Oxoammonium salt oxidations of alcohols in the presence of pyridine bases

Article abstract of DOI:10.1021/jo402519m

Oxoammonium salt oxidations (using 4-acetylamino-2,2,6,6- tetramethylpiperidine-1-oxoammonium tetrafluoroborate) of alcohols containing a β-oxygen atom in the presence of pyridine yield dimeric esters, while in the presence of 2,6-lutidine the product is a simple aldehyde. The formation of a betaine between pyridine and an aldehyde is presented to explain this disparity in reactivity. The betaine is oxidized by the oxoammonium salt to give an N-acylpyridinium ion that serves as an acylating agent for ester formation. Steric effects deter the formation of such a betaine with 2,6-disubstituted pyridines. A series of alcohols containing a β-oxygen substituent were oxidized to aldehydes in the presence of 2,6-lutidine, and a short study of the relative reactivity of various alcohols is given. An overall mechanism for oxoammonium cation oxidations is suggested, premised on nucleophilic additions to the oxygen atom of the positively charged nitrogen-oxygen double bond. Possible mechanisms for both dimeric oxidations and simple oxidations are given.

Full text of DOI:10.1021/jo402519m

Article
pubs.acs.org/joc
Oxoammonium Salt Oxidations of Alcohols in the Presence of
Pyridine Bases
James M. Bobbitt,*,† Ashley L. Bartelson,†,‡ William F. Bailey,† Trevor A. Hamlin,†
and Christopher B. Kelly†
†Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269-3060, United States
‡Department of Chemistry, Seton Hill University, 1 Seton Hill Drive, Greensburg, Pennsylvania 15601, United States
S
* Supporting Information
ABSTRACT: Oxoammonium salt oxidations (using 4-acetylamino-
2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate) of
alcohols containing a β-oxygen atom in the presence of pyridine
yield dimeric esters, while in the presence of 2,6-lutidine the product is
a simple aldehyde. The formation of a betaine between pyridine and an
aldehyde is presented to explain this disparity in reactivity. The betaine
is oxidized by the oxoammonium salt to give an N-acylpyridinium ion
that serves as an acylating agent for ester formation. Steric effects deter
the formation of such a betaine with 2,6-disubstituted pyridines. A
series of alcohols containing a β-oxygen substituent were oxidized to
aldehydes in the presence of 2,6-lutidine, and a short study of the relative reactivity of various alcohols is given. An overall
mechanism for oxoammonium cation oxidations is suggested, premised on nucleophilic additions to the oxygen atom of the
positively charged nitrogen−oxygen double bond. Possible mechanisms for both dimeric oxidations and simple oxidations are
given.
systems. These have been summarized in our chapter in
Organic Reactions,2 in recent papers,4,5 and in several recent
reviews.6−11
INTRODUCTION
■
The oxoammonium cation, 1, along with various anions
(commonly tetrafluoroborate) can be used to oxidize primary
and secondary alcohols to aldehydes or ketones in high yield
and with convenient isolation procedures.1 Overall oxoammo-
nium ion chemistry can be summarized as shown in Scheme 1
In this paper, we are concerned with oxoammonium
oxidations in the presence of various pyridine bases. In 1998,
we reported that, although most alcohols were smoothly
oxidized to aldehydes or ketones with oxoammonium salts such
as 1a or 1b, alcohols containing a β-oxygen substituent were
not oxidized at all.1,12 In 2004, we reported that these alcohols
were oxidized by 1b to dimeric esters in good yields in the
presence of pyridine (4), and that alcohols without a β-oxygen
substituent (such as 1-octanol) could be oxidized to dimeric
esters in the presence of pyridine, albeit in low yield.13 Later,
we reported that oxidations with 1b in the presence of 2,6-
lutidine (5), gave good yields of aldehydes; this chemistry is
summarized in Scheme 2 and in more detail in a previous
paper.13,14
Scheme 1. Overall Oxidation and Reduction of
Oxoammonium Compounds
a
The use of pyridine bases in oxoammonium oxidations is not
unprecedented. The first use of this chemistry involved
electrochemical oxidations of alcohols and amines catalyzed
with TEMPO (2a).15−17 These reactions were carried out in
the presence of 2,6-lutidine (5). More recently, other
electrooxidations in the presence of 5 have been reported.18−21
Electrooxidations using nitroxides immobilized on a polymer
in the presence of 5 have also been discovered.18,22−24 2,6-
a
The R group and the anion are highly variable. In most of our work,
R = NHAc, and the anion is tetrafluoroborate.
for the TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, 2a)
derived compounds. The oxidant 1a/b can be reduced either
to the nitroxide 2a/b or to the hydroxyamine tetrafluoroborate
3a/b. The nitroxide, 2a or 2b, itself, can be used as a catalyst for
a large number of oxidations using various secondary oxidants.2
In addition, 2b can be used with p-toluenesulfonic acid as a
stoichiometric oxidant.3 There are several miscellaneous
oxidations using these reagents and several different nitroxide
Received: November 13, 2013
© XXXX American Chemical Society
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Scheme 2. Overall Oxidation of β-Oxygen Alcohols in the Presence of Pyridine Bases
Lutidine (5) has been used in stoichiometric oxoammonium
oxidations of trifluoromethyl carbinols25 and carbohydrates.26
Pyridine (4) itself has been used in conjunction with
oxoammonium salt 1b for the stoichiometric oxidation of
carbohydrates,27 β-oxygen alcohols,13 and long chain unsatu-
rated alcohols.28 It has also been recently used in TEMPO
catalyzed oxidations of alcohols and aldehydes.29,30 Alter-
natively, 2,2′-bipyridine (Bipy) can be used in place of 4 for
catalyzed reactions.31,32
Table 1. Oxidation of 6 in the Presence of Various Pyridine
Bases
In this paper, we present the experimental details related in
our initial presentation,14 and the mechanistic details of the
oxidations of β-oxygen alcohols in the presence of pyridine (4)
or 2,6-lutidine (5). In addition, we report the preparative
oxidations of β-oxygen alcohols with 1b in the presence of 5
and some relative reactivities of various alcohols under these
oxidizing conditions. Finally, we suggest an overall mechanism
for oxoammonium oxidations based upon steric effects.
Plausible mechanisms for the oxidations of simple alcohols to
aldehydes in the presence of pyridine bases are discussed.
