Aerobic reduction of olefins by in situ generation of diimide with synthetic flavin catalysts

Article abstract of DOI:10.1002/chem.201003278

A versatile reducing agent, diimide, can be generated efficiently by the aerobic oxidation of hydrazine with neutral and cationic synthetic flavin catalysts 1 and 2. This technique provides a convenient and safe method for the aerobic reduction of olefins, which proceeds with 1 equiv of hydrazine under an atmosphere of O₂ or air. The synthetic advantage over the conventional gas-based method has been illustrated through high hydrazine efficiency, easy and safe handling, and characteristic chemoselectivity. Vitamin B₂ derivative 6 acts as a highly practical, robust catalyst for this purpose because of its high availability and recyclability. Association complexes of 1b with dendritic 2,5-bis(acylamino)pyridine 15 exhibit unprecedented catalytic activities, with the reduction of aromatic and hydroxy olefins proceeding significantly faster when a higher-generation dendrimer is used as a host pair for the association catalysts. Contrasting retardation is observed upon similar treatment of non-aromatic or non-hydroxy olefins with the dendrimer catalysts. Control experiments and kinetic studies revealed that these catalytic reactions include two independent, anaerobic and aerobic, processes for the generation of diimide from hydrazine. Positive and negative dendrimer effects on the catalytic reactions have been ascribed to the specific inclusion of hydrazine and olefinic substrates into the enzyme-like reaction cavities of the association complex catalysts. Copyright

Full text of DOI:10.1002/chem.201003278

DOI: 10.1002/chem.201003278
Aerobic Reduction of Olefins by In Situ Generation of Diimide with
Synthetic Flavin Catalysts
Yasushi Imada,* Hiroki Iida, Takahiro Kitagawa, and Takeshi Naota*[a]
Abstract: A versatile reducing agent,
diimide, can be generated efficiently by
the aerobic oxidation of hydrazine with
neutral and cationic synthetic flavin
catalysts 1 and 2. This technique pro-
vides a convenient and safe method for
the aerobic reduction of olefins, which
proceeds with 1 equiv of hydrazine
under an atmosphere of O2 or air. The
synthetic advantage over the conven-
tional gas-based method has been illus-
trated through high hydrazine efficien-
cy, easy and safe handling, and charac-
teristic chemoselectivity. Vitamin B2
derivative 6 acts as a highly practical,
robust catalyst for this purpose because
of its high availability and recyclability.
Association complexes of 1b with den-
dritic 2,5-bis(acylamino)pyridine 15 ex-
hibit unprecedented catalytic activities,
with the reduction of aromatic and hy-
droxy olefins proceeding significantly
faster when a higher-generation dendri-
mer is used as a host pair for the asso-
ciation catalysts. Contrasting retarda-
tion is observed upon similar treatment
of non-aromatic or non-hydroxy olefins
with the dendrimer catalysts. Control
experiments and kinetic studies re-
vealed that these catalytic reactions in-
clude two independent, anaerobic and
aerobic, processes for the generation of
diimide from hydrazine. Positive and
negative dendrimer effects on the cata-
lytic reactions have been ascribed to
the specific inclusion of hydrazine and
olefinic substrates into the enzyme-like
reaction cavities of the association
complex catalysts.
Keywords: alkenes · dendrimers ·
host–guest systems · hydrogenation ·
organocatalysis
Introduction
Flavin-containing oxygenases[1a] and oxidases[1b] catalyze a
variety of oxidative organic transformations in biological
processes.[2] Simulation of these processes has been studied
extensively by using various synthetic flavin organocata-
lysts.[3,4] Scheme 1a shows a common catalytic cycle for oxy-
genase model reactions with a representative synthetic
flavin,
5-ethyl-3,7,8,10-tetramethylisoalloxazinium
salt
(FlEt+). A highly reactive flavin hydroperoxide (FlEtOOH)
is generated by either direct addition of H2O2 (the shunt
process) or reduction and subsequent incorporation of O2.[5]
Oxygen atom transfer to the substrate (Sub) and dehydra-
tion complete the catalytic cycle.[4] By this catalytic process,
various heteroatomic compounds, including amines,[6a,c,d,7a,c]
sulfides,[6a,d,f–h,7a,c] and ketones,[6b,7b] undergo oxygenation re-
[6]
actions with H2O2 or O2 (1 atm)[7] under mild conditions.
Model reactions of flavin-containing oxidases/dehydrogenas-
es have also been extensively studied with cationic FlEt+
and neutral synthetic flavin, 3,7,8,10-tetramethylisoalloxa-
zine (Fl), as catalyst (Scheme 1b). The reaction proceeds by
[a] Prof. Dr. Y. Imada, Dr. H. Iida, Dr. T. Kitagawa, Prof. Dr. T. Naota
Department of Chemistry, Graduate School of Engineering Science
Osaka University
Machikaneyama, Toyonaka, Osaka 560-8531 (Japan)
Fax : (+81)6-6850-6222
E-mail: imada@chem.es.osaka-u.ac.jp
naota@chem.es.osaka-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003278.
Scheme 1. Catalytic cycle for typical model reactions of a) flavin monoox-
ygenases and b) flavin dehydrogenases.
