under study. Currently accepted structure of the initial Duff coupling product and currently accepted mechanism
for the Duff reaction.
Interestingly, if the starting phenol is non-symmetrically ratio presented by Zhang and coworkers of 0:0:100 (R /R /R ).
2
4
6
substituted, two potential regioisomers could be formed (R and Furthermore, when the same analysis was performed considering
2
R6). A beforehand knowledge of the outcome of the transformation the energies of the reaction products, a 3:50:47 (R /R /R )
2
4
6
could be beneficial during the planning stage of multistep syntheses selectivity was obtained, also contradicting the experimental
in order to make the most accurate strategic decisions, which would results.
avoid arriving at the wrong regioisomer and, indirectly, favor an
increase in the frequency of use of this reaction.
The poor agreement between our initial theoretical calculations
and the corresponding experimental results with regards to the
Considering the desirability and potential usefulness of this reaction selectivity prompted us to perform a closer examination of
information, and with the aim of gaining a deeper insight into the the model behind the selectivity-determining step. After further
origins of the regioselectivity of the transformation, we have investigations, we found that during the transition state (TS) of this
performed a theoretical study of the key step of the Duff step (for both ortho- and the para- regioisomers), one of the
formylation, in which the selectivity is defined, and herein we nitrogen atoms of the tetraamino moiety of the formylating agent
disclose our results.
captures the phenolic proton, causing dearomatization of the
substrate and giving rise to a reactive conjugated cyclohexadienone
intermediate.
Results and Discussion
However, during this process, no changes in the net charge of the
HMTA portion were observed. This is because this hydrogen
migration does not entail a second protonation of a nitrogen atom
of the intermediate, but rather a system rearrangement,
+
In order to carry out the projected study, we employed the M06-
X functional , coupled with the 6-311+G(d,p) basis set based on
15
2
16
recent work by Vilarrasa and coworkers, including acetic acid as
17
18
concomitant with the desired C-C bond formation, so the reaction
may take place. The generation of a keto-enamine species has been
previously observed in similar cases and confirmed through X-Ray
diffraction, being attributed to the relatively higher basicity of the
solvent using SMD as implemented in Gaussian 09 at the
corresponding temperature for each studied reaction (70-140 ºC).
The theoretical calculations were initially performed with 3-
methylphenol (1, meta-cresol), as a simple model of a meta-
substituted, non-symmetrically functionalized phenol. This
substrate carries two well-differentiated free ortho sites (R and R ),
21
nitrogen against that of the phenolic oxygen.
The comparison of the traditionally admitted and the newly
proposed TSs, revealed that in the accepted approximation the C-C
bond being formed has smaller distances (1.81-1.87 Å) and smaller
Wiberg bond indexes (WBI, 0.56-0.59) than in this newly discovered
attack mode (Figure 1). For the latter approximation, bond
distances up to 2.24 Å and WBI > 0.34 were found.
2
6
and an available para position (R4), designated following
substitutent priority rules. The Duff formylation of 1 was reported
to generate only one isomer (R6).
19
Since there are some scattered reports informing that with
suitable substrates the Duff reaction is also able to yield the para
20
Interestingly, for TS-3+HMTA-R H, these parameters are roughly
6
isomer, the selection of compound 1 also made us possible to
20
similar to those computed for the TS without the hydrogen
migration, although they differ in approximately 7 kcal/mol. This
energy difference may be an evidence of the important role played
by the O···H-N interaction.
study all three possible substitution points. The availability of
reported data on the reaction regioselectivity for this molecule,
which also contains three potentially reactive positions, seemed to
make of it an adequate substrate in order to study the reaction.
To this end, we examined the reaction mechanism, shown in
Scheme 2, where the key initial C-C bond is formed. In this currently
accepted proposal, the charge is transferred from the protonated
For the R approximation, this newly found geometry of the TS
2
+
(
TS-1+HMTA -R H) was almost 10 kcal/mol lower in energy than
2
+
that computed for the accepted one (TS-1+HMTA -R A).
2
+
Interestingly, for the para (R
4
) attack, no energy difference was
HMTA (HMTA ) to the phenolic oxygen.
+
found between the newly proposed (TS-1+HMTA -R H) and the
4
Unexpectedly, we realized that the distribution of products that
arose from a Boltzmann analysis of the activation energies
associated to each possible substitution position was 13:87:0
+
accepted TS (TS-1+HMTA -R A).
4
(
R /R /R ). This selectivity is completely different from the product
2 4 6
2
| Org. Biomol. Chem., 2016, 00, 1-3
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12a
3).