RESULTS AND DISCUSSION
■
Oxidation of a Representative β-Oxygen Alcohol, 2-
Butoxyethanol (6), in the Presence of Various Pyridine
Bases.14 The oxidation of 2-butoxyethanol (6) with 1b in the
presence of various pyridine bases was explored. The results are
summarized in Table 1 and in Scheme 2. Bases with
substituents in the 2- and 6-positions predominantly gave
aldehydes, while bases with no substituents in these positions
gave dimeric esters. Since the difference in pKb’s among the
bases is minor,33 the controlling factor is likely steric. This is
supported by the fact that 2,6-di-tert-butylpyridine (entry 6,
Table 1) gives only the ester product despite being close in
basicity to pyridine. However, in the other cases, a mixture of
ester and aldehyde were obtained, implying that methyl groups
cannot completely impede the oxidative esterification pathway.
Oxidation of Mixtures of 2-Butoxyethanol (6) and 1-
Nonanol (9) in the Presence of Pyridine (4) or 2,6-
Lutidine (5). We further confirmed the results in Table 1 by
conducting a study of the relative oxidation reactions of 2-
butoxyethanol (6) in the presence of a suitable long-chain
primary alcohol, 1-nonanol (9). This was done by half-
oxidations of an equimolar mixture of the two alcohols in the
presence of 4 and in the presence of 5. The equations are given
in Scheme 3, and the results are shown in Figure 1.
a
b
pKb in H2O. Unless otherwise noted, values obtained from ref 33.
c
Yields were determined by GC analysis of product mixtures and
d
corrected for detector response. Taken from Hopkins, H. P and co-
workers, J. Am. Chem. Soc., 1984, 106, 4341.
nonanol (exact details provided in Experimental Section).
Compound 12 is known and was prepared as described in the
Experimental Section.
It is apparent from Figure 1 that the structure of the pyridine
base is crucial to product formation. The oxidations of the
alcohols 6 and 9 give only aldehydes in the presence of 2,6-
lutidine (5), implying that they are equally liable toward
oxidation (Figure 1a). In Figure 1b with pyridine, aldehyde 7 is
consumed quite rapidly and the two resulting esters 8 and 11
are observed. Compound 10 reacts significantly slower to give
the nonacyl esters 12 and 13. If the reaction is carried to
completion (Figure 1c), all four possible esters (8, 11−13) are
clearly observed. In Figure 1c, a small peak at 14.6 min
corresponds to nonanonic anhydride (14). The presence of this
side product is in agreement with a recent paper describing the
TEMPO (2a)-catalyzed direct oxidation of aldehydes to mixed
anhydrides.30
All of the peaks in the scans in Figure 1 were confirmed by
comparison with authentic samples. Compounds 6, 7, 9, 10,
and 13 are commercially available samples. Compound 8 was
prepared in our original paper.13 This leaves the two
unsymmetrical esters 11 and 12, of which, 11 has not been
reported and was prepared from butoxyacetic acid and 1-
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Scheme 3. Half-Oxidation of a Mixture of 2-Butoxyethanol (6) and 1-Nonanol (9)
From the results of Table 1 and Figure 1, we were able to
deduce a plausible mechanistic rationale, shown in Scheme 4.
The first step in the sequence is the oxidation of the β-oxygen
alcohol to its corresponding aldehyde, as expected. However,
the aldehyde then reacts with pyridine (4) to form, reversibly, a
betaine. Such a betaine does not form readily with 2, 6-lutidine
(5) due to the steric constraints of the methyl groups flanking
the pyridine nitrogen. We suggest that the rapidity in which 2-
butoxyacetaldehyde (7) is converted into its corresponding
ester product 8 may be attributed to the neighboring group
participation of the β-oxygen atom with the free 2-position of
pyridine. This interaction acts to stabilize the pyridinium
species, thereby enhancing its lifetime. Such participation has
been noted in carbocationic oxygen structures; therefore, a
similar interaction in this system is reasonable.34,35 This betaine
is then rapidly and irreversibly oxidized by 1b to an N-
acylpyridinium species, a highly reactive acylating agent. This
species is commonly cited as the key intermediate in
nucleophilic acyl substitution reactions.36−38 Such a mecha-
nistic path involving oxoammonium salts has not, to the best of
our knowledge, been proposed elsewhere in the literature.
Considering the two separate steps, oxidation and
esterification, we hoped to find a method to prepare
unsymmetrical esters from aldehydes and alcohols. To this
end, we investigated a wide range of alcohols in the presence of
benzaldehyde and hexanal. Unfortunately, yields were unac-
ceptably low. The best result was the oxidative esterification of
hexanal with isopropanol in 51% yield, eq 1.
These fluoroesters are formed in good yield and are themselves
good acylating agents.39
The second possibility is more complex and was discovered
in an experiment using a nonoxidizable alcohol, tert-butyl
alcohol. When benzaldehyde was oxidized in the presence of
pyridine and tert-butyl alcohol, we expected to get solely tert-
butyl benzoate, and we did observe the formation of the ester in
37% yield by GC/MS. However, a solid product that was later
found to be 1-[benzoyloxy-N-(1-phenylmethyl)]-piperidinium
tetrafluoroborate (15) was obtained in a 47% isolated yield, (eq
2). When a similar oxidation was carried out in the absence of
any alcohol, compound 15 was isolated in 83% yield, (eq 3).
The structure of compound 15 was proven by an
independent synthesis utilizing the method of French and
Adams,40 which produces the analogous chloride salt of 15, 19.
The chloride was converted to the tetrafluoroborate by an
anion-exchange reaction (eqs 4 and 5 in Scheme 5). One final
point is that benzoyl fluoride was observed as a very minor
product in these aldehyde oxidations. This fluoride has been
noted as a decomposition product of N-acylpyridinium
tetrafluoroborate.41
There are two explanations for the low yield of these
oxidative esterifications. The first possibility is that the alcohol
is oxidized to its corresponding carbonyl species before it can
react with the acylpyridinium intermediate. This possibility is
supported by a recent paper in which hexafluoroisopropanol
(HFIP) can be used successfully in the oxidative esterification
of aldehydes in the presence of 1b and pyridine.39 This
fluorinated alcohol reacts very slowly, if at all, with the
oxoammonium salt and therefore the alcohol is free to react
with the acylpyridinium intermediate to give HFIP esters.
We envision 15 as being formed from benzaldehyde and
pyridine through the betaine 16, oxidized by oxoammonium
salt to the acylpyridinium salt 17 and thence to 15 by reaction
with a second benzaldehyde (dotted arrows). This supports our
proposed intermediacy of a betaine in the oxidative
esterification pathway.
Preparative Oxidations in the Presence of 2,6-
Lutidine (5). There are appreciable differences between the
neutral/silica gel-catalyzed oxidations1 and oxidation reactions
in the presence of 2,6-lutidine (5). First, product isolation is
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Figure 1. The oxidations of a mixture of 2-butoxyethanol (6) and 1-nonanol (9) in the presence of 5 (a ∼ half oxidation) and 4 (b ∼ half oxidation
and c ∼ complete oxidation).
trivial in the simple neutral reactions1 and somewhat more
complex in the pyridine-mediated (“basic”) oxidation reactions.