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FULL PAPER
a similar redox process, including anaerobic dehydrogena-
tion of the substrate (AH2),[3b] O2 incorporation into the re-
duced flavin (FlH2), and elimination of H2O2. These process-
es with neutral[8] and cationic[9] flavin catalysts provide vari-
ous dehydrogenative transformations of alcohols,[8a,b,e] ami-
nes,[8e,9a] hydrazines,[9b] thiols,[8c,d] NADH model com-
pounds,[8d] and nitroalkanes.[8c] During the course of our
systematic studies on the simulation of enzymatic functions
of flavin monooxygenases with synthetic flavin catal-
ysts,[4b,6a,c,h,7] we found that a series of synthetic flavins act as
efficient catalysts for the generation of the reducing agent
diimide, NH=NH,[10] by the above aerobic and anaerobic
processes for the oxidation of hydrazine. This finding led to
the development of a mild and convenient method for the
aerobic reduction of olefins that proceeds under an atmos-
phere of O2 (1 atm), as depicted in Equation (1).[11]
ation complexes of neutral flavins with 2,6-bis(acylamino)-
pyridines[25] bearing poly(benzyl ether) dendron units have
been proven to act as efficient supramolecular organocata-
lysts for the aerobic reduction studied herein.[26] Recently, a
variety of dendritic compounds with transition-metal[27] and
organic[28] active cores have been studied extensively as cata-
lysts for various molecular transformations.[29] Higher cata-
lytic activities due to various dendrimer effects, including
local condensation of the substrate around the reactive
core,[28b–e] electrical stabilization of the intermediates,[28a] and
inhibition of the formation of inert dimer species,[27b,e–g] have
been achieved. Stereochemical congestion by dendron units
has sometimes caused valuable size selectivity of substra-
tes[27a,c] and products.[27d] Rotello and co-workers independ-
ently reported that neutral flavins covalently linked to a
benzyl ether dendron unit at the 3-position showed high cat-
alytic activity in the aerobic dehydrogenation of 1-benzyl-
1,4-dihydronicotinamide in water[30] in which strong hydro-
philic–hydrophobic interactions generated between the den-
drimer and water would give rise to localization of the sub-
strate around the flavin site. This leads to acceleration of
the rate-determining dehydrogenation step (Scheme 1b).
The flavin–dendrimer association catalysts reported herein
show remarkable specificity in their catalytic activity to-
wards aromatic and hydroxy olefins, and they retard the re-
duction of aliphatic olefins. This is a very rare case of cata-
lytic specificity achieved by the design of artificial reaction
cavities.[31] Herein, we describe full details of the aerobic re-
duction of olefins with a variety of synthetic flavin catalysts
from both synthetic and mechanistic viewpoints.
Diimide is a powerful reducing agent for various symmet-
rical unsaturated compounds, as depicted in Equation (2).
Because of its low stability, this reagent must be used direct-
ly after generation from protected diimide derivatives, such
as arylsulfonyl hydrazine,[12] azodiformate salts,[12b,13] and an-
thracene-9,10-diimine.[14] On the other hand, diimide has
been generated by the oxidation of hydrazine [Eq. (3)] with
H2O2,[13c,15]
NaIO4,[16]
Se,[17]
PhSe(O)OH,[18]
K3[Fe(CN)6],[12b,19] and O2 with metal catalysts.[13c,20] These
methods generally require an excess amount of hydrazine
and oxidants for completion of the reaction[21] because reac-
tive diimide readily undergoes both a self-process [Eq. (4)]
and over-oxidation [Eq. (5)]. Despite this limitation, the
aerobic oxidation of hydrazine is one of the most promising
methods for diimide generation because the method princi-
pally provides an environmentally benign process for the hy-
drogenation of olefins that proceeds in air with the ultimate-
ly safe chemical byproducts of nitrogen and water. This
method for diimide generation shows extraordinarily high
hydrazine efficiency because the catalytic system of flavins
can avoid the inevitable disproportionation reaction. Thus,
the method provides a highly convenient and safe process
for the hydrogenation of olefins that can be performed with
1 equiv of hydrazine, 1 atm of O2 or air, and an organocata-
lyst,[22] which is a convenient alternative to transition-metal
catalysts and H2 gas[23] with respect to atom efficiency and
safety. In this study, a series of neutral and cationic flavins
and their association complexes with various 2,6-bis(acyla-
mino)pyridines have been prepared, characterized, and ex-
amined for catalytic behavior in this new type of aerobic re-
duction.
Results and Discussion
Synthesis of flavins: A variety of synthetic flavins were pre-
pared to examine their catalytic activity in the aerobic re-
duction of olefins (Scheme 2). Neutral flavins, isoalloxazines
1, were prepared by the condensation of alloxanes with N-
alkyl-o-nitroaniline.[32] Cationic flavins, 5-ethylisoalloxazini-
um salts 2, were derived by reductive ethylation of 1 with
acetaldehyde and subsequent oxidation with NaNO2.[7c] Re-
lated analogues, 3,10-dimethyl-8-azaisoalloxazine (3)[8c] and
5-ethyl-1,3-dimethylalloxazinium perchlorate (4),[6d] were
also prepared according to literature procedures. Compound
6 was derived from commercially available riboflavin 5a (vi-
tamin B2) by acetalization and N5-ethylation.[7b] Although
cationic flavins 2 and 4 should be handled carefully under
As part of our program to develop new organocatalysts
bearing more sophisticated enzymatic functions, such as sub-
strate specificity,[2,24] we continue to study the catalytic activ-
ities of new flavin–dendrimer association complexes. Associ-
Chem. Eur. J. 2011, 17, 5908 – 5920
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Y. Imada, T Naota et al.
Table 1. Catalytic activities of the synthetic flavins 1–6 used for the re-
duction of trans-5-decene.[a]
[c]
Entry
Catalyst
Eo’ [mV][b]
TOF [hÀ1
]
1
2
3
4
5
6
2a
2b
2c
2d
2e
4
306
316
388
427
512
18
13
8.4
15
4.4
15
109
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
1d
1e
3
5a
5b
5c
6
À809
À761
À721
À695
À569
À496
4.7
3.4
7.6
6.2
8.8
14
3.8
4.9
6.9
8.2
[d]
–
À725
À725
À803
[a] The reaction of trans-5-decene (0.25m) with NH2NH2·H2O (1.2 equiv)
in CH3CN was carried out in the presence of catalyst (1 mol%) at 258C
under an atmosphere of O2. [b] Determined by cyclic voltammetry
(1.0 mm solution in CH3CN, 0.10m tetrabutylammonium perchlorate, scan
rate 0.1 VsÀ1) based on the relationship E8’=(Epc +Epa)/2. [c] Deter-
mined by GLC analysis based on the formation of decane. [d] Not deter-
mined because of low solubility.
