An insight into the mechanism of the aerobic oxidation of aldehydes catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1039/c3cc48929a

N-Heterocyclic carbene catalysis for the aerobic oxidation and esterification of aromatic aldehydes was monitored by ESI-MS (MS/MS) and the key intermediates were intercepted and characterized using the charge-tag strategy.

Full text of DOI:10.1039/c3cc48929a

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An insight into the mechanism of the
aerobic oxidation of aldehydes catalyzed
by N-heterocyclic carbenes†
Cite this: Chem. Commun., 2014,
50, 2008
Received 22nd November 2013,
Accepted 26th December 2013
O. Bortolini,*a C. Chiappe,b M. Fogagnolo,a P. P. Giovannini,a A. Massi,*a
C. S. Pomellib and D. Ragnoa
DOI: 10.1039/c3cc48929a
www.rsc.org/chemcomm
N-Heterocyclic carbene catalysis for the aerobic oxidation and esterifi-
cation of aromatic aldehydes was monitored by ESI-MS (MS/MS) and
the key intermediates were intercepted and characterized using the
charge-tag strategy.
The electron richness and structure of the N-heterocyclic carbenes
(NHCs) provide a unique class of s-donor species, which have found
widespread applications in organocatalysis.1 The most successful
uses of these azolylidene catalysts involve the polarity reversal of
aldehydes, in which the NHC promotes the formation of an acyl
anion equivalent commonly referred to as the Breslow intermediate
(II of Fig. 1). This NHC-catalysis has been recently enriched with
oxidative protocols to access a wide range of organic compounds,
especially acids and esters.2 The key oxidation event characterizing
these transformations takes place on the Breslow intermediate II,
which may be converted by air as the terminal oxidant into an
electrophilic acyl azolium ion III3 (stoichiometric external oxidants
such as MnO2, azobenzene, riboflavin, phenazine, TEMPO, and
quinones can also be employed),2 and/or into an azolium peroxidic
species V.3 In the former case III is prone to transfer the acyl group
to an alcohol forming the corresponding ester (oxidative pattern);3a,b,e
Fig. 1 Most commonly proposed mechanisms for the NHC-catalyzed
aerobic oxidation of aldehydes.
In an attempt to provide responses to these issues and as part of
in the latter case V is supposed to intercept a second molecule our ongoing research on the chemistry of NHCs,6 we envisaged the
of aldehyde or II to generate the carboxylic acid via formation of use of charge-tagged N-heterocyclic carbenes as mass spectrometric
the corresponding peracid and/or the anionic intermediate VI probes to identify the species involved in the different oxidation
(oxygenative pattern).3c–g,i Eventually, the acid is converted into the steps and their dynamic equilibria. The charge-tag strategy entails
ester by O-alkylating reagents and base (Fig. 1).3f,g,4 A number of the use of reagents, catalysts or ligands bearing a cationic or anionic
mechanistic studies have been performed on the NHC-catalyzed unit installed remotely from the reaction site.7 It is noteworthy, also,
aerobic oxidation of aldehydes;3b,c,e,g,h,4a,5b nevertheless, key questions that mass spectrometry (MS) has gained great benefit from the
concerning the fate of the Breslow intermediate are still unanswered, advent of electrospray ionization (ESI), since molecules of high
including a precise characterization of the postulated intermediates polarity and complexity can be gently transferred directly from
and a rationalization of the proposed mechanistic dichotomy.
solution to gas-phase, thus permitting the detection of elusive and
highly reactive intermediates.8
Dipartimento di Scienze Chimiche e Farmaceutiche, Universita di Ferrara, Via
In the present study, the 3,30-dimethyl-1,10-(hexane-1,6-diyl)
diimidazolium glutarate 1 has served as the precursor of
carbene catalysts 2, which displays the second imidazolium
ring as a positive label for MS detection (Scheme 1). By this
approach, we provide evidence of the key intermediates III, V,
and VI as well as justification of preferential oxidative or
a
`
Fossato di Mortara 17, 44121 Ferrara, Italy. E-mail: olga.bortolini@unife.it,
alessandro.massi@unife.it; Fax: +39 0532240709; Tel: +39 0532455171
b
`
Dipartimento di Farmacia, Universita di Pisa, Via Bonanno 33, 56126 Pisa, Italy
† Electronic supplementary information (ESI) available: Experimental proce-
dures, mass spectrometric experiments, theoretical calculations and spectra.
See DOI: 10.1039/c3cc48929a
2008 | Chem. Commun., 2014, 50, 2008--2011
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Scheme 1 Generation of the charge-tagged NHC 2.
oxygenative patterns with dependence on aldehyde stereoelec-
tronic features.