In base reactions, one must remove the products, nitroxide 2b,
and lutidinium tetrafluoroborate. This is done by partially
evaporating the DCM, followed by precipitation of the
byproducts with dry Et2O. The ether solution is passed
through silica gel to remove any remaining byproducts. GC/
MS scans of these ether solutions are given in the Supporting
Information [SI].
The base-catalyzed reactions are, in general, capable of
oxidizing a much wider array of alcohols including the β-oxygen
alcohols in this paper, those with an electron-withdrawing
group in the 2- or 3-position,42 and those whose oxidations are
nontrivial (e.g., trifluoromethyl carbinols25). With the knowl-
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Scheme 4. Plausible Mechanistic Pathway to Explain Ester Formation
Scheme 5. Identification of 15
Table 2. Oxidations of Various Alcohols In the Presence of
2,6-Lutidine
a
edge that oxidations in the presence of 2,6-lutidine (5) would
give primarily aldehydes rather than esters in basic oxidative
reactions, we screened a number of β-oxygen alcohols. To
further minimize the formation of dimeric esters, the reaction
mixtures were made dilute, (20 mL of DCM per mmol of
alcohol). The results of the oxidations are given in Table 2. By
monitoring the progress of these reactions by NMR and GC/
MS, it was apparent that the oxidation was complete in about 1
h, although the subsequent reactions to give the byproducts
(Scheme 2 and Scheme 6, mechanism 2) was not complete for
about 4 h. Like the neutral reactions, which are colormetric,
turning from yellow to white, these oxidation are also
colorimetric, but turn from yellow to red.
a
Conditions unless otherwise noted: alcohol (1 equiv), 2,6-lutidine
1H NMR spectra are given in the SI for all of the crude
reaction mixtures described in Table 2. Integration of the
aldehyde peak against the peak for the C-4 proton in lutidinium
tetrafluoroborate tells whether the reaction did indeed take
place and the approximate conversion to the aldehyde.
(2.2 equiv), oxoammonium salt (2.4 equiv), DCM (0.05 M in starting
alcohol). Reaction progress was followed by H NMR.
b
1
suitable for tandem reactions since the products are free of any
other contaminants at this point. Accurate determination by
weight percent assay would be required in this case to
determine the yield of the aldehyde, although one can assume
that the yield is at least as good as the isolated yields. Less
Low-molecular-weight aldehydes were somewhat problem-
atic due to their volatility, and diminished yields were obtained
(entry 4). While these aldehydes can be isolated, the final
ethereal solutions obtained after silica gel chromatography are
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a
Scheme 6. Oxidations of Alcohols to Aldehydes or Ketones
a
The hydrides shifting are in red.
volatile, higher molecular weight aldehydes gave far better
isolated yields (entries 1−3, 5, 6).
hindered neopentyl alcohol (Table 3, entry 8) was 10 times less
prone to oxidation, despite being a primary alcohol.
When these oxidation reactions are combined with our
original paper on neutral, silica gel oxidations1 and the recent
paper on the preparation of HFIP esters,39 one can imagine a
tandem series of oxidations of almost any primary alcohol to
aldehydes and subsequently to HFIP esters, which themselves
can be further functionalized.39
GENERAL MECHANISTIC CONSIDERATIONS
■
There are two mechanistic aspects at work in the oxidations
presented in this paper. The first was previously discussed and
addressed differences in product formation in pyridine (4)- and
2,6-lutidine (5)-mediated oxidations (Scheme 4). The second
aspect is more general and involves the simple oxidation of
alcohols to aldehydes or ketones in the presence of pyridine
bases. There have been at least four general mechanistic studies
of oxoammonium ion oxidations.15,44−46 Two of the studies
explored deuterium isotope effects and indicated that the rate
determining step was the breaking of the α-hydrogen bond of
the carbinol. One study suggested that it was a proton cleavage
pathway,15 and one preferred a hydride transfer.44 We prefer
the hydride-transfer mechanism.
The Unique Oxoammonium Cation. Oxoammonium
cation oxidations are unique reactions characterized by high
yields, few side reactions, and readily isolable products. In this
section, we will explore the ramifications and principles of these
reactions. Although there are many reported nitroxides and
oxoammmonium salts,2,47,48 this discussion will be limited to
Relative Reactivities of Some Alcohols in the
Presence of 2,6-Lutidine (5). Finally, we have measured
the relative reactivities in some miscellaneous oxidations in the
presence of 2,6-lutidine (5) in Table 3. The primary alcohols,
interestingly, have negligible differences in reactivities and are
all set to a reactivity of 1 (Table 3, entries 2−4). This is in sharp
contrast to the rates noted by us in our preceding paper, where
benzyl alcohols and secondary alcohols were 10 and 2 times
more reactive, respectively, as compared to primary alcohols.1,43
However, there are small differences in benzyl alcohols with
varying ring electron densities (Table 3, entries 1, 2, 5), in
general accord with the earlier papers. Interestingly, secondary
alcohols are quite slow (Table 3, entries 6, 7), and this allows
good selectivity for primary alcohols. This has been observed
extensively in carbohydrate chemistry.2 Moreover, the sterically
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The oxoammonium cation can therefore behave as though the
positive charge is on the oxygen, effectively giving rise to an
electrophilic oxygen. This concept was originally suggested by
Golubev44 and discussed in detail in our review,2 but without
serious considerations of the steric substitution effects. It is
shown in Scheme 6 in mechanism 1. Such an effective
electrophilic oxygen is a rare situation in organic chemistry.
In most alcohol oxidation mechanisms, the electrons used to
form the carbonyl double bond come from the α-hydrogen bond
of the carbinol.50,51 In oxoammonium oxidations, the electrons
used to form the carbonyl double bond come from the
hydrogen−oxygen bond of the hydroxyl group by means of a
hydride transfer.44
Table 3. Relative Reactivities of Various Alcohols in the
Presence of 1b and 2,6-Lutidine (5)
a
Other oxidations involving hydride transfers (i.e. when
electrons used to form the carbonyl double bond come from
the hydroxyl group of the carbinol) are known. Three oxidation
systems involving a hydride transfer similar to the oxoammo-
nium system exist: the Oppenauer oxidation,52 the Canizzaro53
reaction, and in the action of alcohol dehydrogenase54 on
ethanol with NAD+ as a cofactor. The hydride transfer model of
oxoammonium cation oxidation implies that a transient
carbocation is formed at the α-carbon during the course of
an oxidation. Factors which seem to influence oxoammonium
oxidations of alcohols appear to be the electron density around
the carbinol carbon and the steric effects surrounding it. In
simple alcohols, the hydride transfer is facilitated by an
electron-rich hydroxyl group. In alcohols containing an
electron-withdrawing group close to the carbinol carbon such
as β-oxygen systems, α-CF3 systems, acyloxy alcohols42,55 and
the p-nitrobenzyl group (Table 2 and previously cited
cases1,43), this electron density is reduced, as is the reactivity.