View Article Online
To our delight, we obtained a mixture oDfObI:o1t0h.10e3x9p/eCc6tOedB0o1r8t8h7oD-
1
isomers, in a 21:79 (R /R ) distribution ratio according to H NMR
2
6
1
.81
1
.87
1.84
(0.59)
(0.62)
integration of the mixture, in perfect agreement with that resulting
from the calculated energies of the products of the newly proposed
TSs (R /R = 26:74).
(0.56)
+
+
+
2
6
TS-1+HMTA -R A
TS-1+HMTA -R A
TS-1+HMTA -R A
2
4
6
Bearing in mind the analysis performed for 1 and the newly
discovered mechanism for this key-step, seven additional
representative phenols, entailing different non-symmetric
substitution patterns and considering steric hindrance, electron
donating and withdrawing groups, were selected from the recent
1
.51
1.49
(0.21)
1
.57
(
0.16)
(
0.14)
2
.24
2.20
0.37)
1
.91
(
0.34)
(
(0.56)
13a,23
literature for closer examination.
+
+
+
TS-1+HMTA -R H TS-1+HMTA -R H
TS-1+HMTA -R H
6
2
4
Figure 1. Top: The TSs for the accepted mechanism. Bottom: The
newly proposed mechanism, where migration of phenolic hydrogen
is involved. The distances are in angstroms and the Wiberg bond
indexes in parentheses.
On the other hand, the comparatively higher energy required for
this approximation (up to 8 kcal/mol) is in perfect agreement with
the recognized preference of the Duff reaction to afford ortho
formylation products. Unfortunately, the ratio distribution resulting
from this newly found TSs (97:0:3, R /R /R ) was also in collision
2
4
6
Scheme 3. Duff Reaction of 3-methylphenol (1).
with the experimental results reported in the literature for phenol
19
In agreement with the thermodynamics of the reaction for 1, we
found that the formylation process of all the studied phenol
derivatives (2-8) is endergonic, with energies between 1.50 and
1.
When we analyzed and compared the energies of the products,
corresponding to all the approximations under study, we found that
the products resulting from the newly found TSs geometry were
between 17 kcal/mol and 21 kcal/mol lower in energy than those of
the currently accepted products of this reaction step. Considering
the most stable products, we also took note that the calculated
R /R distribution (26:74) was also contradicting the literature.
1
5.05 kcal/mol (Table 1), and that the calculated product ratios
based on their energies were in excellent agreement with the
reported regioselectivities.
Table 1. Calculated activation, formation energies and theoretical
2
6
24
and experimental Duff distribution ratios.
In light of these adverse results, we decided to more carefully
O
scrutinize the literature, and found a report where two isomeric
products were described, as resulting from the Duff formylation of
OHC R6
HO
N
S
O
O
22
Me
3
-methylphenol (1), in a 1:1 ratio. This finding prompted us to
Me
HO
R2
carry out the reaction experimentally, in order to clear out all of our
doubts.
HO
R2
O
CHO
CHO
CHO
2
3
4
OH
OH
OH
OH
R6
OHC
R6
R2
R2
CHO OHC
CO2Me
Me
Me
CO2Me
Cl
Br
OMe
Me
5
6
7
8
≠
a
Calc. Ratio
a
Calc. Ratio Exp. Ratio
b
Phenol Isomer ΔG
b
ΔG
(
R /R )
(R /R )
(R /R )
2 6
2
6
2
6
R2
R6
21.17
23.91
17.73
8.97
8.33
6.03
13.90
11.08
1.50
1
2
97:3
95:5
26:74
100:0
21:79
R2
23d
100:0
0:100
100:0
89:11
100:0
R6
20.03
24.36
20.22
17.61
19.93
20.84
23.29
22.31
24.42
19.88
R2
23b
23e
23c
3
4
5
0:100
95:5
96:4
0:100
100:0
98:2
R6
R2
4.99
Figure 2. Reaction coordinate for the Duff reaction of 3-
methylphenol (1).
R6
11.68
10.09
12.60
12.38
15.05
9.50
R2
R6
Taking into account that our calculations were performed in
acetic acid, the most widely employed solvent for the Duff reaction,
we decided to set up the reaction in this solvent, following a
modification of the procedure disclosed by Rychnovsky (Scheme
R2
13a
6
7
94:6
99:1
5:95
R6
R2
23f
73:27
0:100
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ARTICLE
Org. Biomol. Chem.
