Formation, Oxidation, and Fate of the Breslow Intermediate in the N-Heterocyclic Carbene-Catalyzed Aerobic Oxidation of Aldehydes

Article abstract of DOI:10.1021/acs.joc.6b02414

The reaction paths and intermediate structures related to the formation of the Breslow intermediate and its oxidation along the oxidative/oxygenative lanes have been studied from a mechanistic point of view, with the support of gas-phase and computational studies. The results confirm the occurrence of a single-electron transfer from the Breslow intermediate to the molecular oxygen with formation of a radical couple that recombines either as a peroxide anion 7′ to afford the aldehyde-to-carboxylic acid product or as a hydroperoxy derivative 7″ that evolved into an electrophilic acyl azolium, opening to the aldehyde-to-ester conversion. Steric factors enter into determining the different reactivity. All of the intermediates of both catalytic paths have been observed and characterized under mass spectrometric conditions. In particular, for the imidazoline catalyst, the (+)ESI-MS/(MS) detection of the genuine Breslow intermediate was made possible in virtue of its limited reactivity. Mechanistic aspects of the N-heterocyclic carbenes catalyzed aerobic oxidation of aldehydes shares important similarities with that one of the recently revisited benzoin condensation.

Full text of DOI:10.1021/acs.joc.6b02414

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Article
Formation, oxidation and fate of the Breslow intermediate in the N-
heterocyclic carbenes catalyzed aerobic oxidation of aldehydes
Olga Bortolini, Cinzia Chiappe, Marco Fogagnolo, Alessandro Massi, and Christian Silvio Pomelli
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02414 • Publication Date (Web): 14 Dec 2016
Downloaded from http://pubs.acs.org on December 14, 2016
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Formation, oxidation and fate of the Breslow intermediate in the Nꢀheterocyclic
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1
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carbenes catalyzed aerobic oxidation of aldehydes
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,
‡
†
‡
‡
Olga Bortolini,* Cinzia Chiappe, Marco Fogagnolo, Alessandro Massi, and Christian Silvio
,†
Pomelli*
‡
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-
19, 44121 Ferrara, Italy E-mail olga.bortolini@unife.it
†
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy E-mail:
christian.pomelli@gmail.com
H
O
H
Me
Br
PhCHO
Me
O
O
Br
O
O
N
N
N
N
H
O
O
Me
Me
PhCOOH
Ar
Me
O
Me
O
2
N
N
ortho-substitued: oxygenative path
OH
Ar
N
SET
N
H
O
Me
O
Me
Me
Me
O
O
N
N
N
N
HOO
Br
Me
Me
Br
para-substitued:oxidative path
Abstract
The reaction paths and the intermediate structures related to the formation of the Breslow intermediate
and its oxidation along the oxidative/oxygenative lanes have been studied from a mechanistic point of
view, with the support of gas phase and computational studies. The results confirm the occurrence of a
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single electron transfer from the Breslow intermediate to the molecular oxygen with formation of a
radical couple, that recombines either as a peroxide anion 7’ affording the aldehyde-to-carboxylic acid
product, or as a hydroperoxy derivative 7’’ that evolved into an electrophilic acyl azolium, opening to
the aldehyde-to-ester conversion. Steric factors enter into determining the different reactivity. All the
intermediates of both catalytic paths have been observed and characterized under mass spectrometric
conditions. In particular, for the imidazoline catalyst, the (+)ESI-MS/(MS) detection of the genuine
Breslow intermediate was made possible in virtue of its limited reactivity. Mechanistic aspects of the
N-heterocyclic carbenes catalyzed aerobic oxidation of aldehydes shares important similarities with
that one of the recently revisited benzoin condensation.
0
1
2
3
4
5
6
7
8
9
0
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Introduction
N-heterocyclic carbenes (NHCs) are a peculiar class of organic compounds widely employed as ligands
for the ability to coordinate transition metals and as catalysts for the aptitude to bind to carbon
1
electrophiles. As organocatalysts NHCs display the remarkable capability to promote the polarity
reversal of specific functional groups, in particular aldehydes. This umpolung effect has been explored
in many organic transformations most of them involving the initial nucleophilic attack of the carbene 1
2
to the carbonyl group of 2 (Scheme 1). As proposed by Breslow, along the lines of the Lapworth’s
3
4
5
6
cyanide mechanism, an intramolecular, intermolecular or solvent mediated proton transfer in the
adduct 3 generates the amino enol 4, known as Breslow intermediate, which is nucleophilic at the C(1)
7
,8
carbon. Subsequent nucleophilic attack to a second aldehyde molecule with formation of a new C-C
bond and release of the NHC catalyst affords the benzoin product 6.
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O
O
N
1
Ar
OH
Ar
H
Ar
2
Y
X
6
1
N
Ar OH
N
O
2
H
Y
O
Y
10
11
12
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56
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58
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60
X
X
Ar
Ar
H
5
umpolung
event
3
O
N
X
OH
Ar
2
1
Ar
H
Y
2
4
Scheme 1. Commonly proposed mechanism for the benzoin condensation.
Although postulated in 1958 the first successful generation of the amino enol 4 from aldehydes and
9
carbenes and its characterization by in situ NMR spectroscopy was reported only in 2012. Studies on
the observation and evaluation of the nucleophilicity of related deoxy and methoxy Breslow-like
10,11
compounds,
as well as the characterization of sila-Breslow intermediates have been also carried
12
out.
This prominent chemistry, of which the benzoin condensation and Stetter reaction are the archetypal
examples, has been recently enriched with oxidative protocols for the direct construction of different
1
3
classes of compounds, principally acids, esters, and amides. All these oxidative NHC-mediated
reactions share a common key event, represented by the oxidation of the Breslow intermediate 4, that
occurs in the presence of inorganic or organic oxidants, including O . In the majority of cases, 4 is
2
converted into the corresponding electrophilic acylazolium ion 10, that may be easily intercepted by
1
4
nucleophiles, however not all the oxidations necessarily proceed in this direction. When oxygen is
used as oxidant, activation of O can occur with formation of the complex 7 that after radical
2
recombination may evolve to the peroxide anion 7’ or to the hydroperoxy intermediate 7’’ (Scheme 2).