H, À569 mV) (entries 7, 9, and 11). Also, electron-deficient
flavin analogue 3[8c] (À496 mV) shows a relatively high activ-
ity compared with those of the cationic flavins (entry 12).
The higher catalytic activities of the electron-deficient neu-
tral flavins strongly suggest that the rate-determining step of
the reaction is different to that of the reaction with cationic
flavins. As for the solvents, CH3CN gave the best results.
However, the reaction also proceeds in various protic and
halogenated solvents, including CF3CH2OH, MeOH, EtOH,
and CHCl3.
Representative results of the aerobic reduction of olefins
with typical flavin catalysts are shown in Table 2. Various
olefins were converted into the corresponding hydrogenated
products quantitatively when the reactions were carried out
with NH2NH2·H2O (1.2–2.0 equiv) and 2a (1 mol%) at
258C for 5–6 h under O2 (entries 1, 4, 5, 10, 13, 14, 16, and
17). Although the initial rates of the reactions with neutral
flavin catalysts 1a, 5c, and 6 were lower than those with the
cationic catalyst 2a (Table 1), most of the reactions with
neutral flavins gave rise to the quantitative formation of
products after stirring for 24 h (entries 2, 3, 6–9, 11, 12, 15,
and 18–21). Vitamin B2 derivatives 5c and 6 are especially
useful catalysts due to their high availability and stability.
Benzyl and benzyloxycarbonyl protecting groups, easily re-
moved by metal-catalyzed hydrogenation,[34] can tolerate the
applied reaction conditions (entries 6, 7, and 15). Alkylthio
groups, which frequently inhibit the catalytic activity of tran-
sition-metal complexes, do not retard the organocatalytic re-
actions studied herein (entries 17–21).[16a] Terminal olefins
are selectively reduced in the presence of trisubstituted ole-
fins (entries 10 and 11).[15] Alkynes undergo consecutive re-
duction with excess hydrazine to afford the corresponding
alkanes chemoselectively (entry 12).[13c] The reduction of
Scheme 2. Synthetic flavins 1–6 used for the aerobic reduction of olefins.
argon, neutral flavins 1, 3, 5, and 6 are easy to prepare and
can be stored under air, and even under weak basic and
acidic conditions. Recently, a reduced form of protected ri-
boflavin 7 was reported to be an alternative catalyst for the
aerobic reduction of olefins.[33] The preparation and han-
dling of 7 should be carried out under strict anaerobic con-
ditions using sophisticated laboratory techniques because re-
duced flavins have a high reactivity towards O2, as shown in
Scheme 1b.
Catalytic reduction of olefins: The catalytic activities of vari-
ous flavins (1 mol%) were examined in the reduction of
trans-5-decene with NH2NH2·H2O (1.2 equiv) in CH3CN at
258C under O2. Table 1 shows the turnover frequencies and
redox potentials of various flavin catalysts. Cationic flavins 2
generally exhibit higher catalytic activities (entries 1–5) with
the flavin analogue 4[5b–d,f,g] also showing comparable catalyt-
ic activity presenting this reduction reaction (entry 6). The
activities of various substituted flavins decrease in the order
2a (R1, R2 =Me)>2c (R1, R2 =H)>2e (R1 =CN, R2 =H)
(entries 1, 3, and 5). This tendency is consistent with the
redox potentials (2a: 306 mV; 2c: 388 mV; 2e: 512 mV),
which indicates that the rate-determining step of this reac-
tion accelerates with electron-rich flavins. Neutral flavins 1,
5, and 6 show moderate activities (entries 7–11 and 13–16).
In contrast to the cationic flavins, electron-deficient flavins
accelerate the reaction in the order 1a (R1, R2 =Me,
À809 mV)<1c (R1, R2 =H, À721 mV)<1e (R1 =CN, R2 =
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Aerobic Reduction of Olefins
FULL PAPER
camphene proceeds with higher endo selectivity (endo/exo=
90:10) than the reduction performed by conventional hydro-
genation with Pd/C catalyst (68:32; entry 5).[13a] This method
provides an alternative, inexpensive strategy for the stereo-
selective 1,2-dideuteriation of olefins, whereas the conven-
tional methods require expensive D2 gas[35] or an excess
amount of ND2ND2.[36] In a typical reaction, selective 1,2-
on the third run (entry 7). Another vitamin B2 derivative, ri-
boflavin tetrabutyrate 5c, lost activity on the second run
(entry 4) because of hydrolysis of the ester moieties. None
of the cationic flavins, including 2a, were robust, although
they exhibited the highest catalytic activities in the first runs
(entries 1 and 2).
deuteriation
of
2-exo,3-exo-bis(acetoxymethyl)bicyclo-
Catalysis of noncovalently dendronized flavins: With the
aim of creating novel enzyme-like catalytic functions, we de-
signed new association complexes of neutral flavins with
2,6-bis(acylamino)pyridine derivatives doubly linked to two
benzyl ether dendron units (Scheme 3). Dendronized bis-
ACHTUNGTRENNUNG[2.2.1]hept-5-ene (8) can be performed with only 1.2 equiv
of ND2ND2·D2O to afford 9 in a yield of 93% [Eq. (6)].
