Water as efficient medium for mild decarbonylation of tertiary aldehydes

Article abstract of DOI:10.1016/j.tetlet.2011.03.012

Decarbonylation of the tertiary aldehydes 4-ethyl-4-formyl-hexanenitrile (2) and 2-methyl-2-phenylpropanal (4) promoted by dioxygen occurs at room temperature only if suspended in water probably via the sequential acyl radical-CO liberation-tertiary radical that is promoted by an 'on water' process originating preferentially from the corresponding tertiary hydroperoxide.

Full text of DOI:10.1016/j.tetlet.2011.03.012

Tetrahedron Letters 52 (2011) 2803–2807
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Water as efficient medium for mild decarbonylation of tertiary aldehydes
Catarina A. B. Rodrigues a, , Marta Norton de Matos a, , Bruno M. H. Guerreiro a, , Ana M. L. Gonçalves a,
,
Carlos C. Romão a,b, , , Carlos A. M. Afonso c,
⇑
⇑
a Alfama Lda, Taguspark, Nucleo Central 267, Porto Salvo, Portugal
b Instituto de Tecnologia Química e Biológica da Universidade Nova de Lisboa, Av da República, EAN, 2780-157 Oeiras, Portugal
c CQFM – Centro de Química-Física Molecular and IN – Institute of Nanosciences and Nanotechnology, Instituto Superior Técnico, 1049-001 Lisboa, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Decarbonylation of the tertiary aldehydes 4-ethyl-4-formyl-hexanenitrile (2) and 2-methyl-2-phenyl-
propanal (4) promoted by dioxygen occurs at room temperature only if suspended in water probably
via the sequential acyl radical–CO liberation–tertiary radical that is promoted by an ‘on water’ process
originating preferentially from the corresponding tertiary hydroperoxide.
Received 2 June 2010
Revised 28 February 2011
Accepted 2 March 2011
Available online 8 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Water
Acyl radicals
Tertiary aldehyde
Oxygen
Hydroperoxide
Decarbonylation
1. Introduction
Aldehyde decarbonylation is a well known process that occurs
under drastic conditions like UV irradiation,7,8 high temperatures,9
Despite being long known as a dangerous, toxic, and pollutant
gas,1 carbon monoxide (CO) has been found to have advantageous
biological effects.2 Since the discovery of the endogenous produc-
tion of CO in stress situations3 a considerable research has been
done in order to understand the biological mechanisms and the
beneficial effects of CO in several disease models like: systemic
and pulmonary hypertension, cardiac, renal and small bowel graft
rejection, preservation of organs for transplantation.2
extremely acidic or basic conditions,10,11 radical, and metal cata-
lyzed reactions.12 Obviously, these conditions are incompatible
with biological applications in physiological medium.
Recently, de Matos and Romão reported that tertiary aldehydes
are able to release a significant amount of CO under mild oxidative
conditions, compatible with physiological uses.6 They describe a
group of aldehydes that have the general structure shown in
Figure 1.
Due to its toxicity CO is rather unsafe to administer by inhala-
tion requiring special equipment and stringent control procedures.
In order to circumvent these difficulties CO releasing molecules
(CORM’s) have been developed to deliver CO at specific sites with
a controllable appropriate rate.4 Among the CO releasing mole-
cules, disclosed metal carbonyl complexes and dichloromethane,
both of which release CO under mild and physiological conditions,
have been shown to have therapeutic efficacy.5 More recently it
was found that tertiary aldehydes are also CO releasing compounds
under such conditions.6
The ability of these compounds to liberate CO was evaluated
in vitro, using oxidizing agents, such as tert-butyl hydroperoxide
(TBHP) and hydrogen peroxide that are or mimic reactive oxygen
species (ROS) present in inflamed physiological environments.
The addition of a radical inhibitor (2,6-di-tert-butylphenol–BHT)
reduces the amount of CO released indicating that this type of alde-
hydes liberates CO through a radical mechanism (Fig. 2). The pro-
posed mechanism relies on aldehyde decarbonylation via
formation of an acyl radical.
Acyl radicals have gained an increasing significance in synthetic
chemistry.13 Lately some new methods for carbon–carbon bond
formation involving acyl radicals have been successfully devel-
oped.14 One of the major problems encountered for these reactions
is the decarbonylation of acyl radicals. This decarbonylation is
dependent on the nature of the substituents. Substituents that
stabilize the alkyl radical after CO liberation (tertiary alkyl and
benzylic substituents) favor decarbonylation. Additionally,
⇑
Corresponding authors. Tel.: + 351 218419785; fax: + 351 218464455 (C.A.B.R.);
tel.: +351 214469751; fax: +351 214411277 (C.C.R.).
E-mail addresses: ccr@itqb.unl.pt (C.C. Romão), carlosafonso@ist.utl.pt (C.A.M.
Afonso).
Tel.: +351 214240001; fax: +351 214240033.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.012