R6
R2
20.63
22.64
23.87
7.71
11.57
7.87
hydrogen bond distances varied from 1.45 to 1.67 ÅViaewndArttichleeOWnlinBeI
fluctuated between 0.08 and 0.24. InterestiDnOglIy: 1,0a.s10d3e9t/eCc6tOeBd0i1n88t7hDe
case of phenol 1, the smaller the distance between carbons in the
new C-C bond, the shorter was the length of the hydrogen bond. A
concomitant WBI increase was also noticed.
23a
8
83:17
0:100
0:100
R6
a
b
Energies in kcal/mol. According to the Boltzmann distribution.
The formylation of phenol 8 seems to be a suitable example for
the conclusions observed herein. According to the studied TSs of
the key intermediate of this reaction, it is expected that the
transformation will take place to give the product, with a R /R
For all cases the energy barrier of this step demonstrated to be
relatively low, between 17.61 and 24.42 kcal/mol. Curiously, in the
cases of phenols 7 and 8, the TS-based calculations predicted
selectivities opposite to those observed experimentally.
Nevertheless, the real outcome of this forecast was corrected to
finally agree with the experimental observations, by the
thermodynamic analysis, as is encountered by the initial study with
phenol 1.
In accordance with the analyzed 3-methylphenol 1, when the
distances and WBI values were of phenols 2-8 were examined, we
observed a scenario similar to the above described. The distances
varied from 1.86 to 2.25 Å and the WBI values changed between
2
6
selectivity of ~80:20; that is, favoring the R product (Figure 3),
2
23a
contrary to the experimental results (R /R : 0:100).
2
6
However, examination of the TS structure of 8 corresponding to
+
an R -substitution (TS-8+HMTA -R ) revealed that the proton has
6
6
not yet migrated from the oxygen to the nearby nitrogen; this detail
may be at the roots of its higher energies. Contrarily, however, a
correct prediction of the selectivity could be achieved when the
thermodynamics of the reaction was also analyzed.
0
.27 and 0.57 for the C-C bond formation. On the other hand, the
1
(
.65
0.08)
1
.62
1.60
(0.11)
1.49
(0.21)
(0.10)
2.17
(0.32)
2
.09
2.20
0.37)
1.90
(0.54)
(
0.39)
2.12
0.35)
(
(
+
+
+
TS-8+HMTA -R6
+
TS-5+HMTA -R6
TS-8+HMTA -R2
TS-5+HMTA -R2
1
.90
1.86
(0.04)
(0.04)
≠
≠
DG 23.87
DG 23.29
≠
DG 22.64
≠
DG 20.84
+
+
P-5+HMTA -R2
P-8+HMTA -R
2
DG 12.60
DG 10.09
1.88
(0.04)
1
.87
OH
OH
(0.04)
DG 11.57
DG 7.87
O
Me
Me
Me
5
+ HMTA+
5
O
P-5+HMTA -R6 8 + HMTA+
+
+
8
Me
P-8+HMTA -R
6
Reaction Coordinate
Figure 3. Comparison of the reaction first stage for phenols 5 and 8 with distances in Å and Wiberg bond indices between parentheses.
Energies in kcal/mol.
On the basis of these results, we rationalized that R is preferably
2
functionalized in cases where the aromatic ring was substituted
with electron-withdrawing groups (phenols 5 and 6), whereas
substitution at R6 prevailed when donor groups were involved
≠
H
N
H
R
d+
d+O
d+
N
(
phenols 1, 3, 7 and 8).
The influence of similar electronic effects of the aromatic ring
N
H
N
H
R
N
O
H
N
H
O
substituents was previously noticed by the group of Marsaioli in
their study on the selectivity of the Claisen rearrangment of allyl
+
N
N
N
N
N
25
phenyl ethers. However, the electronic effects do not seem to be
the only variable affecting the reaction selectivity.
N
HMTA+
R
On the basis of the results obtained for phenols 1 and 8, it is clear
that in some cases it should also be considered the steric factor as a
relevant influence to the reaction outcome. On the other hand, the
exact nature of the behavior of the substituents in the more
complex heterocycles (2 and 4) is still unknown, being probably
related to the impact of electronic effects and other factors.
Based on all these observations, we propose that the C-C bond
formation step of the Duff Reaction should be represented as
depicted in Scheme 4, and not as commonly accepted (Scheme 2).
Scheme 4. Proposed initial step for the Duff reaction. The C-C bond
formation stage.
Conclusions
In conclusion, here we have reported the first theoretical study
of the regioselectivity-defining step of the Duff reaction. Through
DFT calculations, we have found that the transition state of this
step differs from that traditionally accepted. Based on the
4
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Org. Biomol. Chem.