Our investigation began with the ESI-MS monitoring of the
reaction between pre-catalyst 1 and the model 2-bromo benzalde-
hyde 3a using acetonitrile–MeOH (5 : 1) as the eluent. Firstly, it was
observed that significant amounts of 2 could be produced without
the need of an external base, the relative intensity of 2 (m/z 247)
being about 70% in the absence of aldehyde. Upon addition of 3a
the intensity of 2 quickly decreased in parallel with an increase
(up to 100%) of the signal at m/z 447 (79Br isotope) unequivocally
assigned, by accurate mass analysis, to the Breslow intermediate
4a containing an additional oxygen atom [4a + O]+ (Fig. 2 and
Scheme 2). Noteworthily, when this ionic species was mass selected
and subjected to collision induced fragmentation (MS/MS), the
release of the neutral carboxylic acid 7a and formation of the NHC
2 were observed. Significantly, this decomposition perfectly fits with
the reactivity found in solution (Table 1), thus corroborating the
structure proposed in Fig. 2 for the [4a + O]+ ion.
Scheme 2 Proposed mechanism for the aerobic oxidation of aldehydes:
path A, oxygenative, path B, oxidative.
Table 1 Oxidation–esterification of aldehydes 3a–k
In addition, the full scan acquisition highlighted the presence,
although in a much lower relative intensity (ca. 2%), of a second
important ion cluster (m/z 463), identified as the Breslow intermedi-
ate formally containing two oxygen atoms [4a + 2O]+.9 The MS/MS
analysis of this ionic species disclosed even more important infor-
mation consisting in the release of O2 with formation of the genuine
Breslow intermediate 4a (m/z 431), species otherwise not detectable
in the full mass spectrum. The detailed snapshots of the involved
intermediates and their preferential decomposition substantiate the
mechanism described in path A of Scheme 2. Accordingly, molecular
oxygen adds to the Breslow intermediate 4 with formation of the
zwitterionic peroxide 5 (heretofore named [4a + 2O]+); reasonably,
5 then attacks a second molecule of aldehyde by a mechanism
reminiscent of the Baeyer–Villiger oxidation to yield a first molecule
of acid 7.10 The final event consists in the release of an additional
molecule of 7 from the intermediate 8 (heretofore named [4a + O]+)
Entry
Aldehyde
X
8 a (ab. %)
10 b
7/11 c (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
2-Br
2-Cl
2-NO2
2-OMe
4-Br
100
80
N
N
N
N
Y
Y
Y
Y
Y
N
N
45/5 (37/8)d
32/8
40/0
[5]e
60
24/0
o1
11/78 (19/72)d
10/76
4-Cl
8
4-NO2
4-OMe
3-Br
2,6-Cl2
2,4,6-Me3
o1
10
8
80
100
5/84
6/32
10/72
25/5
9
10
11
3j
3k
28/0
a
b
Relative abundance as determined by ESI-MS (see ESI). N = not
c
d
detected; Y = detected and characterized. Isolated yield. Reaction
performed with bmim(OTf). Very unstable species that spontaneously
undergoes fragmentation.
e
with regeneration of catalyst 2. Remarkably, in our MS experiments
we observed no evidence of the formation of free deprotonated
peracids (Fig. 1), species that survive the (ꢀ)-ESI MS conditions, as
proved by control experiments with genuine samples.
To corroborate the above findings, the reaction of 2-bromo
benzaldehyde 3a with pre-catalyst 1 (1 equiv.) was investigated in
solution (anhydrous THF, molecular sieves, 55 1C) using DBU
(1.1 equiv.) as the base. As hinted in the mechanistic proposal
(path A), aldehyde 3a was converted into the corresponding acid
7a in 51% yield. However, when this reaction was performed
in THF–MeOH (2: 1), a low amount (5%) of methyl ester 11a
was detected together with the acid 7a (45%; Table 1, entry 1).
Extension of these conditions to aldehydes 3b–k possessing
ortho-, meta- or para-groups, with either electron-withdrawing
Fig. 2 MS/MS of the Breslow intermediate 4a containing an additional
oxygen atom (m/z 447) formed by the 1/3a reaction.
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+
or electron-donating properties, confirmed the concurring partial or on [4]ꢁ , mainly on the C-atom next to the OH group. This result
almost complete esterification of the substrates (Table 1). Although fully conforms with those reported for triazolium-based systems.3c
the activity of pre-catalyst 1 in solution was limited,11 its utilization
Significantly, peroxide 5 appears as the common intermediate
represented the gateway for accessing key intermediates by ESI-MS. of both oxygenative and oxidative mechanisms. Indeed, DFT
Replacement of the cationic imidazolium tag of 1 with an uncharged calculations showed the H-bonded transition state TS (Scheme 2,
alkyl chain as in 1-butyl-3-methylimidazolium trifluoromethane- R1 = Me; R2 = Me; Ar = Ph) in the tautomeric equilibrium between 5
sulfonate [bmim(OTf)] produced similar results in terms of isolated and 9. In the oxidative mechanism, 5 is converted into the acyl
yields of acids 7 and esters 11 (entries 1 and 5).