In a recent mass spectrometric investigation on the NHC-catalyzed oxidative transformation of
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5
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6
aldehyde substrates, the isobaric intermediates 7’ and 7’’ have been intercepted and their reactivity
1
4a
characterized. Depending on steric factors, the complex 7 is prone to evolve to the intermediate 8 by
reaction of 7’ with an additional aldehyde molecule in a process reminiscent of the Baeyer Villiger
oxidation. The rearrangement of 8 gives rise to a carboxylic acid and the oxo-Breslow 9 that completed
the cycle by reforming the NHC catalyst 1 through release of a second molecule of acid (oxygenative
path). Alternatively, 7 converts into the acylic cation equivalent 10, through the intermediate 7’’, with
liberation of the hydroperoxy anion, (oxidative path).
0
1
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9
0
O
O
N
Nu
HO
H
Ar
Y
Ar
X
Nu
1
O
OH
N
X
O
Ar
Y
Ar
2
N
X
O
O
9
HO
Y
OH
N
Ar
Ar
1
0
Y
X
Ar
Ar
O
4
OH
H
N
X
oxidative
path
oxygenative
path
O
2
O
Y
O
Ar
HOO
8
N
X
OH
Ar
2
Y
O
2
O
OH
O
N
N
OH
O
7
Y
O
Y
X
X
Ar
''
Ar
7
7'
Scheme 2. Proposed mechanisms for the NHC-catalyzed aerobic oxidation of aldehydes (oxygenative and oxidative paths).
Despite the efforts to observe the genuine Breslow intermediate 4 in gas phase, however, all attempts
1
2,14a,15,16
met with failure.
In the present study we approached the problem by playing on the different reactivity of the NHC
catalysts both in solution and gas-phase, in parallel with computational studies. In particular, we
investigated the detailed mechanism of formation of the Breslow intermediate and its oxidation along
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the oxygenative/oxidative paths, explaining the key factors that control the formation of the peroxidic
4
5
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9
1
1
1
1
1
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4
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4
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5
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5
5
5
6
species 7’ and 7’’ via a single-electron-transfer (SET) process with O and their evolution toward the
2
observed divergent reactivity under aerobic conditions. Gas phase studies and theoretical calculations
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
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9
0
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8
9
0
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2
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4
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6
7
8
9
0
17
unequivocally support the involvement of an oxidative SET during the activation of molecular
oxygen and the proposed mechanism shares important similarities with that one of the recently
8
a
revisited benzoin condensation.
Results and Discussion
The possibility to study a reaction in gas phase is intimately linked to the presence of charged species.
Since all the intermediates involved in the catalytic cycles depicted in Scheme 2 are neutral, suitable
carbene precursors bearing a charged moiety for mass spectrometric detection are required. Bis-
diazolium derivatives are particularly appropriate for the role and therefore we synthesized the N-
methylated 1,1’-(hexane-1,6-diyl) azolium salts of the most common heterocyclic scaffolds imidazole
1
1a, imidazolinium 11b, triazole 11c and the thiazole compound 11d, in combination with different
-
-
counterions i.e.Tf N , PF , glutarate (Scheme 3). The dual role of these bis-azolium derivatives is that
2
6
12, 14a,18
of precursors of the carbene catalysts 1aꢀd and, in the meanwhile, of charge-tags.
N
N
N
N
N
N
5
N
N
X
N
1
1a
Y
X
N
Y
5
base
1
1b
N
+
N
N
N
N
N
N
5
5
1 a-d
N
11c
N
Y
X
S
S
11d
Scheme 3. Structure of the NHC catalysts used in the study. The azolium salts have been numbered on the basis of the
heterocycle typology, independently from the anionic counterpart.
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5
6
Oxidative conversion of ortho- 2’ and para-bromo-benzaldehydes 2’’ and ESI MS investigation
As anticipated, during the oxidative conversion of aromatic aldehydes using 11a as pre-catalyst in
THF-MeOH (2:1) and DBU as base, we observed a significantly different product distribution
switching between ortho-substituted and para-substituted benzaldehydes. As an example the ratio
between methyl ester/carboxylic acid changes from 5:47 to 89:11, ongoing from ortho-bromo- 2’ to
para-bromo-benzaldehyde 2’’. Hence our investigation commenced with the evaluation of the activity
of the different azolium catalysts 1aꢀd in solution, using 2’ and 2’’ as exemplary substrates. Table 1
collects the results that pertain to the oxidation of the ortho derivative.
0
1
2
3
4
5
6
7
8
9
0
1
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9
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0
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9
0
a
Table 1. Oxidation–esterification of aldehyde 2’.
Br
O
Br
O
Br
O
11a-d (1 equiv.)
DBU (1.1 equiv.)
OMe
H
OH
+
THF-MeOH (2:1), 4 Å MS
air, 55 °C, 16 h
2'
b
Entry
NHC
Unreacted
Acid
Ester
c
c
c
2
’ (%)
18
(%)
(%)
1
2
3
4
5
6
1a (X= PF
6
)
41
47
5
5
5
1a (X= glutarate)
12
1b (X= PF
1c (X= PF
1c (X= Tf
1d (X= PF
6
)
91
-
6
)
23
19
17
21
21
25
8
2
N)
16
6
)
24
a
b
See the Experimental Section for details. Obtained from the corresponding
c
precursors 11aꢀd associated with different anions X. Isolated yield.
Collectively, the oxidative reaction of 2’ is low yielding and the conversion of the substrate never
reaches completeness, also after 16 h reaction time. Notable however, is the acid-over-ester formation
found for 1a, 1b and 1d, whereas 1c resulted the less selective, affording almost equal amounts of acid
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and ester (entries 4, 5). These findings are consistent with literature data reporting discrete amounts of
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ester formation during the oxidative conversion of ortho-substituted aromatic aldehydes in the presence
1
4
of triazolium pre-catalysts. The catalysts activity sequence is in the order: imidazole, triazole, thiazole
and imidazoline derivative 1b, as the poorest reactive catalyst (entry 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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4
5
6
7
8
9
0
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2
3
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9
0
Para-bromo benzaldehyde 2’’ turned out to be more reactive than the ortho-substituted counterpart,
affording good to excellent yields of the methyl ester, as shown in Table 2. The limited catalytic
activity of 1b is confirmed also in this case, opening to the direct observation and characterization of
the Breslow intermediate 4b, as discussed later on. Furthermore, the results indicate a minor effect of
n-
the azolium salt anion X , either singly or doubly charged, on the reaction.
a
Table 2. Oxidation–esterification of aldehyde 2’’.