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C. A. B. Rodrigues et al. / Tetrahedron Letters 52 (2011) 2803–2807
Table 2
O
Aldehydes CO release in water (0.1 M) after 24 h
R1
R2
H
Compound
Aldehyde
% CO released
6.4
R3
O
1
H
Figure 1. General structure of aldehydes that release CO under mild oxidative
conditions, where R1 = R2 = Me and R3 = Me, allyl, hydroxymethyl, acetoxymethyl,
p-methylbenzyl, phenyl or R1 = R2 = Ethyl and R3 = Me, cyanoethyl.
O
2
3
4
28.4
H
NC
O
35.1a
34.2a
O
O
R3
H
R
O.
+
CO + ROH
R1
R2
R1
R1
R2
O
H
R2
R3
R3
H
a
Figure 2. Proposed mechanism of CO liberation from tertiary aldehydes.
Less accurate value lying outside the range of the calibration curve.
coupling reactions with acyl radicals are favored by substituents,
necessary. Experiments performed under nitrogen as well as in the
presence of an antioxidant showed almost no CO liberation (Table 3
and Fig. 3). In fact, the decarbonylation of these aldehydes was fol-
lowed by NMR. No evolution of the reaction was observed under
nitrogen, while complete decarbonylation was achieved under air
(see Supporting information). The aldehyde signal of 4 is almost
undetectable after 22 h of reaction in water under air. However,
under nitrogen none of the aldehyde signals disappeared within
24 h.
Similar results were obtained with aldehyde 2. After 17 days of
reaction under nitrogen no decarbonylation was observed by NMR.
On the contrary, a rapid evolution of reaction was observed after
24 h under air and after 7 days the signal of aldehyde had practi-
cally disappeared. GC-TCD results are in accordance with these
observations (Table 3 and Fig. 3).
which stabilize the acyl radical like aryl,
a-unsubstituted alkyl,
and conjugated unsaturated alkyl substituents.15
Given the increasing importance of these types of reactions sev-
eral techniques to produce acyl radicals were discovered and im-
proved.13,14 Acyl radicals can be formed by RCO-X homolytic
cleavage where X can be: –H, –Cl, –OH, –SR, –SeR, –TeR, –CoLn, –
P(@O)Ar2 and metal carbene complexes. Acyl radicals are also pro-
duced from the cleavage of CO–C bonds of ketones,
-acylalkoxy, and from carbonylation16 of alkyl, aryl, and vinyl rad-
icals. Aldehydes give acyl radicals by hydrogen abstraction using
radical initiators, UV light,
-irradiation, or transition metal ions.13
a-keto acids or
a
c
Besides these, there are also some reported examples of hydrogen
abstraction by the less reactive molecular oxygen17 which can act
as efficient source for new C–C bond formation17c,d or to green oxi-
dation of aldehydes to carboxylic acids and the further use of the
involved intermediate as co-oxidant.17e,f As described before, the
aldehydes in Table 16 release CO without strong oxidants, only un-
der air and in aqueous solvents.
Table 3
% CO released from aldehydes 2 and 4 within 24 h under different conditions
The intriguing release of CO6 prompted us to perform a detailed
study on the ease formation of acyl radicals from tertiary alde-
hydes under mild conditions. A screening study of the behavior
of aldehydes showed that the molecules presented in Table 2 liber-
ated CO in water. From these preliminary data, aldehydes 2 and 4
were selected and studied in detail, namely the influence of oxy-
gen, light, presence of antioxidant, concentration, and solvent.
Aldehyde decarbonylation was found to be light independent,
some experiments followed by GC-TCD performed in the dark
and under light did not show large CO release differences (see Ta-
ble 3 and Fig. 3). Nevertheless, the presence of molecular oxygen is
Entry
Conditions
% CO
2
4
1
2
3
4
Water, air, light
Water, air, dark
Water, N2, light
Water, air, BHT
28.4
24.4
5.9
101.5
91.9
11.1
0.0
0.0
100,0
80,0
60,0
40,0
20,0
0,0
Table 1
% of CO released in aqueous media6
Entry
1
Aldehyde
Buffer (pH=2)
8.5%, 16 h
RPMI18
O
3.2%, 16 h
H
O
2
3
4
21.2%, 23.5 h
16.6%, 23 h
34.9%, 25 h
20.7%, 24 h
15.5%, 19 h
—
H
0
5
10
time (hours)
4, water, air, light
15
20
25
NC
O
4, water, air, dark
4, water, air, BHT
2, water, air, dark
2, water, air, BHT
H
4, water, N2, light
2, water, air, light
2, water, N2, light
O
H
Figure 3. % CO release of aldehydes 2 and 4 under different conditions. These
assays were repeated up to 4 times.