The reactivity is also reduced in sterically hindered systems.
There are a number of oxidations that do not involve
alcohols but do involve hydride-transfer reactions. In the case of
benzyl hydrogens, activation is provided by a benzyl oxy-
gen,56−58 an amide nitrogen,57,59,60 an anilino nitrogen in a
tertiary amine,61 or in an α-position to an ester.59 These
reactions provide effective carbocations that can undergo
numerous cyclization reactions, many catalyzed by metal ions.
In some cases, the nucleophiles are unsaturated moieties such
as a suitably activated carbon−carbon double bond (three alkyl
groups),62 enols,45,63−66 enol ethers,67,68 enamines.64,69
Grignard reagents70 (to give N-alkoxytetramethylpiperidines),
and indole derivatives.71 For alkenes, enols, enol ethers,
enamines, and Grignard reactions the products are often stable
addition products.
a
The two alcohols being compared (both 1 equiv), 2,6-lutidine (2
equiv), oxoammonium salt (2 equiv), DCM (0.04 M in the alcohols).
b
1
Reaction progress was followed by H NMR and used to determine
the ratios between oxidized species.
the 2,2,6,6-tetramethylpiperidine system (as in compounds 1, 2,
and 3). Most, or all, of these oxidations are characterized by the
interaction of the oxoammonium cation with a nucleophile
(hydrides as well as other nucleophiles documented below).
Then, the question arises as to where nucleophiles might attack
the cation. In the cation, the nitrogen is surrounded by two
quaternary carbon groups and a double bond to oxygen. Thus,
for steric reasons, it is very likely that the nucleophilic attack is
on the oxygen in the positively charged nitrogen−oxygen bond
(NO+).2,3,14,46 This situation is clearly shown in Figure 2,
which includes a space-filling picture of a typical oxoammonium
ion.
Specific Oxidation Mechanisms. The mechanisms of
pyridine base-mediated oxidations (mechanisms 2 and 3 in
Scheme 6) make more sense if viewed in light of the neutral
oxidations (mechanism 1 in Scheme 6).1 Three mechanisms are
shown in Scheme 6.
The oxidation of an alcohol with a neutral oxoammonium
salt requires the transfer of a hydride and a proton to the salt
from the alcohol (Scheme 6, mechanism 1). The hydrogen
bonding in mechanism 1 was originally suggested in our review
as a reasonable mechanism since it seemed to offer a six-atom
transition state.2 Oxoammonium oxidations in the presence of
pyridine bases are quite different from the neutral reactions.
They are stronger oxidation systems (see above); the relative
reactivities of various alcohols are quite different (Table 2 and
previous papers1,43); and the isolation procedures are different.
Two possible mechanisms for the pyridine base reactions are
suggested in mechanisms 2 and 3 in Scheme 6. The electron
Figure 2. Reaction of the oxoammonium cation with nucleophiles.
A simple analogous functional grouping is the nitronium
cation NO2+ (ON+O), usually sold as its tetrafluoroborate
salt. This cation contains two nitrogen−oxygen double bonds,
but has no steric hindrance. Hence nucleophiles react with the
nitrogen to yield nitro compounds in many reactions.49
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Figure 3. NMR experiment showing the shift of the OH peak of acryloxyethanol in the presence of 4. Conditions: Black: 0.1 M acryloxyethanol in
CD2Cl2; Blue: 0.1 M 2-hydroxyethyl acrylate in CD2Cl2, 1 equiv 4; Red: 0.1 M acryloxyethanol in CD2Cl2, 2 equiv 4; Green: 0.1 acryloxyethanol in
CD2Cl2, 3 equiv 4.
Figure 4. Reaction profiles for the oxidation reaction of the H-bonded complexes with the oxoammonium species at B3LYP/6-311++g(d,p))//
B3LYP/6-31+g(d). Free energies relative to the reactants in DCM. Figures of transition-state structures can be found in the SI.
H
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cascade leading to the product can be initiated by the pyridine
base either through polarization of the alcohol (mechanism 2)
or by activation of the electrophilic oxygen in the
oxoammonium cation (mechanism 3). The ultimate products
of the oxidations shown in mechanism 2 and 3 are the same. It
should be noted that the pyridine bases serve two purposes:
they mediate the reactions and they react with the spent
oxidant to give tetrafluoroborate salts.
with the general nucleophilic attacks on oxygen described
above and shown in Figure 2. It is also interesting that in the
pyridine reactions, all of the primary alcohols are oxidized at
about the same rate, while in neutral reactions there is a
tremendous difference in the reactivities (allyl and benzyl, very
fast; alkyl much slower; and finally, the fact that secondary alkyl
alcohols are oxidized at almost twice the rate of similar primary
alcohols).1,43 This implies that the electronic configurations in
the alcohols are less important in the pyridine oxidations
because the initial reaction is similar for all cases and may be
the rate-controlling step. In essence, the pyridine facilitates the
same sort of displacement (by the hydride) as is shown in
acylpyridinium systems in Scheme 4 because it is a good leaving
group.
NMR spectra of mixtures of pyridine and oxoammonium salt
showed no evidence for the intermediate pyridinium complex
in mechanism 3, nor did an MS study using electrospray
ionization (ESI) measured on a Quattro II mass spectrometer.
There is some precedence for this hydride displacement
reaction. Salts of the N-methoxypyridinium ion are stable and
have been investigated in detail.75,76 N-Methoxypyridinium
perchlorate was treated with NaBH4 to give pyridine (isolated
as a picrate) and, presumably, methanol.76 This is quite similar
to the hydride displacement of an oxygen-containing
pyridinium as a leaving group in mechanism 3.