O
O
O
11a-d (1 equiv.)
DBU (1.1 equiv.)
OMe
H
OH
+
Br
THF-MeOH (2:1), 4 Å MS Br
air, 55 °C, 16 h
Br
2''
b
Entry
NHC
Unreacted
Acid
Ester
c
c
c
2’ (%)
(%)
(%)
1
2
3
4
5
6
7
1a (X= PF
1a (X= glutarate)
1a (X= Tf N)
1b (X= PF
1c (X= PF
1c (X= Tf
1d (X= PF
6
)
22
-
18
11
14
2
60
89
75
10
89
93
77
2
11
88
-
6
)
6
)
11
7
2
N)
-
6
)
-
23
a
b
See the Experimental Section for details. Obtained from the corresponding
c
precursors 11aꢀd associated with different anions X. Isolated yield.
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1
1
1
1
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1
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2
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2
2
2
2
2
3
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The results shown in Tables 1 and 2 documented the divergent oxidative reactivity of substituted
aromatic aldehydes for all the most commonly used NHC catalysts as dependent on the position of the
1
9
substituent on the aromatic ring.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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5
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7
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9
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1
2
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0
1
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3
4
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7
8
9
0
In the mechanistic proposal depicted in Scheme 2 the pivoting intermediates in this oxidative
transformation are the peroxidic Breslow derivatives 7’ and 7’’, formed from the Breslow intermediate
4
by addition of molecular oxygen. This activation is believed to proceed via a single electron-transfer
.+
(
SET) processes with O , to give the complex 7 formed by the radical cation [4] and the superoxide
2
.
-
20
radical anion [O ] , that recombine affording 7’ or 7’’. We have calculated the structure of the
2
.
+
.-
.+
complex between [4] and [O ] and found that a fraction of the oxygen spin density spreads on [4] ,
2
mainly on the C(2) atom (see computational discussion section for details). The peroxo Breslow
intermediates are characterized by a divergent reactivity either as a peroxide anion 7’ affording the
aldehyde-to-carboxylic acid product or as hydroperoxy derivative 7’’ with the formation of the ester
product. This dual reactivity is earmarked by specific intermediates that should be observed in gas
phase: the elusive Breslow 4, the isobaric peroxidic derivatives 7’/7’’, common species of the overall
mechanism, and either the oxo Breslow 9 or the acyl intermediate 10 that should be preferably
intercepted when the oxygenative or oxidative paths of Scheme 2 are occurring. Table 3 collects the
relative amounts of the mentioned intermediates, as observed by (+)-ESI-MS experiments carried out
using aldehydes 2’ (entries 1-4) and 2’’ (entries 5-8).
The mass spectrometric results are fully consistent with the reactivity found in solution. With the ortho-
substituted benzaldehyde 2’ all the catalyst typologies afford consistent amounts of the oxo Breslow
9
aꢀd suggestive of the preferred acid formation. On the other hand, this same intermediate is barely
detectable with para-bromo benzaldehyde 2’ in favor of the formation of the acyl species 10aꢀd. The
triazole-based catalyst 1c is the only example for which the acyl intermediate 10c and 9c coexist,
indicating the concurrent presence of both reactivities, as actually found.
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1
1
1
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1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3. Occurrence of the most important intermediates detected in (+)-ESI-MS spectra of solutions containing ortho-
a,b,c,d
bromo 2’ or para-bromo benzaldehyde 2’’ and the selected catalyst 1, using DBU as base.
Entry
NHC
Aldehyde
H
O
N
X
O
N
X
OH
Ar
N
X
OH
N
X
O
O
Y
Y
Y
Y
O
Ar
Ar
Ar
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
1
0aꢀd
4aꢀd
9
aꢀd
7’/7’’aꢀd
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1b
1c
1d
2’
2’
⊗
⊗
+
⊗
+
+++
++
+
+
+
⊗
2’
⊗
⊗
⊗
⊗
⊗
⊗
2’
⊗
+
++
+/-
+/-
+/-
+
+/-
+/-
⊗
2’’
2’’
2’’
2’’
+/-
d
++
⊗
+
⊗
a
b
c
See the Experimenatl Section for details. The charge-tag portion has been omitted for clarity.
⊗ Not detected, relative
d
abundance of the MS signal: below 2% (+/-), up to 10% (+); up to 50% (++); up to 100% (+++). For more MS and
MS/MS details and spectra carried out in the absence of MeOH see S.I.
A remarkable result of this study is the detection of the genuine Breslow intermediate 4b made possible
by the limited reactivity of 1b, as shown in Figure 1. It is well established in fact that the saturation of
9
a,11b
C(4)-C(5) bond precludes aromatization, giving to the Breslow intermediate a higher stability.
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Figure 1. Expanded section of the (+)ESI-MS full scan of solutions containing ortho-bromo benzaldehyde 2’, 11b as
precursor catalyst and DBU, dissolved in THF-MeOH (2:1)
To our knowledge, there are only two earlier attempts to intercept and characterize the Breslow
16
intermediate using mass spectrometric techniques. Glorius and coworkers reported the formation of a
protonated Breslow-like complex formed from an imidazolium derivative and an α,β-unsaturated
15
aldehyde as model for the “conjugate” umpolung. The group of Lee described the formation of an
adduct between a thiazolium carbene containing a sulfonate charge tag and benzaldehyde. In this latter
case, the easy release of the benzaldehyde with re-formation of the NHC catalyst observed in the
MS/MS spectrum is more consistent with an addition product prior to the proton transfer, similar to 3
1
2
79
of Scheme 1. In the MS/MS spectrum of 4b (m/z 435 Br), by contrast, the dissociation back to
catalyst 1b (m/z 251) and aldehyde 2’ represents a marginal fragmentation path, attesting a solid
connection, likely a double bond, between the carbene and the aldehyde. The cleavage of the
imidazolinium ring is the relevant event of this MS/MS spectrum, affording the ions at m/z 253 and
2
40 respectively, Figure 2 and Scheme 4.
