Direct experimental evidence for an enamine radical cation in SOMO catalysis

Article abstract of DOI:10.1039/c0cc05347c

SOMO catalysis has lately obtained large interest as a new and powerful version of enantioselective organocatalysis which includes radical steps initiated by a one-electron oxidation. The intermediate enamine radical cation has been postulated, but has no

Full text of DOI:10.1039/c0cc05347c

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COMMUNICATION
Direct experimental evidence for an enamine radical cation in SOMO
catalysisw
Rita Beel, Stefanie Kobialka, Martin L. Schmidt and Marianne Engeser*
Received 3rd December 2010, Accepted 19th January 2011
DOI: 10.1039/c0cc05347c
SOMO catalysis has lately obtained large interest as a new and
powerful version of enantioselective organocatalysis which
includes radical steps initiated by a one-electron oxidation.
The intermediate enamine radical cation has been postulated,
but has not been observed directly so far. This communication
now reports the direct detection of this key intermediate.
Enantioselective organocatalysis has been a major issue in
recent years.1 In 2007, a new version of amine-mediated
enantioselective organocatalysis, now termed SOMO catalysis,
was introduced by the group of MacMillan.2 Adding a one-
electron oxidant to an enamine compound formed in situ from
an amine catalyst and an aldehyde should give an enamine
radical cation, which reacts with TEMPO, a long-lived organic
radical (Scheme 1a).3j,4 The group of MacMillan has recently
shown in a series of publications2a,3 that the proposed inter
mediate enamine radical cation can also undergo a variety of
subsequent reactions typical for radical reactivity (Scheme 1b
with styrene as a representative example). A second one-
electron oxidation followed by anion addition or proton
elimination and hydrolytic release of the catalyst terminates
the putative catalytic cycle. In this work, we used electrospray
(ESI) mass spectrometry to obtain direct experimental evidence
for the selective one-electron oxidation of an enamine to the
respective enamine radical cation.
Scheme 1 SOMO catalysis: the proposed intermediate enamine radical
cation can be trapped by the stable radical TEMPO (a) or react with i.e.
styrene (b) followed by a second oxidation and hydrolytic release of the
catalyst 1.
ESI mass spectrum of a solution of 1ÁTFA. After addition
of butyraldehyde or phenylacetaldehyde, the corresponding
enamines are detectable (Fig. 1b and c). The signal for the
respective protonated enamine is most intense approximately
1 h after aldehyde addition.
ESI mass spectrometry is not only a versatile method for
analytical purposes,5 but can also act as a link between
solution and gas-phase chemistry and has been shown to
be an excellent tool to investigate reaction mechanisms.6
Even very reactive radical intermediates have already been
observed and characterized experimentally by a sophisticated
combination of API-MS/MS with online coupling to a
microreactor.6b,7
Tris(p-bromophenyl)aminiumhexachloroantimonate (3) has
been successfully used in mechanistic ESI studies.7b–d A typical
ESI spectrum of 3 is shown in Fig. 2a. The deep blue solution
immediately turns colourless upon addition of one of the
enamine solutions described above, indicating a fast oxidation.
ESI spectra of the colourless reaction mixtures do not show
any signal for radical species. In contrast, when mixing
solutions of 2b and 3 in a microreactor directly coupled to
the ESI source, very instructive spectra can be recorded
We have used a similar microreactor to study the oxidation
of an enamine with a one-electron oxidant. Enamines are
formed in situ by mixing a solution of a typical MacMillan
catalyst 1ÁTFA with an aldehyde. Fig. 1a shows a representative
(Fig. 2b and c). Thus, a new signal at m/z 348.2 is observed.
+
This signal is due to the enamine radical cation [2b]ꢀ
,
Kekule´-Institut fur Organische Chemie und Biochemie, Universitat
¨
¨
Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany.
evidenced by the exact mass difference of Dm = 1.0078 u to
the signal of the protonated enamine [2b + H]+. In contrast,
no additional signal is observed one mass below the signal for
the protonated catalyst [1 + H]+. Therefore, only the enamine
is oxidized. This finding is in full accordance with the
E-mail: Marianne.Engeser@uni-bonn.de; Fax: +49 228 73 5683;
Tel: +49 228 73 2849
w Electronic supplementary information (ESI) available: Experimental
details and spectra of double microreactor experiments with TEMPO
and styrene, respectively. See DOI: 10.1039/c0cc05347c
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3293–3295 3293