ARTICLE
calculations, the migration of a proton from the phenolic OH (C-1), 121.1 (C-5), 133.5 (H-6), 148.9 (C-4), 161.7 (CV-i2ew) Aarntidcle1O9n5lin.8e
+
(
donor) to a nitrogen (acceptor) of the formylating agent (HTMA ) (CHO) ppm.
DOI: 10.1039/C6OB01887D
1
was proposed to take place with concomitant dearomatization of 2-Hydroxy-6-methylbenzaldehyde: H NMR (δ, CDCl , 75 MHz):
3
the phenolic substrate, giving rise to a cyclohexa-2,4-dienone 2.61 (s, 3H, ArMe), 6.72 (d, 1H, J= 7.0 Hz, H-5), 6.82 (d, 1H, J= 7.0 Hz,
intermediate. This newly found transition state, which is formed by H-3), 7.38 (t, 1H, J= 6.8 Hz, H-4), 10.33 (s, 1H, CHO) and 11.90 (s, 1H,
13
migration of the proton initially attached to the phenolic oxygen to OH) ppm; C NMR (δ, CDCl , 75 MHz): 18.1 (ArMe), 116.1 (C-3),
3
the nitrogen of the formylating agent, enables a better stabilization 118.6 (C-1), 121.8 (C-5), 137.4 (C-4), 142.1 (C-6), 163.2 (C-2) and
of the TS.
We expect that this study, which demonstrated the ability of
theoretical calculations to predict the regioselectivity of this
195.3 (CHO) ppm.
reaction in non-symmetrically substituted phenols, will encourage Acknowledgements
the more frequent use of the Duff formylation in advanced stages
of complex syntheses.
In addition we anticipate that, on the basis of these observations,
the remaining stages of the reaction should also be re-examined,
since our findings suggest that the transformation takes place
through a path different from that traditionally accepted.
This research was supported by the Agencia Nacional para la
Promoción Científica y Tecnológica (ANPCyT), PICT-2012-0970 and
PICT-2014-0445. N.G. and S.O.S. acknowledge CONICET for
awarding their fellowships.
Notes and references
Experimental Section
Computational Methods
1
(a) A. Bagno, W. Kantlehner, O. Scherr, J. Vetter and G.
Ziegler, Eur. J. Org. Chem., 2001, 2947; (b) W. Kantlehner,
Eur. J. Org. Chem., 2003, 2530; (c) G. A. Olah, L. Ohannesian
and M. Arvanaghi, Chem. Rev., 1987, 87, 671.
(a) X. Chen, J. Wang, S. Sun, J. Fan, S. Wu, J. Liu, S. Ma, L.
Zhang and X. Peng, Bioorg. Med. Chem. Lett., 2008, 18, 109;
Conformational searches for the reactants, the transition structures
(
TSs) and the products were run to locate the global minima
2
15
employing the M06-2X functional coupled with the 6-311+G(d,p)
level of theory. Initially, a large number of geometries were
(
b) D. A. Horton, G. T. Bourne, J. Coughlan, S. M. Kaiser, C. M.
Jacobs, A. Jones, A. Ruhmann and J. Y. Smythe, Org. Biomol.
Chem., 2008, , 1386; (c) G. Marzaro, A. Chilin, G. Pastorini
and A. Guiotto, Org. Lett., 2006,
26
generated using the conformational search module of Hyperchem
with the MM+ method for the TSs and Spartan’s conformer
6
8
, 255.
distribution module, employing MMFF for both, reactants and
3
L. Ma, J. Chen, X. Wang, X. Liang, Y. Luo, W. Zhu, T. Wang, M.
2
7
products.
The selected structures were then optimized at the M06-2X/6-
Peng, S. Li, S. Jie, A. Peng, Y. Wei and L. Chen, J. Med. Chem.,
2
011, 54, 6469.
18
3
11+G(d,p) level of theory, using Gaussian 09. The geometries for
4
5
6
7
8
9
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17
as solvent using SMD.
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2
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2
4
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mg, 12%). The spectral data of the so obtained compounds were in
1
2
8
agreement with those reported.
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1
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.38 (s, 3H, ArMe), 6.80 (s, 1H, H-3), 6.82 (d, 1H, J= 6.8 Hz, H-5),
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1
968, 24, 5001 (c) Z. Wang, Comprehensive organic name
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ppm; C NMR (δ, CDCl , 75 MHz): 22.2 (ArMe), 117.6 (C-3), 118.7
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3
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2
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- 110 ºC; - 90 ºC;
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-
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- 110 ºC; 8 - 110 ºC.
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