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9
Figure 2. (+)ESI-MS/MS spectrum of the ionic species at m/z 435 ( Br)
Recent studies have proved the occurrence of the keto tautomer of the Breslow intermediate 12b under
specific conditions, as the azole ring typology and a suitable substitution of the heterocyclic
9
b,21
nitrogen(s).
According to its structure, ion 12b would presumably dissociate in the MS/MS
+
experiment by release of the acyl cation (Br-C H -CO ) at m/z 183, that however was observed in very
6
4
low relative abundance. By contrast, our results are fully consistent with the classical enol structure of
the Breslow intermediate.
m/z 240
N
N
m/z 253
N
N
N
5
N
H
N
5
Br
O
Br
N
HO
4b
12b
Scheme 4. Major fragmentation patterns observed in the MS/MS spectrum of 4b and structure of the keto form of the
Breslow intermediate 12b.
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Formation and fate of the Breslow intermediate: the computational approach
To obtain reliable information from a computational study of chemical reactivity in solution it is
fundamental to define adequately the model system. Since the charged moiety of the tagged NHC 1aꢀd,
is located far from the reactive site, in order to reduce the computational cost the charged catalyst 1aꢀd
has been replaced with the simpler N,N-dimethyazolium structure (black portion in Scheme 3).
0
1
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9
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0
22
Furthermore, in the framework of the supermolecular approach, widely used in the ionic liquids field ,
we have included five explicit methanol molecules in our model system considering the role that a
protic solvent can play in a reaction involving proton transfer and charge reorganization. The five
molecules were collocated as follows: one localized in the central part of the reaction site: i.e. hydrogen
bonded to the C2 carbon of the carbene catalyst; two methanol molecules were hydrogen bonded to the
aldehyde carbonyl oxygen (O1); and two positioned near the bromine substituent on the phenyl ring.
2
3
All calculations has been performed using the Terachem 1.50 package . The B3LYP/6-311++G(d,p)
2
4
level of theory. Dispersion corrections according to D3 Grimme scheme has been included. All
optimized geometries are reported in Supporting Information.
The first step of the reaction is the addition of the heterocyclic carbene to the carbonyl group of the
ortho-bromo benzaldehyde 2’. An encounter complex (EC(1aꢀd+2’)) for each heteroazolium has been
designed arranging the two reagent rings (azol-2-ylidene and phenyl) facing each other and the reacting
centres (carbonyl and carbene) as close as possible. After structures optimization, the distances
between the carbene carbon (C2) and the aldehyde carbonyl carbon (C1) resulted 3.54 Å. These
optimized structures have been taken as the zero energy point (reference). The intermediate 3’ (where
the apostrophe refers to the complex obtained starting from ortho-substituted benzaldehyde 2’) with a
new single covalent bond between C1 and C2, was obtained starting from the optimized encounter
complexes reducing, step by step, the C1-C2 distance and re-optimizing each time the structure. This
procedure allowed obtaining the starting and ending point of the first reaction step. These two points
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has been used to calculate the reaction path applying the nudged elastic band procedure (NEB). This
reaction path is characterized by the formation of the new C-C bond and by the contemporaneous shift
of the methanol molecule, hydrogen bonded to C2 carbene atom, towards one of the methanol
molecules coordinated to the aldehyde carbonyl oxygen, O1. To complete the formation of the Breslow
intermediate 4’ the hydrogen atom, still bonded to C1 in 3’, must be transferred to the negatively
charged oxygen. This transfer is not direct but mediated by two methanol molecules, as shown in
Figure 3.
4
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0
1
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3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Geometrical arrangement of the methanol mediated proton transfer that transforms the intermediate 3’ into the
Breslow intermediate 4’. The apostrophe refers to the complex obtained starting from 2’. The O-H bonds involved in this
rearrangement are represented as dotted lines.
The hydrogen atom at C1 migrates to the nearby methanol molecule which, in turn, transfers its
hydrogen atom to a second methanol molecule that, finally, donates a proton to quench the negatively
charged alkoxide. The whole process is synchronous. The NBO analysis, reported in Table 4, confirms
that the transformation of the aldehyde group into the corresponding enol is characterized by the
transfer of some charge to the azol-2-ylidene ring, inverting the polarity of the C1 carbon. Only a
limited amount of charge migrates to the substituted phenyl ring. On the other hand, transfer of the
alcoholic protons occurs without alteration in their polarity.
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The relevant energetic parameters of the entire process are summarized in Table 4 and Figure 4.
Additional information and absolute energies may be found in S.I.. The addition of carbene 1aꢀd to
ortho-bromo benzaldehyde 2’ TS (1+2’→3’) is particularly favored with imidazole and triazole
0
1
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c
derivatives, whereas the most stable adduct 4’ refers to imidazoline, in line with literature data. This
is a particularly relevant information in agreement with the observation of this key intermediate in gas
phase. Overall process of the formation of 4’ is exothermic.
-1
Table 4. Relative free energies (KJ mol ) for the formation of the Breslow intermediate between o-Br-benzaldehyde 2’ and
carbenes 1aꢀd.
∆
E*
Imidazole
Thiazole
Triazole
Imidazoline
direct
inverse
direct
inverse
direct
inverse
direct
inverse
1+2’→3’
14.1
106.4
21.0
86.9
9.3
66.0
60.4
38.7
116.4
105.0
3
’→4’
85.9
37.1
87.4
87.9
83.2
113.4
∆
E
3
4’+ O →7’(t)
-214.1
-161.3
-30.6
-222.1
-24.6
-178.4
-18.8
2
7
’(t)→7’(s)
-78.9
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Figure 4. Energy profile for the transformations 1aꢀd→7’ and 1a→7”. Chemical structures for intermediates are shown.