cation equivalent 10 through the intermediate 9 by intramolecular
This divergent reactivity was deeply examined by the ESI-MS proton transfer and liberation of the hydroperoxide anion.3a,l Path
monitoring of the reaction between 1 and a model aldehyde B is finally completed with acylation of MeOH to give the ester 11
that predominantly affords the ester rather than the acid, and catalyst 2. Both A and B reaction patterns fully conform to the
i.e. the 4-bromo benzaldehyde 3e.
oxygenative and oxidative classification proposed by von Wangelin
The most resounding evidence in the (+)-ESI full spectrum was et al.,2b and the divergent reactivity seems to be mainly directed by
the absence of the oxidized Breslow intermediate 8e. In contrast, steric factors. Indeed, meta- and para-substituted aldehydes 3e–i are
the peroxidic Breslow intermediate 5e remained detectable, whose good substrates for esterification. By contrast, path A is preferred
MS/MS spectrum showed the release of O2, thus confirming by ortho-substituted aldehydes 3a–d, 3j, and 3k that, however,
oxygen insertion on 4 to be still effective. Pleasantly, it was also give the corresponding acids with lower efficiency (24–45%).
possible to detect and characterize the crucial intermediate 10e of
We would like to stress that the mechanistic picture of
the oxygenative mechanism (path B), which was intercepted as a Scheme 2 is proposed for imidazolium type catalysts and
doubly charged ion at m/z 215. The MS/MS spectrum of 10e that paths A and B coexist in most of the investigated cases.
enlightened us about its structure since the observed fragments As imidazolinium-, triazolium-, and thiazolium-based protocols
were the acyl cation (m/z 183) and the singly charged catalyst 2 have also been reported for the aerobic oxidation of aldehydes,3,5a
(m/z 247; Fig. S16, ESI†). It is worth emphasizing that all further investigation on these systems is currently underway using
aldehydes having preference for ester over acid formation the charge-tag strategy.
showed the presence of the related acyl intermediate 10 and
traces of the oxidized Breslow species 8, while the detection of 8
in high relative abundance (Table 1, columns 4 and 5) was
distinctive for preferential acid production.
Notes and references
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Few mechanistic considerations would be appropriate in light of
these results. Nucleophilic addition of carbene 2 to aldehyde 3,
irrespective of its electronic and steric features, results in the
formation of the Breslow intermediate 4. This new nucleophile then
intercepts molecular oxygen affording the zwitterionic peroxide 5.
In analogy with Studer et al.,3c we suggest for this step oxidation of 4
Int. Ed., 2012, 51, 314; (c) H. U. Vora and T. Rovis, Aldrichimica Acta,
2011, 44, 3.
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(a) S. De Sarkar, A. Biswas, R. C. Samanta and A. Studer,
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3 (a) L. Mohlmann, S. Ludwig and S. Blechert, Beilstein J. Org. Chem.,
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+
by O2 to give the radical cation [4]ꢁ and the superoxide radical
anion [O2]ꢁꢀ. Accordingly, we calculated the structure of the
+
complex between [4]ꢁ and [O2]ꢁꢀ at the DFT level. The optimized
structures for 4a and 4e along with spin densities are shown in
Fig. 3. We found that a fraction of the [O2]ꢁꢀ spin density spreads
4 The occurrence of the O-alkylation step before O2 insertion has also
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+
ꢀ
Fig. 3 Complexes between [4]ꢁ and [O2]ꢁ (Ar = 2-Br-Ph, left; and Ar =
4-Br-Ph, right. For model simplification, R1 = R2 = Me). The threshold value
of the spin density is 0.03 a.u. The spin densities, calculated using the
Mulliken population analysis, on the C-atom next to the OH group are
+
+
0.149 and 0.140 a.u. ([4a]ꢁ and [4e]ꢁ respectively). The total spin
densities on [4a]ꢁ and [4e]ꢁ are 0.260 and 0.262 a.u., respectively.
+
+
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A. Massi, Tetrahedron, 2011, 67, 8110; (e) O. Bortolini, A. Cavazzini,
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56, 9375. Attempts to intercept and characterize intermediate 6
were unsuccessful; the possibility of a reaction between 4 and 5 as
suggested in ref. 2b cannot be ruled out.
¨
7 (a) K. G. Stirk and H. I. Kenttamaa, J. Am. Chem. Soc., 1991,
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Wiley-VCH, Weinheim, 2010; (b) G. W. Amarante, M. Benassi,
H. M. S. Milagre, A. A. C. Braga, F. Maseras, M. N. Eberlin and
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Reaction of 3e with equimolar 1 at 25 1C (72 h): 7e (28%), 11e (45%).
Background oxidation of 3a–i under optimized conditions are
reported in Table S1 (ESI†).
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