Substituent effects in the oxidation of 2-alkyl-1,4-dialkoxybenzenes with ceric ammonium nitrate

Article abstract of DOI:10.1016/j.tetlet.2016.11.042

Increased steric size of alkyl groups and the presence of coordinating atoms on alkoxy groups have both been found to contribute to decreasing yields of diquinones upon reaction of 2-alkyl-1,4-dialkoxybenzenes with CAN. The overall hydrophilicity of the substrates does not appear to be a significant factor in determining the diquinone yield for these reactions.

Full text of DOI:10.1016/j.tetlet.2016.11.042

Accepted Manuscript
Substituent Effects in the Oxidation of 2-Alkyl-1,4-dialkoxybenzenes with Ce-
ric Ammonium Nitrate
Brian E. Love, Alexander L. Simmons
PII:
S0040-4039(16)31510-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.042
TETL 48328
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
7 October 2016
2 November 2016
8 November 2016
Please cite this article as: Love, B.E., Simmons, A.L., Substituent Effects in the Oxidation of 2-Alkyl-1,4-
dialkoxybenzenes with Ceric Ammonium Nitrate, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.11.042
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Substituent Effects in the Oxidation of 2-Alkyl-1,4-dialkoxybenzenes with Ceric Ammonium Nitrate
Brian E. Love* and Alexander L. Simmons
Department of Chemistry, East Carolina University, Greenville, NC, 27858, USA
_______________
* Corresponding author. Tel: +1 252 328 9778; fax: +1 252 328 6210
E-mail address: loveb@ecu.edu
Abstract
Increased steric size of alkyl groups and the presence of coordinating atoms on alkoxy groups
have both been found to contribute to decreasing yields of diquinones upon reaction of 2-alkyl-1,4-
dialkoxybenzenes with CAN. The overall hydrophilicity of the substrates does not appear to be a
significant factor in determining the diquinone yield for these reactions.
Keywords
Quinone, Diquinone, Ceric Ammonium Nitrate, Oxidation
1

Treatment of 1,4-dimethoxybenzene derivatives 1 with ceric ammonium nitrate (CAN) is known
to result in their oxidation to the corresponding quinones 2.1,2 Diquinones 3 are occasionally observed as
byproducts of such reactions, and in some instances can even be the major product.1,2,3 We have been
interested in determining some of the factors that govern quinone/diquinone product ratios for such
reactions.4
Scheme 1. Oxidation of 1,4-dimethoxybenzene derivatives with CAN
Previously we have noted that reaction conditions (solvents, order of addition, etc.) can affect the
isolated yields of diquinones in these oxidations.5,6 For example, it was found that addition of acetonitrile
solutions of the aromatic substrate to aqueous solutions of CAN gave higher yields of diquinone 3 than
did additions of aqueous solutions of CAN to acetonitrile solutions of the aromatic substrate. Based on
the presumed mechanisms of these reactions (summarized in Scheme 2) one could imagine the fate of
radical cationic intermediate 4 playing a key role in determining the quinone/diquinone product ratio of
the reaction (though other factors such as extent of reversibility of the various steps and relative
intermediate stability could also be significant). Attack of intermediate 4 by aryl ether 1 could lead to
intermediate 5, which could eventually form diquinone 3 after a series of additional steps. On the other
hand, if intermediate 4 undergoes hydrolysis, quinone 2 would be the eventual product. (It has been
shown that 2 does not oxidize to 3 under such reaction conditions).5 Thus quinone/diquinone product
ratios would seem to be dependent upon the relative ease with which the two nucleophiles (aryl ether and
water) react with common intermediate 4.
2

Scheme 2. Partial mechanisms for the formation of quinones and diquinones
One possible explanation for increased diquinone formation upon addition of the aryl ether to the
CAN is that as the aryl ether solution is added dropwise to the aqueous CAN, aggregates of the aryl ether
molecules could form, due to their low solubility in water. This might be expected to increase the
likelihood that intermediate 4 would react with aryl ether 1 instead of water, and therefore favor
diquinone formation (compared to the situation in which aqueous CAN is added slowly to an acetonitrile
solution of the aryl ether, during which no such aggregation would be expected to occur). If this were
true, it would suggest that quinone/diquinone product ratios might be affected by the aqueous solubility of
the aryl ether substrate, with more hydrophilic substrates favoring quinone formation and more
hydrophobic substrates favoring diquinone formation. We therefore prepared a series of substrates in
order to test this hypothesis. Since earlier work had indicated that the electron density of the aromatic
ring could also influence quinone/diquinone product ratios,5 we limited our substrates to 2-alkyl-1,4-
dialkoxybenzenes in order to minimize such electronic effects.
Due to the ready availability of BHA 7a7 and the fact that 2-t-butyl-1,4-dimethoxybenzene 7b
produced significant quantities of both quinone and diquinone upon treatment with CAN, we initially
investigated the series of substrates 7 shown in Figure 1. We also investigated the analogous series of
3