The profile is in scale. It is remarkable that the path relative to the carbene 1b that is derived from a not aromatic
heterocyclic system (Imidazoline) presents energy barriers very different (and higher) than the ones of the aromatic derived
-1
carbenes 1a,c-d. Energies in KJ mol .
The Breslow intermediate 4’ is now ready to react with oxygen. This step introduces a possible
stereoselection during the complex formation. When the bromine atom is in the ortho position, in fact,
3
there are two possibilities: O enters from the same side (syn) of the bromine atom, or from the
2
opposite one (anti) leading to two different 7’. Both cases have been considered. The two structures
are conformers (through rotation of the phenyl group). The most energetically stable conformer is
always the syn one for all the NHCs considered in this study thus only this conformer is reported in
Table 4.
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A parallel computational sequence has been done also for para-bromo benzaldehyde 2’’ and the two
sets of calculations have been compared. Figure 5 and Table 5 report the pertinent results, using the
imidazolium based NHC 1a as exemplary catalyst. The most distinctive feature in the reaction
pathways characterizing the two substrates 2’ and 2’’ relates to the significant difference of the
0
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3
intermediates arising in the activation of O . In the two ortho syn/anti adducts, O bonds the C(1)
2
2
atom leading to a superoxide like structure 7’, while in the case of para-bromobenzaldehyde the proton
is removed from the OH group bounded to the same carbon atom leading to a hydroperoxidic structure
7’’. The non-existence of the other structures has been verified computationally. Ortho arrangements
for other NHCs, considered in this paper, present the same structure.
-1
Table 5. Relative free energies (KJ mol ) for the formation of the Breslow intermediate between o-Br-benzaldehyde 2’ or
p-Br-benzaldehyde 2” and carbene 1a
E* Ortho
inverse
106.4
49.9
.
∆
Para
inverse
100.8
49.6
direct
14.1
66.9
Ortho
direct
27.5
1
+2→3
3→4
100.1
∆
E
Para
syn
anti
3
3
4
+ O →7’(t)
-214.1
-78.9
-212.3
4.1
4+ O
2
→7’’(t) -317.4
-0.2
2
7’(t)→7’(s)
7’(t)→7’’(s)
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Figure 5. Energy profile for the transformations 1a→7’ and 1a→7”. Chemical structures for intermediates are shown. The
profile is in scale. This profile shows the different reactivity of ortho (2’) and para (2”) substituted substrates. It shows also
-1
that the attack of the oxygen molecule to 4’ occur from the same side of the bromine substituent. Energies in KJ mol .
Therefore, it is evident that the position of the bromine atom on the aldehyde phenyl ring dramatically
affects the chemical behavior of the Breslow intermediate 4 in the oxidation process. However, to
obtain further information about this phenomenon we have analyzed the electronic structure of the
3
14a
4+ O complexes. In our previous paper, we reported the spin distribution for a solvent-less model.
2
The new calculations confirm the transfer of an electron from the Breslow intermediate to the oxygen
fragment as first stage of the oxidation process. With respect to the orbitals hosting the two unpaired
electrons, the one having higher energy, is localized on the Br-C H fragment. Calculations performed
6
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at the same level of theory on bromobenzene show that this orbital correspond to the HOMO orbital of
bromobenzene in the case of the two conformers of the ortho isomer and to the LUMO+1 orbital for
the para isomer. Bromobenzene orbitals are reported in the bottom of Figure 6, for a visual
comparison. In particular, in the case of the para isomer there is a component of the orbital that is
localized on the C1 atom directly bonded to the aromatic ring. The orientation of this orbital, as well as
the dimension of the orbital lobe localized on the bromine atom, depends on the bromine position and
therefore they are different for the two considered compounds. On the other hand, also the other spin-
unpaired orbital is significantly different in the para-complex with respect the ortho one: it is localized
on the O-O fragment and on the nearby methanol molecule in the para complex, and is spread on the
O-O, OH and imidazolic fragments in the ortho isomer.
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
Figure 6 Geometrical structures of 4+ O complexes: anti-ortho (top/left), syn-ortho (top/right) and para (bottom/left).
2
Orbitals with unpaired electrons are shown (threshold value: 0.03 a.u.). For comparison purposes, the HOMO (top) and
LUMO+1 (bottom) orbitals of bromobenzene are also reported.
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Consequently, it is possible to state that the different position of the bromine atom on the phenyl ring
changes the orientation of the molecular orbitals localized on this region changing qualitatively the
electronic structure of 7’(t)/7’’(t). This feature determines the geometry and reactivity of the system.
Although the presence of the same substituent in ortho and para position is generally thought to exert a
similar electronic effect, the case here considered breaks only apparently this well-established concept.
As expected, steric effects are significantly different in the case of ortho and para isomers. Bromine is
a large and electron rich atom that lies far from the reactive moiety of the Breslow complex in the case
of the para isomer and close (or very close for the syn isomer) in the case of ortho-bromo complex.
Furthermore, the orientation and the nature of the single occupied HOMO orbital is affected by the
bromine atom position without any analogy between ortho and para.
6
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0
Since the final products do not have a radicalic nature at some stage of the process an intersystem
crossing process, e.g. a non-radioactive transition from triplet to singlet. The candidate stage is this
one: the triplet state of molecular oxygen is strictly related to its symmetry. When the symmetry is
3
broken (as in almost any reaction of O ) the triplet state become unstable, especially in condensed
2
phase where third bodies processes (e.g. collision with solvent molecules) occurs very easy. We have
optimized the geometries of the two syn/anti ortho conformers and of the para isomers of 7’(s)/7’’(s)
starting from the corresponding triplets. There are only small differences from the geometrical point of
view but the stabilization energies are very different. The difference in energy of the two ortho
conformers diverge significantly. While the 7’(s) anti conformer even is less stable than the
corresponding 7’(t) complex (a situation resembling molecular oxygen) the syn isomer show a
stabilization energy of 78.9 KJ/mol. In the para case there is only a small energetic stabilization related
to the triplet quencing. The less stable anti conformer of ortho 7’(s) complex will not be considered
further in this paper.