Mechanisms 1 and 2 in Scheme 6 show hydrogen bonding as
parts of the reactions. This is not true in mechanism 3. While
there is no direct evidence for any hydrogen bonding in
mechanism 1 except the convenient six-membered transition
state, there is some evidence for the hydrogen bonding in
mechanism 2. If one mixes an alcohol and pyridine, some heat
is given off, indicating a favorable intermolecular interaction of
some type is occurring. Further evidence of such an interaction
1
is observed by H NMR (Figure 3). The hydroxyl proton of
acryloxyethanol (Table 2, entry 4) in CD2Cl2 appears at about
2.0 ppm and has a well-defined hydrogen-bonded structure
given the sharpness of its signal. If one adds varying equivalents
of pyridine, the hydroxyl proton is shifted consistently
downfield and become far less defined, implying a mixed
mode of hydrogen bonding.72,73
In order to study the mechanism in base systems, we
attempted to model the three mechanisms using quantum
mechanical calculations with methanol as substrate and DCM
as solvent. The calculations on mechanisms 1 and 2 in Scheme
6 were made assuming hydrogen bonding, represented by
dotted lines, as in 26b−d in Figure 4. The thermodynamics of
these pathways were probed using B3LYP/6-311++g(d,p)/
PCM(DCM)//B3LYP/6-31+g(d)/ PCM(DCM) calculations;
details can be found in the SI. The energy of complexation is
enthalpically favorable for mechanisms 1 and 2 with DCM as
the implicit solvent (See Table 2 in the SI). It was not possible
to carry out calculations of mechanism 3.
A key feature of the hydrogen-bonding complexes is that it
enables polarization of the bonds, possibly resulting in greater
partial negative character of the α-hydrogen on the alcohol
substrate. This can effectively enhance the hydridic character of
the α-hydrogen and possibly lowers the activation energy of the
hydride-transfer step in the oxidations. The results of these
calculations are shown in Figure 4. It is clear from Figure 4 that
mechanism 1 has a much higher activation energy, thereby
making it a much slower reaction. This has been experimentally
observed; reaction times of neutral oxidations (mechanism 1)
are much longer (12−48 h) than analogous base reactions (1−
4 h).3 The role of the basicity of pyridine bases was also probed
in the calculations in mechanism 2. It is clear that the activation
barriers decrease with increasing basicity (Table 1). Thus, the
reactions should be faster for the more basic amines, which was
confirmed by a recent publication.25 While one cannot discount
such hydrogen bonding, the reaction could also simply be
written as a pyridine base-catalyzed reaction and is therefore
quite similar to mechanism 1 if the pyridine is considered as an
external base.
In most of the nitroxide-catalyzed oxidations with various
secondary oxidants,2 the bromide ion is a specific catalyst (not
chloride or iodide).74 Since bromide is a weak base and a good
leaving group, it is possible that it serves in the same role as do
the pyridine bases.
CONCLUSION
■
We have studied the reactions of oxoammonium cations with
alcohols in the presence of pyridine and pyridine derivatives
with various substitution patterns. Those pyridines having
substitution in the 2- and 6-positions lead to aldehyde
formation, and pyridines having little or no substitutions at
these positions lead to dimeric esters. A plausible mechanism
has been proposed to explain these results. We have defined
experimental conditions for the alcohol−aldehyde reactions
and studied the relative reactivities of several alcohols. Finally,
we suggest that oxoammonium oxidations occur by nucleo-
philic reactions on the charged nitrogen−oxygen double bond
and have suggested mechanisms for the other reactions in this
paper.
EXPERIMENTAL SECTION
■
General Methods. Oxidations were carried out under
nitrogen. Rotary evaporations of DCM and Et2O solutions
were carried out at about 80 mm (house vacuum) using a water
bath at 25 °C, and with the flask just touching the water. GC/
MS scans were measured on an HP-1 column (starting temp 40
°C, starting time at 40 °C for 2 min, 15 °C per min to a final
temperature of 270 °C). High-resolution mass spectra were
measured by the time-of-flight (TOF) method. NMR spectra of
the oxidation products were measured at 400 MHz with 5 mm
of molecular sieves 4 Å in the tube to dry the sample. When
noted, equiv refers to the molar equivalents.
The case for mechanism 3 is more difficult to make. There
are two reactions in this mechanism: (1) The reaction of
pyridine with the positive oxygen; (2) The collapse of this
intermediate to give products. We can find no precedence for
the first reaction, although one would intuitively expect that a
pyridine would react with the positive oxygen (or the oxygen−
nitrogen system) rather than extract a proton from the hydroxyl
group (as in mechanism 2). Such a reaction would be in accord
Chemicals. Although the oxoammonium salt 1b is
commercially available, our material was prepared from 4-
amino-2,2,6,6-tetramethylpiperidine on multimole scale using
our published protocol.6,77 It was recrystallized from water and
I
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Article
dried under vacuum at 80 °C.6,77 All other chemicals were
commercial samples used without purification. DCM, pyridine,
and 2,6-lutidine were dried over molecular sieves 4 Å.
Commercial dry Et2O was used without treatment.
2-Butoxyethyl Nonanoate (12).78,79 Compound 12 was
prepared by heating a mixture of nonanoyl chloride (1.76 g, 10
mmol, 1 equiv) and 2-butoxyethanol (6) (1.77 g, 15 mmol, 1.5
equiv) to 100 °C for 15 h. The mixture was dissolved in 50 mL
of DCM and filtered through a 4.5 × 2 cm pad of silica gel to
remove excess 2-butoxyethanol (6), giving 12 as a clear,
Comparative Oxidations of 2-Butoxyethanol (6) with
Various Pyridine Bases (Table 1). Oxoammonium salt 1b
(0.75 g, 2.5 mmol, 2.5 equiv), activated molecular sieves 4 Å
(0.5 g), and pyridine base (2.3 mmol, 2.3 equiv) were added to
40 mL of DCM and stirred for 30 min. 2-Butoxyethanol (6)
(0.118 g, 1 mmol, 1 equiv) was added dropwise, and the
mixture was stirred for 3 h, during which time it turned from
yellow to red, and some of the tetrafluoroborate salt of the
protonated base precipitated. Five drops of methanol were
added to the reaction vessel to complete the reaction, and the
mixture was filtered and evaporated to dryness. The solids were
triturated with dry Et2O (50 mL), and the Et2O solution was
passed over a column of silica gel (5 × 1 cm). The red−orange
nitroxide moved very slowly through the column. Elution was
continued until the red band neared the bottom of the column,
and the eluate was analyzed by GC on a 10 m × 0.53 mm OV-1
capillary column. The results were corrected by comparison
with known compounds, and the results are given in Table 1.
Partial Oxidations of a Mixture of 2-Butoxyethanol (6)
and 1-Nonanol (9) in the Presence of Pyridine (4) and
Separately with 2,6-Lutidine (5), (Scheme 4 and Figure
1). A mixture of 2-butoxyethanol (6) (0.236 g, 2 mmol) and 1-
nonanol (9) (0.289 g, 2 mmol) were dissolved in 100 mL of
DCM, and enough oxoammonium salt 1b (1.20 g, 4 mmol)
and base, either pyridine (4) (0.316 g, 4 mmol) or 2,6-lutidine
(5) (0.429 g, 4 mmol), to oxidize just one molar equivalent of
alcohol. After 4 h, the reaction mixture was concentrated under
vacuum to about 10 mL, and 50 mL of dry Et2O was added to
precipitate pyridinium or lutidinium tetrafluoroborate and most
of the nitroxide 2b. The GC/MS scans are given in Figure 1a
for the oxidations in the presence of 2,6-lutidine and in Figure
1b for pyridine. Some nitroxide remained in the Et2O solution
and appears at 11.8 min in Figure 1a−c.