ACHUTNGREN(NUG acylamino)pyridines 15a (first generation: 2,6-bis(3-{4-ACHTUNGTRENNUNG[3,5-
bis(phenylmethoxy)phenylmethoxy]phenyl}propanoylami-
no)pyridine, abbreviated as G1PAP), 15b (second genera-
tion: G2PAP), and 15c (third generation: G3PAP) were pre-
pared by the reaction of 2,6-bis[3-(4-hydroxyphenyl)propa-
noylamino]pyridine with the corresponding dendritic benzyl
bromides.[38] Dendrimer 16 with different branching points
Note that the reactivity of inert thioalkyl groups can be
enhanced by the addition of protic media. Table 3 shows the
product distribution in the catalytic aerobic reduction of
phenyl 2-propenyl sulfide (10) in the presence of varying
amounts of phenol. The reaction of 10 with less than 1 equiv
of phenol affords the hydrogenated product, phenyl propyl
sulfide (11), selectively (Table 3, entry 1), whereas similar
treatment with a large amount of phenol affords increasing
amounts of the S-oxidation products, phenyl 2-propenyl sulf-
oxide (12) and phenyl propyl sulfoxide (13). Such a drastic
change in chemoselectivity has previously been observed ex-
clusively with highly acidic alcohols such as phenol
(pKa 9.99) and CF3CH2OH (12.4).[37] The use of solvents of
low acidity such as CH3CN, MeOH, EtOH, CHCl3, and
CH2Cl2 gives rise to the selective formation of 11. Thus, the
hydrogenation and simultaneous S-oxidation can be con-
trolled, as depicted in Equations (7) and (8). The latter is a
very rare case of a reduction proceeding simultaneously
with an oxygenation process.
(2,6-bisACTHNUGRTNENUG{3,5-bisACHTUNGTRENN[UGN 3,5-bis(phenylmethoxy)phenylmethoxy]ben-
zoylamino}pyridine, abbreviated as G2BAP) was prepared
by the condensation of dendritic methyl benzoate with 2,6-
diaminopyridine. The association properties of the dendritic
and nondendritic bis(acylamino)pyridines with neutral flavin
1
1b were examined in CDCl3 by H NMR (400 MHz) analy-
sis. Jobꢁs plots indicated that neutral flavin 1b forms a 1:1
complex with dendrimer 15a (see the Supporting Informa-
tion).[25,39] The association constants Ka for the interaction of
1b with 15, 16, and 2,6-bis(acetylamino)pyridine (17, AAP)
were determined in CDCl3 at 303 K on the basis of the con-
1
centration dependence of the H chemical shift of the N3-H
signal (Figure 1 and Table 5). The Ka values for the dendritic
bis(acylamino)pyridines 15 at 303 K are in the range of 404–
434mÀ1 (Table 5, entries 1–3), similar to the values deter-
mined for 17 (AAP, 437mÀ1 (entry 5); reported value:[25]
510mÀ1 at 298 K). These results indicate that the association
of 1b with 15 is not hindered by steric congestion with inte-
rior and exterior benzyl ether units. This is in contrast to the
much smaller Ka value (11mÀ1) determined for the associa-
tion of 1b with 16 bearing shorter linkers (entry 4). Thus, it
can be said that the high association properties of 15 can be
Bis(methylenedioxy)flavin 6 has been proven to be the
most robust, practical catalyst for this purpose. The reusabil-
ity of various flavin catalysts (2 mol%) was examined for
the aerobic reduction of 4-tert-butylstyrene (14) with
NH2NH2·H2O (2.0 equiv) at 308C in CH3CN. After the reac-
tion, the product alkane was isolated by extraction with
hexane. The next runs were performed simply by adding
new substrate olefin and hydrazine to the remaining cata-
lyst-containing organic solution. Table 4 shows typical results
for the recycling of catalysts 2a, 5c, and 6. Neutral ribofla-
vin derivative 6 did not show any loss of product yield even
Figure 1. Plot of changes in the 1H NMR chemical shift of N(3)H proton
signal of 1b versus concentration of bis(acylamino)pyridine receptors
&
*
*
15a (G1PAP, ), 15b (G2PAP, ), 15c (G3PAP, ), 16 (G2BAP, &), and
17 (AAP, ) in CDCl3 at 303 K. [1b]0 =4.00ꢂ10À4 m.
~
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Y. Imada, T Naota et al.
Table 2. Flavin-catalyzed aerobic reduction of olefins.[a]
points of the dendron units.
This characteristic molecular
structure gives rise to the
smooth association of 1b with-
out any significant steric hin-
drance from bulky benzyl ether
moieties. The association con-
stants Ka observed for 1b with
15a–c at 298–313 K fit well
(R2 =0.998–0.999) with the
van’t Hoff relationship of lnKa
versus
Entry
Substrate
Product[b]
Hydrazine hy-
drate [equiv]
Catalyst
t
Isolated
[h] yield [%]
1
2
3
1.2
2.0
2.0
2a
5c[b]
6[b]
4
24
24
99
94
93
4
5
1.2
1.2
2a
2a
5
8
96
54[c]
1/T, from which thermodynamic
paraACTHNUTRGNEmNUG eters DH8 and DS8 were
6
7
2.0
2.0
5b[b]
5c[b]
24
24
91
93
determined, as shown in
Table 5. None of the thermody-
namic paraACTHNUTRGNEUmGN eters for the com-
8
9
10
11
2.0
2.0
2.0
1.5
5b[b]
5c[b]
2a
24
24
5
90
85
96
87
5c[b]
24
plexation of 1b·15 show any
significant difference, which in-
dicates that the association be-
havior of 1b is not influenced
by varying the steric and elec-
tronic effects of dendrimers 15.
Figure 2 shows the changes in
12
5.0[d]
5c[b]
2a
30
5
92
13[e]
2.0
98
1
the H NMR chemical shifts of
14[e]
15
2.0
2.0
2a
5
90
86
the 7-CH3 and 8-CH3 proton
signals of 1b upon varying the
concentration of receptors 15
and 17. Increasing the concen-
tration of nondendritic 17 gives
rise to a slight downfield shift
in the 7- and 8-CH3 proton sig-
nals. This can be attributed to
the decrease in the electron
density in the flavin rings of 1b
as a result of the hydrogen-
bonding association with 17. In
contrast, a remarkable upfield
shift was observed upon similar
treatment with the dendritic bi-
s(acylamino)pyridines 15. Note
that the extent of these shifts
increases significantly when a
dendrimer of higher generation
5c[b]
24
16
2.0
2a
6
92
17
18
19
2.0
2.0
2.0
2a
5c[b]
6[b]
6
24
24
95
90
91
20
2.0
5c[b]
24
89
21[e]
2.4
5c[b]
24
94
[a] The reaction of olefin (2.5ꢂ10À1 m) with NH2NH2·H2O in CH3CN was carried out in the presence of cata-
lyst (1.0 mol%) at room temperature (25–308C) under an atmosphere of O2. [b] 2.0 mol%. [c] GLC yield.