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Intermediate 7 is the point of dissection of two mechanisms: the oxidative, leading to an ester, and the
oxygenative to a carboxylic acid. para-Bromobenzaldehyde follows preferentially the oxidative path
through the elimination of a HOO- ion from 7’’(s) and transformation into 10. Dissociation of a
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zwitterion (ion pair) requires a remarkable electrostatic work. In addition, HOO is a very strong base
and nucleophile. However, in a more realistic medium (and therefore model) the presence of species
able to capture this leaving anion could favor the process. Since electrophilic species of this type are
not present in our model system, we decided to try to add a second aldehyde molecule that could act as
a receiver. An encounter complex between 7’’(s) and the added para-bromobenzaldehyde molecule
(7’’(s)+2’’) has been optimized. A second encounter complex, arising from the migration of the HOO-
group from the oxidized Breslow complex to the aldehyde molecule (2’’-OOH) was obtained. The
geometrical structures of the two encounter complexes and of the climbing image are shown in Figure
7
.
Figure 7. From left to right: geometrical structures of EC(7’’(s)+2’’), climbing image and EC(10+2-OOH).
It is to note that the HOO- group migrates with an ancillary methanol molecule. A geometrical
inspection of the structures characterizing this reaction path shows that the leaving anion has to
“circumnavigate” one of the methyl group bonded to the imidazol-2-ylidene ring to reach the other
aldehyde molecule and, at both the extremities of the reaction path, the HOO group forms a five
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membered ring with the carbonyl oxygen and a hydrogen bond with a methanol molecule. From the
electrostatic point of view EC(7’’(s)+2’’) is constituted by two neutral molecules. The NBO analysis
indicates that the complex between the hydroperoxide anion and its ancillary methanol molecule is
about -0.83 while 7’’(s) carries an almost equivalent charge of opposite sign. The final complex is
therefore an ion pair: the opposite charges have a magnitude of 0.88. In 10 almost all the positive
charge is carried out by the imidazolic fragment. EC(10+2-OOH) is less stable than EC(7’’(s)+2’’) of
only 17.73 KJ/mol. The reaction barrier for this process is however considerably high (253.69 KJ/mol),
although the introduction of other explicit solvent molecules, which take into account of all the
solvation effects, could significantly reduce it. The structure of 2’’-OOH is analogous of the hydrate
form of an aldehyde, that could be in rapid equilibrium with the formal reagents aldehyde and HOO-.
Attempts to detect the hydrogen peroxide anion , however, have been unsuccessful.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
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0
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8
9
0
By contrast, the ortho-bromo benzaldehyde 2’ prefers the oxygenative pathway via the nucleophilic
-
attack of the high reactive C-O-O moiety to an external aldehyde molecule, followed by H-transfer,
Scheme 5. This species I, stabilized by the formation of hydrogen bonds with solvent molecules,
undergoes O-O bond breaking as depicted in II to give two new hydrogen bonded molecules, an ortho-
bromo benzoic acid (in blu) and a gem-diol anion (in red) i.e. the oxo-Breslow 9 of Scheme 2, see also
the mass spectrometry section of the S.I.. The removal of the first acid molecule and the further
dissociation of the remaining oxo-Breslow leads to the second molecule of substituted benzoic acid and
to the regeneration of the catalyst. The specific role exerted by the solvent is worthy of note.
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1
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2
2
2
2
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O
CH3
CH3
H O Ar
O
H
Ar
O
H
H
H
O
H
O
O
O
O
N
Br
O
Br
N
N
N
0
1
2
3
4
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6
7
8
9
0
1
2
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9
0
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7
8
9
0
1
2
3
4
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7
8
9
0
CH3
CH3
Ar
O
CH3
H
Ar
H
O
CH3
H
O
O
O
O
H
O
H
H
O
H
H
O
H
O
H
O
O
O
N
Br
O
CH3
N
Br
CH3
N
N
I
II
-
Scheme 5. Final steps of the oxygenative path. Up: The reactive C-O-O moiety attack a second molecule of 2’. The
methanol molecule displaces its hydrogen bond to the new charged center. Down: In a concerted mechanism the cleavage of
the O-O bond in the structure I occur synchronously to a chained transfer of three hydrogen atoms. The nearby bromine
atom has a stabilizing effect. In the final structure II the aldehydic group of the second molecule of 2’ is now oxidized to a
carboxylic one (blue). The oxo-Breslow (red) has lost an oxygen atom and it is ready to be transformed in the second acidic
molecule after the regeneration of the carbenic catalyst. The whole process is a solvent-mediated transfer of a single oxygen
atom or, in other words the oxidation of an aldehyde by a carbene-activated peracid.
It is not surprising, considering the reactivity of 7’ and the well know instability of the –O-O- bridge,
that the whole process is barrierless, except for a small energetic gap (44.19 KJ/mol) after the bridged
intermediate. This is indeed the fast step of the quenching process of the C-O-O- moiety, which in the
other pathway, occurs simultaneously to the oxidation process. Figure 8 displays some geometrical
structures.
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 8. From left to right: Encounter complex between the ortho isomer of 7’ and a second o-bromobenzaldehyde
molecule 2’. –O-O- bridged intermediate (see Scheme 5, first row right), final complex (see Scheme 5, second row, right).
As stated in previous paragraphs the transfer of an electron from the Breslow intermediate to the
molecular oxygen represents the first segment of the oxidation process. The location of the radical on
the organic moiety depends on the position of the bromine substituent on the aromatic ring and
corresponds to the HOMO orbital of ortho-bromobenzene and to the LUMO+1 orbital for the para
isomer. In a recent paper on the coexistence of ionic and radical steps in the benzoin condensation,
8
a
Rehbein and coworkers claimed that ‘the discovered radical intermediates can be understood as a
link between other reactivities that have been exploited for instance in oxidative transformations of
aldehydes via NHC-catalysis’. Our results represent an example of the mentioned oxidative
transformations and this reactivity share important similarities with the benzoin condensation enabling
the proposal for a common mechanism depicted in Scheme 6.