1
colorless oil (2.25 g, 87%). H NMR (CDCl3, 400 MHz) δ
0.84−0.96 (m, 6 H), 1.19−1.43 (m, 12 H), 1.51−1.68 (m, 4
H), 2.33 (t, J = 7.58 Hz, 2 H), 3.46 (t, J = 6.60 Hz, 2 H), 3.61
(apparent triplet, J = 5.10 Hz, 2 H), 4.21 (apparent triplet, J =
4.90 Hz, 2 H) ppm; 13C NMR (CDCl3, 100 MHz) δ 14.1, 14.3,
19.5, 22.9, 25.2, 29.4, 29.4, 29.5, 31.9, 32.1, 34.5, 63.7, 68.8,
71.4, 174.1 ppm; HRMS (DART) calcd for C15H3103, [M +
H+] 259.2273, found 259.2237.
Oxidation of Hexanal to Isopropyl Hexanoate with
Oxoammonium Salt in the Presence of Pyridine (4), eq
1. A slurry of 1b (3.74 g, 12.5 mmol, 2.5 equiv), pyridine (4)
(1.60 g, 20.2 mmol, 4.04 equiv), and 4 Å molecular sieves (0.50
g, 0.1 g/mL of solvent) in 5 mL of DCM was stirred at rt, and a
mixture of hexanal (0.500 g, 5.00 mmol, 1 equiv) and 2-
propanol (0.371 g, 6.17 mmol, 1.23 equiv) in 1 mL of DCM
was added through a syringe pump over 30 min. After stirring
for 30 min, the resulting orange slurry was filtered, and the
residual white precipitate was washed with DCM. The filtrate
was reduced to dryness under vacuum. The orange residue was
triturated with 40 mL of dry Et2O, filtered and washed again
with two 10-mL portions of Et2O. The combined ethereal
solution and washings were reduced to approximately 5 mL
under vacuum and filtered through a pad of silica gel on a 5 cm
× 1 cm column using Et2O as the eluant. The eluate, which was
collected until the orange color reached the bottom of the
column, was washed with 10% aq. HCl (4 × 10 mL), deionized
water (2 × 10 mL), dried with Na2SO4, and concentrated to
yield isopropyl hexanoate (0.402 g, 51%). The compound was
found to be pure by GC and GC/MS and was identified by
comparison of its GC retention time and mass spectrum to that
of an authentic sample.
The experiment was repeated for pyridine but with enough
oxidant 1b (2.41 g, 8 mmol) and pyridine (4) (0.633 g, 8
mmol) to complete the oxidation. The mixture was worked up
the same way, and the results are shown in Figure 1c.
All of the products of the oxidations were on hand for
corroboration of the peaks except for the unsymmetrical esters
11 and 12. One ester, 1-nonyl 2-butoxyacetate (11) has not
been previously reported. The other ester, 2-butoxyethyl
nonanoate (12) is known, but no spectral data have been
reported for it.
Oxidation of Benzaldehyde with Oxoammonium Salt
in the Presence of Pyridine and tert-Butyl Alcohol, eq 2.
A slurry of 1b (3.78 g, 12.3 mmol, 2.43 equiv), pyridine (4)
(1.33 g,16.8 mmol, 3.33 equiv), and tert-butyl alcohol (0.893 g,
12.0 mmol, 2.38 equiv) in 30 mL of DCM was stirred at rt. To
this slurry, was added benzaldehyde (0.536 g, 5.05 mmol, 1
equiv) in 4 mL of DCM dropwise over 30 min. After stirring
overnight, the resulting orange slurry was filtered, and the white
precipitate was washed with DCM. The filtrate was reduced to
dryness under vacuum, and the orange residue was triturated
with 30 mL of absolute EtOH. The solid was isolated by
filtration and washed with EtOH to yield 15 (0.437 g, 46%).
This compound was identified by comparison of its mp and 1H
NMR to that of an authentic sample, prepared as described
below. The filtrate was evaporated to dryness under vacuum by
rotary evaporation, triturated with 30 mL of dry Et2O, and
filtered to remove the nitroxide (2b). The ethereal solution was
reduced to approximately 5 mL and chromatographed on a 5
cm × 1 cm column of silica gel using Et2O as the eluant. The
eluate, which was collected until the orange color reached the
bottom of the column, was reduced to dryness under vacuum
by rotary evaporation. Analysis of the residue by GC/MS on a
25 m × 0.2 mm × 0.33 μm HP-5 capillary column indicated
that it consisted of a mixture of tert-butyl benzoate and benzoic
acid. The compounds were identified by comparison of their
1-Nonyl 2-Butoxyacetate (11). 2-Butoxyacetic acid (1.75
g, 13.2 mmol, 1.32 equiv) and 1-nonanol (9) (1.44 g, 10 mmol,
1 equiv) were dissolved in 100 mL of benzene containing 1 g of
Amberlyst 15 (dry), and the mixture was heated to reflux within
a flask equipped with a Dean−Stark trap until no more water
collected (14 h). The Amberlyst 15 was removed by filtration,
and the filtrate was evaporated to dryness under vacuum. The
crude ester was distilled in a Kugelrohr to give 11 as a clear,
1
colorless oil (2.57 g, 100%). H NMR (CDCl3, 400 MHz) δ
0.83−0.95 (m, 6 H), 1.18−1.45 (m, 14 H), 1.55−1.68 (m, 4
H), 3.52 (t, J = 6.60 Hz, 2 H), 4.05 (s, 2 H), 4.14 (t, J = 6.85
Hz, 2 H) ppm; 13C NMR (CDCl3, 100 MHz) δ 14.1, 14.3,
19.4, 22.9, 26.1, 28.9, 29.5, 29.7, 31.9, 32.1, 65.2, 68.6, 71.9,
171.0; HRMS (DART) calcd for C15H3103, [M + H+] 259.2273,
found 259.2276.