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significantly lower ionization potential expected for the enamine
with respect to the reactants 1 and the aldehyde.2a The signal at
m/z 383.2 shows an isotope pattern for a monochlorinated
species and can be assigned to [2b + Cl]+. Although the
aggregation with chloride anions is a common phenomenon in
ESI mass spectra, the signal is highly remarkable in this case
because the enamine radical cation [2b]ꢀ+ must have experienced
a second one-electron oxidation to form [2b + Cl]+ with a
chloride anion. This is an indication that two subsequent one-
electron oxidation steps can occur in the course of the reaction
even in the absence of other reactants like styrene. Further, an
interesting signal is found at m/z 291.1. It can be assigned to a
+
loss of a butyl radical from the enamine radical cation [2b]ꢀ
which probably happens due to collisions in the ESI process.
Reasonable intensities for the enamine radical cation are
obtained by tuning the ESI parameters, so that the ion could
be mass-selected and fragmented in the FT-ICR cell using an
infrared laser (IRMPD). The resulting spectrum is shown in
+
Fig. 3a. The only visible fragmentation pathway for [2b]ꢀ is
indeed the loss of a butyl radical. A stable iminium ion with a
delocalized p-system can be assigned to the resulting ion at
m/z 291.2; this fragmentation is in full accordance with typical
signals observed in ESI mass spectra of enamines.8 For
comparison, the protonated enamine [2b + H]+ at m/z
349.2 was fragmented as well. As anticipated by the even-
electron rule, no radical elimination pathway is observed for
this closed-shell ion (Fig. 3b).
Fig. 1 ESI mass spectra of acetonitrile solutions of 1ÁTFA before (a)
and 1 h after adding butyraldehyde (b) or phenylacetaldehyde (c). The
signals at m/z 487.3 and 425.3 correspond to [12–3 H2 + H+] and
[12–C5H8 + H+], respectively. These ions are formed by hydrolytic
condensation of 1 in acidic solution.
Fig. 2 ESI mass spectra of the one-electron oxidant 3 (a), enamine 2b
generated in situ (b), and after mixing the two solutions in a microreactor
coupled directly to the ESI source (c). A new signal for the enamine
radical cation [2b]ꢀ+ appears at m/z 348.2. Capillary length and flow rate
correspond to a reaction time of approximately 8 s. Signals marked with
x correspond to loss of H2 due to collision induced fragmentation in the
ESI source.
Fig. 3 Infrared multiphoton dissociation (IRMPD) MS/MS spectrum
of mass-selected [2b]ꢀ+ (a) and [2b + H]+ (b) with laser power 95% and
irradiation time 2 s (* electronic noise).
c
3294 Chem. Commun., 2011, 47, 3293–3295
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In a first attempt to sample the reactivity of the enamine
radical cation [2b]ꢀ+, a second microreactor was inserted
between the ESI needle and the first microreactor in which
[2b]ꢀ+ was generated as described above (Fig. S1, ESIw). In the
3 (a) H. Jang, J. Hong and D. W. C. MacMillan, J. Am. Chem. Soc.,
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C. MacMillan, Angew. Chem., 2009, 121, 5223 (Angew. Chem.,
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D. W. C. MacMillan, J. Am. Chem. Soc., 2009, 131, 11332;
(f) J. C. Conrad, J. Kong, B. N. Laforteza and D. W. C.
MacMillan, J. Am. Chem. Soc., 2009, 131, 11640; (g) S. Rendler
and D. W. C. MacMillan, J. Am. Chem. Soc., 2010, 132, 5027;
(h) J. M. Um, O. Gutierrez, F. Schoenebeck, K. N. Houk and
D. W. C. MacMillan, J. Am. Chem. Soc., 2010, 132, 6001;
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Soc., 2010, 132, 10015; (j) J. F. Van Humbeck, S. P. Simonovich,
R. R. Knowles and D. W. C. MacMillan, J. Am. Chem. Soc., 2010,
132, 10012.
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X. Ho, S. Mho and H. Jang, Eur. J. Org. Chem., 2009, 5309.
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Wiley & Sons, New York, 1997; (b) Applied Electrospray Mass
Spectrometry, ed. B. N. Pramanik, E. K. Ganguly and M. L. Gross,
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2007, 119, 7040 (Angew. Chem., Int. Ed., 2007, 46, 6915).
+
second microreactor, the solution of [2b]ꢀ was mixed with a
solution of TEMPO (Scheme 1a). The ESI spectra indeed
show the presence of the expected hydrolyzed trapping product
[4 + H]+ at m/z 276.2 (Fig. S2, ESIw). Similarly, the final
reaction product [5 + H]+ at m/z 223.1 was observed when a
solution of styrene (Scheme 1b) was added in the second
microreactor (Fig. S3, ESIw). We are currently optimizing the
conditions of the setup to further study these and other typical
reactions2,3 of enamine radical cations in detail to obtain more
insight into the nature and order of the reaction steps following
the formation of the enamine radical cation in SOMO catalysis.
We present direct experimental evidence for the selective
oxidation of an enamine to an enamine radical cation with a
one-electron oxidant under conditions of SOMO catalysis.
We thank the Deutsche Forschungsgemeinschaft (SFB 624
and SFB 813) for financial support.
Notes and references
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J. O. Metzger, J. Am. Chem. Soc., 2004, 126, 14485;
(d) C. A. Marquez, H. Wang, F. Fabbretti and J. O. Metzger,
J. Am. Chem. Soc., 2008, 130, 17208.
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3293–3295 3295