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
benzoin condensation products
O
Ar
H
Ar
2
N
X
OH
N
X
OH
O
Ar
ionic path
Ar
H
0
1
2
3
4
5
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7
8
9
0
1
2
3
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9
0
1
2
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9
0
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9
0
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2
3
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9
0
4
MS/MS
5
O-G
i
radical path
G=C(R)H
H
O
H
N
X
O
G=O
N
O
G
O
Ar
O
X
ii
Ar
13
7'/7''
oxidative/oxygenative products
Scheme 6. Combined N-heterocyclic carbene catalysis with aldehydes under anaerobic (benzoin) and aerobic
oxidative/oxygenative) conditions.
(
The Breslow intermediate 4 is engaged in a single electron transfer (SET) process with an acceptor
(OG = molecular oxygen or aldehyde) to afford a radical-ion pair species 13. The radical couple, held
together through hydrogen bonding, differs in structure but share the same attitude to form a new bond:
O-C in the peroxidic intermediates 7’/7’’ or C-C in the benzoin intermediate 5. The likely existence of
an equilibrium between the genuine Breslow intermediate 4 and both 13 and 7’/7’’ (steps i and ii) is
supported by electrospray mass spectrometric results that indicate the loss of O [7’b→4b] during the
2
MS/MS decomposition of 7’b that starts to be detected for relatively low excitation voltages of c.a. 20
mV, Figure 9. An analogous equilibrium of 4 with 13, in the case G=C(R)H, has been proposed as pre-
8
a
requisite for the concurrence of ionic and radical steps in the classical benzoin condensation.
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7
9
Figure 9. MS/MS spectrum of the peroxo Breslow 7’b at m/z 467 ( Br)
Conclusions
The reaction paths and the intermediate structures related to the formation of the Breslow intermediate
and its oxidation along the oxidative/oxygenative paths have been studied from a mechanistic point of
view, with the support of gas phase and computational studies. The position of the bromine substituent
on the aromatic ring of aldehyde substrate leads to small energetic and structural differences on the
two-step process related to the formation of the Breslow intermediate,
intercepted and characterized as enol structure by ESI-MS/MS experiments. Our calculations confirm
the transfer of an electron from the Breslow intermediate 4 to the oxygen fragment, as first stage of the
.
+
.-
oxidation process. From the recombination of [4] and [O ] , that arise from the SET process, two
2
distinct peroxidic tautomeric structures are formed, as a consequence of the position of the substituent
on the aromatic ring. These structures have a divergent reactivity. The proton displacement, occurring
in the para-bromobenzaldehyde, makes impossible for this isomer to follow the oxygenative path. On
the other hand, we cannot exclude that, for the ortho isomer, this process takes place concurrently to
the bimolecular reaction here reported. The specific role of the solvent (methanol) has been
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1
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2
2
2
2
2
2
2
2
2
3
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4
4
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6
demonstrated. Overall, computational and gas phase results are fully consistent with the reactivity
observed in solution. The proposed mechanism shares important similarities with that one of the
recently revisited benzoin condensation.
0
1
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9
0
1
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9
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0
Experimental Section
Liquid aldehydes were freshly distilled before their utilization. Reactions were monitored by TLC on
silica gel 60 F254 with detection by charring with phosphomolybdic acid. Flash column
1
13
chromatography was performed on silica gel 60 (230-400 mesh). H (400 MHz) and C (100 MHz)
NMR spectra were recorded in D O or DMSO-d solutions at room temperature. Peaks assignments
2
6
1
1
were aided by H- H COSY and gradient-HMQC/HMBC experiments.
1
,1'-(Hexane-1,6-diyl)bis(3-methyl-1H-imidazolium)bromide 11a(Br2).
1
-Methylimidazole (1.50 g, 18.3 mmol) and 1,6-dibromohexane (1.78 g, 7.30 mmol) were first mixed
at room temperature for 20 min and then heated at 100 °C for 2 h. The resulting mixture was cooled to
room temperature, triturated with Et O, and filtered. The resulting white solid was stirred for 1 h in
2
EtOAc (15 mL), filtered, and dried in vacuo. The desired salt 11aꢀBr (77%, 2.30 g) was obtained as an
1
amorphous solid. H NMR (400 MHz, D O): δ = 8.60 (s, 2 H, 2 NCHN), 7.35 (m, 4 H, 2 NCHCHN),
2
4
.04 (t, 4H, J = 7.2 Hz, 2 NCH ), 3.74 (s, 6 H, 2 NCH ), 1.72 (m, 4 H, 2 NCH CH ), 1.19 (br s, 4 H, 2
2 3 2 2
1
3
1
NCH CH CH ); C{ H} NMR (100 MHz, D O): δ = 135.7 (NCHN), 123.4 (CH N), 122.1 (CH N),
2
2
2
2
2
2
+
4
9.3 (CH N), 35.6 (CH N), 29.0 (CH ), 24.7 (CH ). HRMS for [11a(Br)] C H N Br found 327.1180
2 3 2 2 14 24 4
calc. 327.1179.
1
,1'-(Hexane-1,6-diyl)bis(3-methyl-4,5-dihydro-1H-imidazolium)bromide 11b(Br2).
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1
-Methyl-4,5-dihydro-1H-imidazole (1.50 g, 17.8 mmol) and 1,6-dibromohexane (1.90 g, 7.80 mmol)
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
were first mixed at room temperature for 20 min and then heated at 100 °C for 3 h. The resulting
mixture was cooled to room temperature, dissolved in EtOH (15 mL), precipitated by the addition of
Et2O, decanted, and dried in vacuo. The desired salt 11bꢀBr (68%, 2.20 g) was obtained as a sticky
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
solid. H NMR (400 MHz, D O): δ = 8.34 (s, 2 H, 2 NCHN), 3.97 (br s, 8 H, 2 NCH CH N), 3.50 (t, 4
2
2
2
H, J = 7.1 Hz, 2 NCH ), 3.19 (s, 6 H, 2 NCH ), 1.72 (m, 4 H, 2 NCH CH ), 1.42 (m, 4 H, 2
2
3
2
2
13
1
NCH CH CH ); C{ H} NMR (100 MHz, D O): δ = 159.1 (NCHN), 51.6 (CH N), 49.7 (CH N), 48.9
2
2
2
2
2
2
+
(
CH N), 35.1 (CH N), 27.9 (CH ), 26.7 (CH ). HRMS for [11b(Br)] C H N Br found 331.1492
2 3 2 2 14 28 4
calc. 331.1492.