J
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The Journal of Organic Chemistry
Article
GC retention time and mass spectra to those of the authentic
samples.
column of 15 g of silica gel (43 × 25 mm coarse, fritted funnel,
wet-packed). The solid was washed with two more 50-mL
portions of Et2O which were added to the column. The
nitroxide formed an orange band that moved very slowly
through the column while the aldehyde or ketone product came
out with the 150 mL of Et2O as a clear, colorless solution. The
Et2O eluate was analyzed by GC/MS to show the purity of the
product (suitable for tandem reactions); the Et2O was
evaporated to a constant weight to give an isolated yield; and
α-Benzoyloxybenzylpyridinium Tetrafluoroborate
(15), eq 3. A slurry of 1b (1.5 g, 5.00 mmol, 1 equiv),
pyridine (4) (0.456 g, 5.76 mmol, 1.15 equiv), and
benzaldehyde (0.825 g, 7.77 mmol, 1.55 equiv) in 20 mL of
DCM was stirred at rt overnight. The resulting red slurry was
then filtered, and the white precipitate was washed with DCM.
The combined filtrate and washings were reduced to dryness
under vacuum. The orange residue was triturated with 40 mL of
absolute EtOH and filtered. The precipitate was dried to yield
15 (0.782 g, 83%), identical in all respects to the 15 isolated in
1
the product was analyzed by H and 13C NMR.
The references for each known compound refer to published
NMR data.
eq 2. H NMR (CDCl3, 400 MHz) δ 7.41−7.53 (m, 5 H),
2-Butoxyacetaldehyde (20).80 2-Butoxyethanol (6)
(0.590 g, 5 mmol, 1 equiv) was oxidized by the General
Procedure to give 20 as a clear, colorless oil (0.566 g, 96%). 1H
NMR (CDCl3, 400 MHz) δ 0.93−0.99 (m, 3 H), 1.43 (dq, J =
14.98, 7.40 Hz, 2 H), 1.60−1.69 (m, 2 H), 3.56 (t, J = 6.60 Hz,
2 H), 4.08 (s, 2 H), 9.76 (s, 1 H) ppm; 13C NMR (CDCl3, 100
MHz) δ 14.0, 19.3, 31.8, 72.1, 76.5, 201.4 ppm.
1
7.57−7.65 (m, 1 H), 7.75−7.84 (m, 2 H), 8.06−8.14 (m, 4 H),
8.17 (s, 1 H), 8.50 (t, J = 7.83 Hz, 1 H), 9.24 (d, J = 6.11 Hz, 2
H); 13C NMR (CDCl3, 100 MHz) δ 77.5, 90.5, 127.1, 127.1,
129.3, 129.4, 130.2, 130.8, 131.9, 132.3, 135.3, 143.0, 148.3,
+
−
164.3 ppm; HRMS (ESI) calcd for C19H16NO2 , [M − BF4 ],
290.1181, found, 290.1190.
α-Benzoyloxybenzylpyridinium chloride (19), eq 4,
Scheme 5. The title compound was prepared following the
procedure of French and Adams.40 A mixture of benzoyl
chloride (4.90 g, 34.9 mmol, 1 equiv) and pyridine (4) (2.80 g,
35.4 mmol, 1.01 equiv) was allowed to stand overnight at rt.
After this time, benzaldehyde (3.70 g, 34.9 mmol, 1 equiv) was
added (CAUTION! Reaction is exothermic!). The white solid
that formed rapidly was dissolved in 30 mL of absolute EtOH
and precipitated by the addition of 400 mL of dry Et2O. The
mixture was filtered to yield 19 as a white solid (8.60 g, 76%),
2,2-Dimethyl-1,3-dioxolane-4-carboxaldehyde (21).81
2,2-Dimethyl-1,3-dioxolane methanol (solketal) (0.660 g, 5
mmol, 1 equiv) was oxidized by the General Procedure to give
1
21 as a clear, colorless oil (0.574 g, 87%). H NMR (CDCl3,
400 MHz) δ 1.41 (s, 3 H), 1.48 (s, 3 H), 4.07−4.12 (m, 1 H),
4.13−4.21 (m, 1 H), 4.38 (ddd, J = 7.21, 4.89, 1.83 Hz, 1 H),
9.71 (d, J = 1.71 Hz, 1 H) ppm; 13C NMR (CDCl3, 100 MHz)
δ 25.4, 26.5, 65.8, 80.1, 111.6, 202.08 ppm.
Tetrahydro-2H-pyran-2-carbaldehyde (22).82 Tetrahy-
dro-2H-pyran-2-methanol (0.580 g, 5 mmol, 1 equiv) was
oxidized by the General Procedure to give 22 as a clear, white
1
mp 188−191 °C [lit. mp 192 °C]; H NMR (CDCl3, 400
1
MHz) δ 7.36−7.47 (m, 5 H), 7.54−7.63 (m, 1 H), 7.99−8.12
(m, 4 H), 8.28 (t, J = 7.09 Hz, 2 H), 8.59 (t, J = 7.82 Hz, 1 H),
9.19 (s, 1 H), 10.12 (d, J = 5.87 Hz, 2 H) ppm; 13C NMR
(CDCl3, 100 MHz) δ 77.5, 89.4, 127.2, 127.4, 129.2, 129.9,
130.6, 131.4, 133.2, 133.2, 135.0, 143.7, 147.6, 164.1 ppm;
oil (0.479 g, 84%). H NMR (CDCl3, 400 MHz) δ 1.38−1.66
(m, 4 H), 1.79−1.94 (m, 2 H), 3.53 (td, J = 10.80, 3.42 Hz, 1
H), 3.81 (dd, J = 11.00, 2.69 Hz, 1 H), 4.01−4.10 (m, 1 H),
9.61 (s, 1 H) ppm; 13C NMR (CDCl3, 100 MHz) δ 22.8, 25.8,
26.5, 68.4, 81.8, 202.1 ppm.
+
−
HRMS (ESI) calcd for C19H16NO2 , [M − BF4 ], 290.1181,
Acryloxyacetaldehyde (23). 2-Acryloxyethanol (0.58 g, 5
found, 290.1172.
mmol, 1 equiv) was oxidized by the General Procedure to give
1
α-Benzoyloxybenzylpyridinium tetrafluoroborate
(15), eq 5, Scheme 5 by Exchange of Ions. A solution of
19 (3.91 g, 12.0 mmol, 1 equiv) and NaBF4 (1.33 g, 12.2 mmol,
1.02 equiv) in 60 mL of deionized water was stirred for 30 min
at rt, and the solution was filtered to yield 15 as a white solid
(2.67 g, 58%), mp 109−112 °C. This sample of 15 was
identical in all respects from that prepared as described in eq 3.