C. A. B. Rodrigues et al. / Tetrahedron Letters 52 (2011) 2803–2807
2805
During the studies with 4 was found that the reaction rate is
also concentration dependent. NMR studies of 4 performed in deu-
terated water with two different concentrations showed that the
reaction is faster at high concentrations (Fig. 4). Two concentra-
tions were studied by NMR: 13 mM and 3.3 mM. At 3.3 mM the
reaction rate is very slow the signal of aldehyde being still present
after 4 days. At 13 mM the signals of aldehyde almost disappeared
after 22 h. Surprisingly, we found that at high concentrations two
signals in the aldehyde region were detected whereas at low con-
centrations only one signal was observed. The explanation for the
two signals observed was that they are due to the solubility of
aldehyde: at 3.3 mM the aldehyde is completely dissolved in water
and at 13 mM the aldehyde is partially emulsified. This leads to the
conclusion that the signal at d = 9.5 ppm was due to dissolved
aldehyde and the signal at d = 9.0 ppm was due to aldehyde in
emulsion form.
These observations are also supported by the behavior noticed
during the GC studies under air. At the beginning of the assay
was observed an emulsion that became more opaque within 4 h
and changed to a colorless and completely transparent solution
after 24 h.
These results led us to conclude that due to partial dissolution
of the aldehyde in water an equilibrium between dissolved and
suspended aldehyde was formed, while the aldehyde suspended
at the surface reacts with oxygen to give carbon monoxide and
water soluble products, the aldehyde dissolved in water remains
unchanged. These results are in accordance with the ‘on-water’
reaction phenomena.19 In fact, no CO liberation was found when
Figure 4. Reaction of 2-methyl-2-phenylpropanal (4) in D2O under air along the time, followed by NMR using 3.3 mM (top) and 13 mM (bottom) concentration.

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C. A. B. Rodrigues et al. / Tetrahedron Letters 52 (2011) 2803–2807
Table 4
not be separated but were identified by NMR in the mixture by
comparison with spectra of authentic samples as the correspond-
ing alcohol 2-phenyl-2-propanol (6) and the peroxide cumene
hydroperoxide (7)–with a total isolated yield between 39% and
44%.
% CO released from 2 and 4 within 24 h in different solvent media
Aldehyde
Conditions
% CO
2
4
2
2
2
4
2
4
Dichloromethane, air
Dichloromethane, air
Methanol, air
Hexane/water 50:50, air
Ethanol/water 50:50, air
Methanol/water 50:50, air
Water, air
0.0
0
0.0
0.3
0.0
OR
0
28.4
101.5
NC
OH
Water, air
6 R = H
5
7 R = OH
the reaction was carried out in methanol, hexane, or dichlorometh-
ane instead of water. Moreover, the addition of methanol or hex-
ane completely inhibited the reaction (Table 4 and Fig. 5). Note
that those aldehydes are completely soluble in these organic sol-
vents but only partially soluble in water. In conclusion decarbony-
lation of aldehyde does not occur in organic solvents or is very slow
in water as a solution (diluted in water). A similar solvent effect
has already been recently described for oxidation of aldehydes,
but no CO release was observed in that case since the aldehydes
studied were not tertiary.17e
Those reactions were scaled up in order to isolate and charac-
terize the products formed. Compound 2 gave a complex mixture
of products that were separated by preparative chromatography.
One of the products was collected pure and identified as being
the corresponding alcohol 4-ethyl-4-hydroxyhexanenitrile (5).
Compound 4 gave, after CO release,20 two products which could
2. Conclusions
Tertiary aldehydes are molecules that easily undergo decarb-
onylation ‘on water’19 in the presence of molecular oxygen by a
radical mechanism, probably via acyl radical (Fig. 2). It was verified
that aldehyde solubility is an important factor in reaction rate
since there is no CO released when aldehydes are dissolved in or-
ganic solvents or when their concentration in water is very low.
Oxygen also plays an important role in decarbonylation of tertiary
aldehydes. In the presence of antioxidants (BHT) or in the absence
of oxygen no CO release was observed. The unique observed reac-
tivity of this type of molecules under very mild conditions may
provide a new tool for further functionalization of the formed ter-
tiary radical.
30
25
20
15
10
5
Acknowledgments
The NMR spectrometers are part of the National NMR Network
and were purchased in the framework of the National Programme
for Scientific Re-equipment, contract REDE/1517/RMN/2005, with
funds from POCI 2010 (FEDER) and Fundação para a Ciência e a
Tecnologia (FCT).
Supplementary data
0
0
5
10
15
20
25
30
Supplementary data (Electronic Supplementary Information
(ESI) available: Experimental procedures, UV, FT-IR, 1H and 13C
NMR data is provided.) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.03.012.
time (hours)
2, dichloromethane, air
2, hexane:water 50:50, air
2, water, air
2, methanol, air
2, ethanol:water 50:50, air
References and notes
100
80
60
40
20
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2807
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20. Reaction of 2-methyl-2-phenylpropanal (4)in water: A mixture of 4 (1.05 g,
0.007 mol) in 10 mL of water was stirred at room temperature and
under air. After 31 days the organics were extracted with diethyl ether,
dried with MgSO4, and the solvent was removed under vacuum to yield
a
yellow oil (crude). The obtained crude was properly characterized
(NMR) and identified as being mixture of 2-phenyl-2-propanol and
(0.42 g, 39–44%) by comparison with authentic
a
6
cumene hydroperoxide
samples.
7