[d] The reaction was carried out with 4.0 equiv NH2NH2·H2O and a further 1.0 equiv NH2NH2·H2O was added
after 24 h. [e] The reaction was carried out at 508C.
Table 3. Product distribution in the reaction of 10.[a]
is employed as the receptor [G3PAP (15c)>G2PAP
(15b)>G1PAP (15a)]. This phenomenon can be ascribed to
the remote shielding effect of the benzene rings of 15, which
appears to significantly overcome the ordinary deshielding
effects of hydrogen-bonding association. The remarkable
upfield shift that is observed upon association of 1b with
15c indicates that specific aromatic protons of the dendri-
mer are located very close to the methyl protons of 1b. In
other words, an artificial deep cavity has been created in the
association complex 1b·15c in which even the outside cir-
cumferences of the 7- and 8-methyl groups of the flavin ex-
perience some shielding effect by the benzyl ether moieties
of the dendrimer. This deep cavity provides an artificial
Entry
PhOH [equiv]
Product ratio[b] [%]
11
12
13
1
2
3
4
0.2
1
5
100
94
40
0
0
5
4
0
6
55
74
20
22
[a] The reaction of 10 (2.5ꢂ10À1 m) in CH3CN was carried out in the pres-
ence of flavin catalyst 2a (1.0 mol%), phenol, and NH2NH2·H2O
(1.0 equiv) at 258C for 24 h under an atmosphere of O2. [b] The ratios of
the three products, 11, 12, and 13, were determined by GLC analysis.
attributed to its long phenylethyl linkers, which provide a
distance of approximately 25 ꢃ between the two branching
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Aerobic Reduction of Olefins
FULL PAPER
Table 4. Recycling of flavin catalysts in the aerobic reduction of 14.[a]
ure 3a. This dendrimer effect appears more prominently in
the reduction of o-allylphenol (19; Figure 3b). In contrast,
the dendrimers act as a retardant in the reduction of aliphat-
ic olefins such as 1-dodecene (20; Figure 3c), although a
slight acceleration effect by the hydroxy group has been ob-
served, as shown in the reduction of 11-undecen-1-ol (21;
Figure 3d). Such remarkable positive and negative effects
are not observed in any reaction with nonassociative dendri-
mer 16 (G2BAP) and nondendritic 17 (AAP), although
these receptors slightly accelerate the reactions on account
of their moderate Lewis acidity. This is unprecedented
enzyme-like catalytic activity, with aromatic or hydroxy ole-
fins being accelerated and aliphatic olefins deactivated with
high specificity.
Entry
Catalyst
Run[b]
Isolated yield [%]
1
2
3
4
5
6
7
2a
2a
5c
5c
6
1
2
1
2
1
2
3
95
34
93
64
93
94
94
6
6
[a] The reaction of 4-tert-butylstyrene (14; 1.25ꢂ10À1 m) with
NH2NH2·H2O (2.0 equiv) in CH3CN was carried out in the presence of
flavin catalyst (2.0 mol%) at 308C for 24 h under an atmosphere of O2.
[b] Extraction with hexane gave the alkane product and the CH3CN solu-
tion from the previous run was reused instead of recharging the catalyst.
Mechanistic investigation: The stoichiometry of the aerobic
reduction was examined in the reaction of 9-decen-1-ol with
NH2NH2·H2O (1.0 equiv) in the presence of neutral flavin
catalyst
6
(1.0 mol%) in
Table 5. Association constants and thermodynamic parameters for the complexation of 1b with bis(acylami-
CH3CN at 258C under air.
When 27 mol% of O2 was con-
sumed after stirring for 22 h,
the conversion of 9-decen-1-ol
was determined to be 58 mol%,
which is almost 2 molequiv of
O2. Given that 1 equiv of
NH2NH2·H2O is sufficient for
the completion of the reaction
in many cases (Table 2, en-
tries 1 and 4), the stoichiometry
no)pyridine receptors in CDCl3.
[a]
Entry
Receptor
Ka [mÀ1
]
DGo[b] [kJmolÀ1
]
DHo[b] [kJmolÀ1
]
TDHo[b] [kJmolÀ1
]
1
2
3
4
5
15a (G1PAP)
15b (G2PAP)
15c (G3PAP)
16 (G2BAP)
17 (AAP)
404Æ20
434Æ27
411Æ35
11Æ1
À15.1
À15.3
À15.2
À29.3
À28.8
À29.1
À14.1
À13.6
À13.9
437Æ60
À15.3
À32.9
À17.6
[a] Evaluated by nonlinear least-squares curve fitting of the data process assuming 1:1 complexation by
1H NMR analysis in CDCl3 at 303 K, as shown in Figure 1. [b] Determined on the basis of the van’t Hoff rela-
tionship using association constants estimated at 298–313 K (see the Supporting Information).
enzyme-like reaction pocket that shows unprecedented sub-
strate specificity, as described in detail in the next section.