4
,4'-(Hexane-1,6-diyl)bis(1-methyl-1,2,4-triazolium)bromide 11c(Br2).
To solution of 1-methyl-1,2,4-triazole (810 mg, 0.01 mol) in acetonitrile (5 ml), cooled in an ice bath,
,6-dibromohexane (1.2 g, 0.05 mol) was added. After the addition was complete, the ice bath was
1
removed, and the reaction mixture was stirred at reflux temperature for 24 hours and then concentrated.
The resultant white solid, 3,3’dimethyl-1,1'-(hexane-1,6-diyl)-1,2,4-ditriazolium bromide 11cꢀBr, was
1
washed with ether (3 x 50 ml) and dried under vacuum for 1 hour. H NMR (D O): δ = 9.77 (s, 2 H),
2
13
1
8.85 (s, 2 H), 4.32 (q, J=7.3 Hz, 4 H), 4.12 (s, 6 H), 1.93 (m, 4 H), 1.41 (m, 4 H). C{ H} NMR (100
+
MHz, D O): δ = 144.4, 142.1, 47.9, 38.5, 28.5, 24.5. HRMS for [11c(Br)] C H N Br found
2
12 22
6
329.1087 calc. 329.1084.
3
,3'-(Hexane-1,6-diyl)bis(4-methylthiazolium)bromide 11d(Br2).
4
-Methylthiazole (1.80 g, 18.3 mmol) and 1,6-dibromohexane (1.78 g, 7.30 mmol) were first mixed at
room temperature and then heated at 100 °C for 4 h. The resulting mixture was cooled to room
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9
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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temperature, triturated with Et2O, and filtered. The resulting white solid was stirred for 1 h in EtOAc
(15 mL) filtered and dried in vacuo. The desired salt 11dꢀBr was obtained (74 %, 2.40 g) as an
1
amorphous solid. H NMR (400 MHz, D O): δ = 9.68 (d, 2 H, J = 2.1 Hz, 2 NCHS), 7.66 (br s, 2 H, 2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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9
0
SCH), 4.30 (t, 4 H, J = 7.6 Hz, 2 NCH ), 2.43 (s, 6 H, 2 CH ), 1.82 (m, 4 H, 2 NCH CH ), 1.30 (m, 4
2
3
2
2
13
1
H, 2 NCH CH CH ); C{ H} NMR (100 MHz, D O): δ = 156.9 (NCHS), 146.6 (CN), 120.8 (CHS),
2
2
2
2
+
5
2.8 (CH N), 28.5 (CH ), 24.9 (CH ), 12.4 (CH ). HRMS for [11d(Br)] C H N S Br found
2
2
2
3
14 22
2 2
3
61.0404 calc. 361.0402.
General procedure for counterion exchange in azolium salts 11aꢀd(Br2).
The selected dibromide salt 11aꢀd(Br ) (1.22 mmol) was dissolved in a minimal amount of water and
2
saturated aqueous solution of potassium hexafluorophosphate or lithium bis(trifluoromethane-
sulfonyl)imide (2.50 mmol) was added. The reaction mixture was stirred at room temperature for one
day. The aqueous layer was decanted and the remaining layer was dissolved in dichloromethane,
washed with water (6 x 100 ml), until the AgNO3 test on the aqueous phase was completely
negative. The organic solvent was removed in vacuo, and the resultant liquid dried under high vacuum.
-
In all case, ESI-MS spectra confirmed that Br , arising from not completely conducted reactions, were
not detectable in the samples arising by exchange reactions.
General procedure for the aerobic oxidation of aldehyde 2’/2’’ catalyzed by 11aꢀd(X2).
A mixture of aldehyde 2’ or 2’’ (0.40 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (66 ꢀL, 0.44 mmol),
azolium salt 11aꢀd(X ) (0.40 mmol), activated 4-Å powdered molecular sieves (100 mg), anhydrous
2
THF (2 mL), and anhydrous MeOH (1 mL) was warmed at 55 °C and stirred at that temperature for 16
h under air (air-filled balloon). The mixture was filtered through a pad of Celite, diluted with CH Cl
2
2
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(15 mL) and 1 M HCl (5 mL), cooled to room temperature, and then poured into a separatory funnel.
4
5
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
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3
4
4
4
4
4
4
4
4
4
4
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5
5
5
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5
5
5
6
The organic phase was separated and the aqueous phase was extracted with CH Cl (3 x 15 mL). The
2
2
combined organic phases were dried (Na SO ) and concentrated to give the corresponding acid and/or
2
4
0
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0
1
the ester (Tables 1 and 2). The reaction conversion and acid/ester ratio was determined by H NMR
analysis (DMSO-d ) using bromoform as the internal standard (5 mg/mL in methanol, analytical
6
standard). The above crude mixture was eluted from a column of silica gel with 15:1 cyclohexane-
AcOEt to isolate the ester and then with 10:1 AcOEt-AcOH to recover the acid.
Mass spectrometric experiments
(+)-ESI and MS/MS mass spectra were acquired using an ion trap mass spectrometer equipped with an
electrospray ionization source. Instrumental parameters: capillary voltage -10 V, spray voltage 4.50 kV,
capillary temperature of 150 °C, mass scan range from m/z 50 to 1000; N was used as sheath gas. The
2
samples were injected into the spectrometer by a syringe pump at a constant flow rate of 8 µL/min,
using THF-MeOH (2:1) as eluting solvent. The appropriate aldehyde 2 and 1 were mixed in equimolar
-3
amounts of 10 M in the presence of DBU (1 eq. ) as base. MS/MS experiments were carried out by
using tickling voltages in the range 10-40 mV. The change of the eluting mixture to ACN-MeOH (3:1)
afforded very similar results. The MS data were acquired following the reaction from the early
moments up to 30 min. Additional checks were carried out after 2 h.
HRMS were obtained on a Q/TOF-MS, using a quadrupole, a hexapole, and a time-of-flight unit
equipped with an electrospray ionization source.
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