Preparative Oxidations; General Procedure. The
alcohol (5 mmol, 1 equiv), and 2,6-lutidine (5) (1.17 g, 11
mmol, 2.2 equiv) were weighed into a flask and diluted to 100
mL with dry DCM. The oxoammonium salt 1b (3.6 g, 12
mmol, 2.4 equiv) was added, and the mixture was stirred under
nitrogen. The yellow suspension gradually turned pink and
then red. In most cases, the reaction was complete after 4 h
with the exception of the secondary alcohols, which took 48 h
to completely oxidize. For several different alcohols, 0.5 mL
samples were withdrawn, quenched with 2 mL of dry Et2O,
centrifuged, and injected into a GC/MS. Alternatively, NMR
spectroscopy could be used to determine both the progress of
the reaction and approximate yield (see below).
23 as a clear, colorless oil (0.399 g, 70%). H NMR (CDCl3,
400 MHz) δ 4.72−4.78 (m, 2 H), 5.97 (d, J = 10.51 Hz, 1 H),
6.24 (dd, J = 17.24, 10.39 Hz, 1 H), 6.54 (d, J = 17.36 Hz, 1 H),
9.65 (s, 1 H) ppm; 13C NMR (CDCl3, 100 MHz) δ 68.9, 127.4,
+
132.9, 165.7, 196.0 ppm; HRMS (DART) calcd for C5H7O3
[M + H+] 115.0395, found, 115.0416.
1,2:3,4-Di-O-isopropylidine-α-galacto-hexodialdo-
1,5-pyranose (24).83 1,2:3,4-di-D-O-isopropylidene-α-D-galac-
topyranose (1.300 g, 5 mmol, 1 equiv) was oxidized by the
General Procedure to give 24 as a clear, colorless oil (1.258 g,
98%). 1H NMR (CDCl3, 400 MHz) δ 1.30 (s, 3 H), 1.33 (s, 4
H), 1.42 (s, 3 H), 1.49 (s, 3 H), 4.17 (d, J = 1.96 Hz, 1 H), 4.37
(dd, J = 4.89, 2.45 Hz, 1 H), 4.55−4.66 (m, 3 H), 5.65 (d, J =
4.89 Hz, 1 H), 9.60 (s, 1 H) ppm; 13C NMR (CDCl3, 100
MHz) δ 24.5, 25.0, 26.0, 26.2, 70.6, 70.7, 72.0, 73.5, 96.5, 109.3,
110.3, 200.4 ppm.
1-Phenoxypropan-2-one (25).84 1-Phenoxy-2-propanol
(0.760 g, 5 mmol, 1 equiv) was oxidized by the General
Procedure with the following modification: the reaction time
was increased to 48 h. Compound 25 was obtained as a clear,
1
The reaction mixture was concentrated to about 5−10 mL of
a viscous oil under vacuum. This oil was stirred, and 50 mL of
dry Et2O was slowly added. This precipitated about 65% of the
theoretical mass balance of a mixture of nitroxide 2b and 2,6-
lutidine tetrafluoroborate as an orange powder. The suspension
was allowed to settle, and the supernatant was poured onto a
colorless oil (0.727 g, 97%). H NMR (CDCl3, 400 MHz) δ
2.28 (s, 3 H), 4.53 (s, 2 H), 6.86−6.92 (m, 2 H), 7.00 (t, J =
7.34 Hz, 1 H), 7.27−7.34 (m, 2 H) ppm; 13C NMR (CDCl3,
100 MHz) δ 26.9, 73.3, 114.8, 122.0, 130.0, 158.0, 206.2 ppm.
1
Analysis of Crude Reaction Mixtures in DCM by H
NMR.85 The crude reaction mixtures consisted of an aldehyde
K
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The Journal of Organic Chemistry
Article
product, nitroxide 2b, and 2,6-lutidine tetrafluoroborate (the
proton peaks of the 2,6-lutidine tetrafluoroborate salt are
shifted downfield from those of 2,6-lutidine; methyl groups
from 2.5 to 2.8 ppm, C3 and C5 protons from 6.9 to 7.2 ppm,
and C4 from 7.4 to 8.3 ppm). The proton NMR spectra of the
mixtures were measured using a preset, external irradiation at
5.34 ppm, the peak of DCM. However, the presence of
nitroxide free radical 2b complicated matters and shifted every
peaks downfield (by the same amount).86 The nitroxide radical
itself could not be observed. Thus, the preirradiation had to be
corrected by measuring one scan and correcting the irradiation
to this position. The proton spectrum was then measured, and
the spectrum was referenced to the residual DCM signal at 5.34
ppm. For the aldehyde products, the aldehyde proton was
clearly seen. When the aldehyde proton was integrated and
compared with the peak of the proton on C-4 of 2,6-lutidine
(5), present in a known amount, it could be seen that an
oxidation had indeed taken place, and the approximate yield of
aldehyde could be calculated. The theoretical integral ratio for
100% conversion is 2.2. Spectra for each of the crude reaction
mixtures in Table 2 are provided in the SI.
Relative Oxidation Reactivities of Various Alcohols in
the Presence of 2,6-Lutidine (5), Table 3. The two alcohols
(2 mmol, 1 equiv) being compared were diluted with 50 mL of
DCM, and 2,6-lutidine (5) (0.428 g, 4 mmol, 2 equiv) was
added. The oxoammonium salt 1b (1.2 g, 4 mmol, 2 equiv) was
added, and the mixture was stirred for 4 h at rt. The solution
was filtered, and the supernatant was examined by NMR. When
the two aldehydes were compared, the relative aldehyde peaks
were integrated. Whereas, when a primary alcohol was
compared to a secondary alcohol, the appropriate peaks of
the products and reactants were integrated, and the relative
reactivity was calculated.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Proton NMR spectra of crude oxidation mixtures, GC/MS
scans of partial oxidations in the presence of 4-picoline and
(23) Kashiwagi, Y.; Yanagisawa, Y.; Kurashima, F.; Anzai, J.; Osa, T.;
Bobbitt, J. M. Chem. Commun. 1996, 2745−2746.
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1999, 51, 1945−1948.
2,4,6-collidine, ether eluates of pure aldehydes, and 1H and 13
C
NMR spectra for all products; GC/MS scans for all liquid
compounds along with the observed fragmentation patterns;
energies and Cartesian coordinates for all stationary points in
Figure 4. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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(28) Zakrzewski, J.; Grodner, J.; Bobbitt, J. M.; Karpinska, M.
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*E-mail: james.bobbitt@uconn.edu
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
(32) Furstner, A.; Aissa, C.; Chevrier, C.; Teply, F.; Nevado, C.;
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Partial funding was provided by Proctor and Gamble
Pharmaceuticals, Mason, Ohio. We express our thanks to
Professor Nicholas Leadbeater of the University of Connecticut
for support and help in this project. We also thank Dr. Martha
D. Morton and Dr. Vitaliy Gorbatyuk for help with NMR
spectroscopy, Dr. You-Jun Fu for help with the GC/MS work,
and to Dr. Santosh Keshipeddy for assistance with the details of
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