The flavin–dendrimer complex catalysts 1b·15 exhibit
characteristic acceleration effects in the reduction of specific
olefins. Figure 3 shows the time-dependence of the product
yield in the aerobic reduction of various olefins with associa-
tion and nonassociation catalysts. Dendrimers 15a–c (G1–
G3PAP) activate the reduction of aromatic olefins such as
4-phenyl-1-butene (18), with the higher-generation dendrim-
ers exhibiting higher catalytic activities, as shown in Fig-
of the reaction can be rationally expressed as depicted in
Equation (1). The stoichiometric reaction of cationic flavin
2a with an excess of NH2NH2·H2O (5.0 equiv) and 9-decen-
1-ol (5.0 equiv) was examined at 258C in CH3CN under
anaerobic conditions (argon). UV analysis of the reaction
mixture showed that FlEt+ (2a; lmax =400 and 558 nm) was
converted quantitatively into reduced flavin FlEtH (22;
344 nm) with a sharp isosbestic point (see the Supporting In-
formation). GLC analysis showed that decan-1-ol was
formed in 96% yield based on 2a during this anaerobic pro-
cess [Eq. (9)]. These results strongly suggest that the catalyt-
ic reduction studied herein includes the anaerobic dehydro-
genation of hydrazine. On the basis that 2 mol of olefin can
be reduced with 1 mol of O2, the catalytic reduction can be
rationalized by a mechanism that includes two independent
steps for the generation of diimide, that is, anaerobic
[Eq. (10)][9b] and aerobic processes [Eqs. (11) and (12)].[5]
Figure 2. Plot of changes in the 1H NMR chemical shifts of the 7-CH3
(closed symbols) and 8-CH3 (open symbols) signals of flavin 1b versus
&
*
*
concentration of 2,6-bis(acylamino)pyridine receptors 15a (
,
), 15b ( ,
!
,
!
~ ~
,
&), 15c (
), and 17 (
) in CDCl3 at 303 K. [1b]0 =4.00ꢂ10À4 m.
Chem. Eur. J. 2011, 17, 5908 – 5920
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5913

Y. Imada, T Naota et al.
tions with catalyst 2a or 1a. A
clear dependence on the con-
centration of hydrazine was ob-
served in the reaction with cata-
lyst 1a (Figure 5b), whereas the
reaction under similar condi-
tions with catalyst 2a showed
much weaker hydrazine de-
pendence (Figure 5a). In con-
trast, O2 dependence was ob-
served exclusively in the reac-
tion with catalyst 2a (Fig-
ure 6a). These results strongly
suggest that the rate-determin-
ing step of the reaction with
catalyst 2a is the incorporation
of O2 [Eq. (11)], whereas the
rate-determining step of the re-
action with catalyst 1a is the
dehydrogenation or oxygena-
tion of hydrazine [Eqs. (10) or
(12)].
The initial reaction rates with
association catalysts 1b·15c and
1b·17 were also examined in
the aerobic reduction of 4-
phenyl-1-butene (18) in CHCl3
at 308C under similar condi-
tions. Similar to nonassociation
catalyst 1a (Figures 4b and 6b),
no significant dependence on
concentration of either olefins
or O2 was observed in the re-
duction reactions with 1b·15c
and 1b·17 (see the Supporting
Information). In contrast,
a
clear dependence on the con-
centration of hydrazine was ob-
served in the reduction reac-
tions with these two association
catalysts (Figure 7). Thus, it can
be concluded that all the sys-
tems with neutral flavin cata-
lysts exhibit a clear dependence
exclusively on the concentra-
tion of hydrazine. These results
Scheme 3. Bis(acylamino)pyridine dendritic receptors examined for supramolecular flavin catalysts.
To gain further insight into the mechanism, the concentra-
tion dependence on the initial rates of the catalytic reactions
was examined in the reduction of trans-5-decene (2.50–
5.00ꢂ10À1 m) with NH2NH2·H2O (2.50–5.00ꢂ10À1 m) in the
presence of a flavin catalyst (2a or 1a, 2.50ꢂ10À3 m) in
CH3CN at 308C under an atmosphere of O2 or air. Fig-
ures 4–6 show initial reaction profiles with varying concen-
trations of trans-5-decene (Figure 4), NH2NH2·H2O
(Figure 5), and O2 (Figure 6). The reaction profiles in Fig-
ure 4a and b indicate that the olefin concentration did not
have a significant influence on the initial rates of the reac-
indicate that the rate-determining step of the reduction with
all neutral flavin catalysts is the oxidation of hydrazine.
Note that the degree of hydrazine dependence increases in
the order of 1a<1b·17<1b·15c, as shown in Figures 5b and
7. Thus, we can be fairly certain that the rate-determining
step of this catalytic reaction is accelerated by both an in-
crease in Lewis acidity by hydrogen-bonding complexation
and the remote cavity effect of the dendron units. This is
consistent with the fact that the reactions of 18 and 19 are
accelerated in the order 1a<1b·17<1b·15c, as mentioned
in Figure 3a and b.
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Aerobic Reduction of Olefins
FULL PAPER
to proceed by similar anaerobic
processes with a flavin cata-
lyst.[9b] The olefin is reduced
with the associated diimide in
24 to give the alkane product,
molecular nitrogen, and re-
duced flavin 22. This anaerobic
process has been confirmed by
control experiments on the stoi-
chiometric reduction of 9-
decen-1-ol with NH2NH2 and
2a, which afforded decan-1-ol
and reduced flavin 22 under
argon [Eq. (9)]. The high hy-
drazine efficiency observed in
this catalytic process can be as-
cribed to the strong hydrogen-
bonding association properties
of the flavin species, which pro-
tects the diimide from self-dis-
proportionation [Eq. (4)] by
tight complexation. Reduced
flavin 22 reacts with O2 to
afford hydroperoxyflavin 25.[5]
Oxygen transfer to NH2NH2
and subsequent dehydration
give the second flavin–diimide
association complex 26, which
performs a similar reduction of
the second olefin to afford the
alkane product, molecular ni-
trogen, and hydroxyflavin 27.
Dehydration of hydroxyflavin
27 gives 2a to complete the cat-
alytic cycle. Given that (1) the
aerobic reduction gives 2 equiv
of olefin per 1 equiv of O2 and
(2) various amino compounds
are known to undergo N-oxy-
genation with flavin catalysts
under aerobic conditions,[7a,c]
one can safely state that this
aerobic reduction includes first
an anaerobic process followed
by an aerobic process to gener-
ate the diimide, although the
second aerobic process must
still be confirmed by direct evi-
Figure 3. Reaction profiles for the flavin-catalyzed aerobic reduction of a) 4-phenyl-1-butene (18), b) o-allyl-
phenol (19), c) 1-dodecene (20), and d) 10-undecen-1-ol (21). Conditions: olefin (6.3ꢂ10À2 m), NH2NH2·H2O
(2.5ꢂ10À1 m), flavin catalyst 1b (2.5ꢂ10À3 m), additional receptor 15a (G1PAP, 1.25ꢂ10À2 m; ), 15b (G2PAP,
*
1.25ꢂ10À2 m; ), 15c (G3PAP, 1.25ꢂ10À2 m; &), 16 (G2BAP, 1.25ꢂ10À2 m; ), 17 (AAP, 1.25ꢂ10À2 m; ), none
~
~
&
*
(
), CHCl3, 308C in air. Product yields were determined by GLC analysis based on an internal standard
(decane).
Figure 4. Concentration dependence of [trans-5-decene]0 in the aerobic reduction of trans-5-decene with hydra-
zine in CH3CN at 308C. Conditions: a) [2a]=2.50ꢂ10À3 m, b) [1a]=2.50ꢂ10À3 m, [trans-5-decene]0 =2.50ꢂ
À1
À1
10À1 m ( ), 3.75ꢂ10 m ( ), 5.00ꢂ10 m ( ), [NH2NH2·H2O]0 =2.50ꢂ10À1 m, O2 (1 atm).
&
*
*
dence to make
a definitive
Mechanism of the aerobic reduction of olefins: The aerobic
reduction of olefins with cationic flavin catalyst 2a can be
rationalized by the mechanism shown in Scheme 4. Nucleo-
philic attack of NH2NH2 at the 4a-position of 2a gives
adduct 4a-NH2NHFlEt (23), which undergoes elimination of
diimide by a 1,3-hydrogen shift to afford reduced flavin–di-
mechanistic conclusion. High O2 dependence, observed ex-
clusively in the reaction with catalyst 2a (Figures 4a, 5a, and
6a), strongly suggests that the rate-determining step of the
2a-catalyzed reaction is the incorporation of O2 into the re-
duced flavin 22 to form flavin hydroperoxide 25. This is con-
sistent with the experimental results that show that electron-
rich flavins accelerate the reactions (Table 1) if we assume
that the incorporation of O2 proceeds by rate-determining
ACHTUNGTRENNUNG
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5915

Y. Imada, T Naota et al.
flavin hydroperoxide 28 under-
goes elimination of H2O2 to
afford flavin–H2O2 association
complex 29. Oxygen transfer
from H2O2 in complex 29 to
NH2NH2 gives rise to the for-
mation of flavin–diimide com-
plex 30, which performs the
second olefin reduction. The
high concentration dependence
of NH2NH2, observed exclusive-
ly in the reduction with neutral
flavin 1a, strongly suggests that
the rate-determining step is the
Figure 5. Concentration dependence of [NH2NH2·H2O]0 in the aerobic reduction of trans-5-decene with hydra-
zine in CH3CN at 308C. Conditions: a) [2a]=2.50ꢂ10À3 m, b) [1a]=2.50ꢂ10À3 m, [trans-5-decene]0 =2.50ꢂ
À1
À1
10À1 m, [NH2NH2·H2O]0 =1.25ꢂ10À1 m ( ), 2.50ꢂ10 m ( ), 3.75ꢂ10 m ( ), 5.00ꢂ10À1 m (&), O2 (1 atm).
nucleophilic
addition
of
&
*
*
NH2NH2 to 1a or the oxygena-
tion of NH2NH2 with the associ-
ated H2O2. It is rare that the
rate-determining step can be
changed by the neutrality of the
catalyst. Considering that elec-
tron-deficient neutral flavins ac-
celerate the reactions, as shown
in Table 1, one can safely state
that the rate-determining step
of the reduction with a neutral
flavin catalyst is the nucleophil-
ic addition of NH2NH2 to 1a.
The acceleration with associa-
tion catalyst 1b·17 (Figure 5b
(1a) and 7b (1b·17)) is attribut-
ed to the high Lewis acidity of
17, which enhances the rate-de-
termining nucleophilic addition
of NH2NH2 to 1a upon hydro-
gen-bonding association.[26]
Figure 6. Dependence of the partial pressure of O2 in the aerobic reduction of trans-5-decene with hydrazine
in CH3CN at 308C. Conditions: a) [2a]=2.50ꢂ10À3 m, b) [1a]=2.50ꢂ10À3 m, [trans-5-decene]0 =2.50ꢂ10À1 m,
[NH2NH2·H2O]0 =2.50ꢂ10À1 m, O2 (1 atm, ), air (1 atm, ).
&
*
The
positive
generation
effect of the dendrimer com-
plex catalyst, observed specifi-
cally in the reduction of aro-
matic and hydroxy olefins
(Figure 3), can be ascribed to
the acceleration of the rate-de-
termining addition of NH2NH2.
As shown in Scheme 7, mixing
dendritic association complex
31 with hydrazine would give
rise to an equilibrium with the
NH2NH2-included complex 32.
Nucleophilic attack of the in-
cluded NH2NH2 on the flavin
Figure 7. Concentration dependence of [NH2NH2·H2O]0 in the aerobic reduction of 4-phenyl-1-butene (18)
with hydrazine in CHCl3 at 308C in the presence of associated flavin catalysts. Conditions: [1b]=2.50ꢂ10À3 m,
[15c]=1.25ꢂ10À2 m (a), [17]=1.25ꢂ10À2 m (b), [18]0 =2.50ꢂ10À1 m, [NH2NH2·H2O]0 =1.00ꢂ10À1 m ( ), 5.00ꢂ
*
10À1 m ( ), air (1 atm).
*
electron transfer from reduced flavin to O2 as a crucial step
(Scheme 5).[5]
Catalytic reduction with neutral flavin 1a proceeds by a
similar mechanism (Scheme 6). After the redox sequence in-
volving the anaerobic dehydrogenation of NH2NH2, the first
reduction of olefin, and O2 incorporation, the resulting
core affords diimide-included complex 33. Base on the as-
sumption that the association constant (Ka) of 31 with
NH2NH2 increases with a higher generation of the dendri-
mer unit, the rate-determining, anaerobic dehydrogenation
of NH2NH2 would be rationally accelerated according to the
rate equation d[33]/dt=kKa.[31]ACHTNUGTRNEG[UN NH2NH2]. Increasing Ka
5916
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Aerobic Reduction of Olefins
FULL PAPER
catalysts would have the possi-
bility of generating intermedi-
ates 34, which include more
than 2 mol equiv of diimide
inside the cavity due to the en-
hanced hydrogen-bonding prop-
erties caused by the benzyl
ether dendron unit (Scheme 8).
This would cause significant dis-
proportionation of the diimide
and subsequent decay in the
concentration
of
NH2NH2
during the reaction. Assuming
that the overall rate of the cata-
lytic reaction is controlled by
the rate-determining dehydro-
genation of NH2NH2, we can
suggest that this undesirable de-
crease in concentration of
NH2NH2 would give rise to a
gradual decrease in the reaction
rate. Aromatic and hydroxy
olefins would undergo faster in-
clusion inside the dendritic
cavity because of their strong
Scheme 4. Proposed catalytic cycle for the aerobic reduction of olefins with cationic flavin catalyst 2a.
stacking or hydrogen-bonding properties. Thus, these sub-
strates can consume the included diimide efficiently for
proper reduction. Scheme 9 shows a schematic representa-
tion of the inclusion of o-allylphenol inside the dendritic
cavity. Higher generation dendrimers would provide much
better opportunities for the inclusion and reduction of ole-
fins, which leads to a positive generation gap in the efficien-
cy of the reduction (Figure 3a, b, and d). In contrast, the
negative effect of the dendrimer observed in the reduction
of aliphatic olefins (Figure 3c) can be attributed to the low
inclusion properties of dendrimers towards aliphatic olefins,
which allows the disproportionation of the included diimide
before the reduction.
Scheme 5. Reaction of reduced flavin with molecular oxygen.
values in higher-generation dendrimers may be the result of
an increasing number of benzyl ether moieties, which would
capture much more NH2NH2 inside the cavity of the den-
drimers. Note also that the dendrimers do not influence the
O2 incorporation process significantly: No O2 dependence
was observed in the reduction with the flavin–dendrimer
complex catalysts.
The specific reactivity of aromatic and hydroxy olefins ob-
served in the reduction with dendrimer–flavin catalysts
might be explained by the localization of the olefins inside
the dendrimer cavity. This would be quite reasonable if the
rate-determining step of the catalytic reaction is the reduc-
tion of the olefins with diimide. However, kinetic studies re-
vealed that the initial rates of the reduction are independent
of the concentration of olefins, as shown in Figure 4. To ra-
tionalize this substrate specificity, we assume the self-dispro-
portionation of diimide, occurring locally inside the dendrit-
ic cavity, and its effective avoidance in the case of specific
olefins. Differing from the proposed 1:1 association of flavin
with diimide in CH3CN, the reaction with flavin–dendrimer
Conclusion
We have developed an efficient method for the generation
of a powerful reducing agent, diimide, by the anaerobic and
aerobic oxidation of NH2NH2 with synthetic flavin catalysts.
This method provides an efficient and convenient approach
to the aerobic reduction of olefins under mild conditions.
Neutral flavin derived from riboflavin acts as a practical cat-
alyst because of its high availability, stability, and reusability,
although a series of cationic flavins exhibit higher catalytic
activities. Unprecedented enzyme-type substrate specificity
has been observed in the reduction with association complex
catalysts of neutral flavin with dendritic 2,6-bis(acylamino)-
pyridines. A remarkable enhancement of catalytic activity is
exhibited exclusively in the reduction of aromatic and/or hy-
droxy olefins, whereas a contrasting negative dendrimer
effect is observed upon similar treatment of aliphatic olefins.
Chem. Eur. J. 2011, 17, 5908 – 5920
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5917

Y. Imada, T Naota et al.
Control experiments and kinet-
ic studies have revealed that
the catalytic reduction de-
scribed herein can proceed by
two independent processes,
anaerobic and aerobic, for the
generation of diimide, with an
unprecedented and significant
change in the rate-determining
step being observed by chang-
ing the neutrality of the flavin
catalyst. A positive dendrimer
effect, observed specifically
with aromatic or hydroxy ole-
fins, is a result of specific inclu-
sion properties of the interior
benzyl ether dendron units of
the flavin–dendrimer associa-
tion complexes.
Scheme 6. Proposed catalytic cycle for the aerobic reduction of olefins with neutral flavin catalyst 1a.
Acknowledgement
This work was supported by Grant-in-
Aids for Scientific Research from the
Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Scheme 7. Plausible rate-determining step for flavin–dendrimer complex catalysis.
Scheme 8. Competitive disproportionation of diimide occurring inside the dendritic cavity.
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Aerobic Reduction of Olefins
FULL PAPER
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[21] 10 equiv/H2O2 (7 equiv),[15] 40 equiv/NaIO4 (6.5 equiv),[16a] 85 equiv/
NaIO4 (20 equiv),[16b] 1.3 equiv/Se (2 equiv),[17] 10 equiv/PhSe(O)OH
(2 equiv),[18] 17 equiv/K3[Fe(CN)6] (5.5 equiv).[19] 11 equiv/CuCl
(0.2 equiv)/air,[20a]
200 equiv/Cu
(OAc)2 (0.27 equiv)/air.[20c]
400 equiv/CuSO4
(0.09 equiv)/O2,[20a]
and
AHCTUNGTRENNUNG
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