compounds 8, since 8b had previously been shown by us5,6 and others1,2 to give almost exclusively the
diquinone product upon treatment with CAN under typical reaction conditions.
O
f R =
O
OCH3
a R = H
OR
OR
b R = Me
c R = Bn
g R =
NMe2
CH3
t-Bu
h R =
N
O
d R = (CH2)6CH3
e R = (CH2)9CH3
O
OMe
OMe
OCH3
OCH3
8
7
N
i R =
Figure 1. Initial 1,4-dialkoxybenzene derivatives investigated
If substrate hydrophilicity were to have a significant effect on quinone/diquinone product ratios,
one would expect 7c – 7e to have increased diquinone formation compared to 7b, while 7f – 7i would be
expected to have decreased diquinone formation. As can be seen from the data in Table 1, however, this
was not observed, leading us to conclude that substrate hydrophilicity is not a major factor in determining
quinone/diquinone product ratios.8
Table 1. Diquinone Percent Yieldsa Upon Treatment of 7 and 8 with CAN
Substituent:
Substrate 7:
Substrate 8:
b
c
d
e
f
g
h
i
46
43
57
49
nd
49b
41b
46
25
61
74
37
66
0
92
25
______________________
a
isolated yields
b substrate not completely soluble in volume of acetonitrile used, therefore added as a suspension
nd = not determined
There were several striking observations upon examining the data in Table 1, however. One is the
complete absence of diquinone formation when substrate 7i was treated with CAN. Instead, the
corresponding quinone 2 was obtained in 79% yield. (We will discuss this observation in more detail
shortly). Secondly, with a few exceptions, the substrates with a methyl group as the alkyl group (8)
generally gave higher diquinone yields than their t-butyl counterparts 7. This prompted a brief
4

investigation into the effects of the steric size of the alkyl group on diquinone yields. 1,4-
Dimethoxybenzene derivatives 1 (Figure 2) were prepared and were allowed to react with CAN under
similar reaction conditions9 as used for substrates 7 and 8. Results of these oxidations are presented in
Table 2.
OMe
e R = i-Bu
i R = c-hexyl
j R = t-Bu
k R = t-amyl
a R = Me
b R = Et
c R = n-Pr
d R = n-Bu
f R = neopentyl
g R = i-Pr
R
h R = s-Bu
1
MeO
Figure 2. Additional 1,4-dimethoxybenzene derivatives investigated
Table 2. Diquinone Percent Yieldsa Upon Treatment of 1 with CAN
Substituent:
a
b
c
d
e
f
g
h
i
j
k
Substrate 1:
93
75
77
78
76
73
60
55
63
46
43b
______________________
a
isolated yields
b
estimated10
Based on the data presented in Table 2, the steric size of the alkyl group at C-2 does appear to
have some effect on diquinone yield. While the methyl-substituted compound 1a produced the
corresponding diquinone 3 in approximately 90% yield, each additional substitution at the benzylic
carbon of the substrate lowered the diquinone yield by approximately 15%. Substrates bearing primary
alkyl groups (1b-1f) gave yields in the range of 75%, while those with secondary alkyl groups (1g-1i)
produced diquinones in the 60% range, and those bearing a tertiary alkyl groups (1j & 1k) had diquinone
yields of around 45%. If one looks at the five substituents that are nominally based on propyl groups (c,
e, f, h, & k), one sees that while substitution at the αcarbon results in significant yield differences
(compare c, h & k), substitution at the βcarbon has relatively little effect (compare c, e & f).
One possible explanation for this trend can be found in an examination of possible reaction
geometries for the carbon-carbon bond forming step of the reaction. In order to produce the observed
diquinone products, a carbon-carbon bond must be formed between C-5 of the two aryl ether molecules.
5

One can envision two possible geometries that would allow the C-5 p orbitals to overlap—one labeled
“end-to-end” in Figure 3 and the other labeled “stacked.”
Figure 3. Possible reaction geometries
While the size of the alkyl group would not be expected to have a significant impact on the “end-
to-end” approach of the two reactants, one might expect significant steric hindrance to the “stacked”
approach. Recent data have shown that in aqueous environments the “stacked” geometry is favored due
to hydrophobic effects.11 If, however, steric interactions between the alkyl side chains were to make this
mode of addition energetically less favorable, that might allow other processes (such as hydrolysis leading
to quinone formation) to compete more effectively.
While the steric size of the alkoxy group in substrate 7i might also be playing a role, the complete
lack of diquinone formation when this substrate is allowed to react with CAN suggested another factor
might be responsible. Though at present we lack definitive proof, one possible explanation is that the
carbonyl group in such substrates can stabilize the radical cationic intermediate 9 through formation of
bicyclic intermediate 10, as shown in Scheme 3. While intermediate 10 would not be expected to be as
effective an electrophile for undergoing electrophilic aromatic substitution with a molecule of aryl ether 1,
it could still undergo hydrolysis as shown, ultimately leading to quinone 2.
Scheme 3. Possible intermediate stabilization by alkoxy group substituent
6

To further investigate this phenomenon, a series of aryl ethers were prepared in which the alkoxy
group at C-1 contained either a tertiary amine or the corresponding tertiary amide. The compounds used
in this study are illustrated in Figure 4. Each of the substrates was treated with CAN under the “standard
reaction conditions”.8 Results of these experiments are summarized in Table 3.
O
OR
OR
OCH3
OCH3
OCH3
OCH3
N
N
k R =
l R =
i R =
j R =
CH3
t-Bu
O
NEt2
OMe
NEt2
OMe
8
7
Figure 4. Additional substrates investigated
Table 3. Diquinone Percent Yieldsa Upon Treatment of 7 and 8 with CAN
Substituent:
Substrate 7:
Substrate 8:
i
j
k
l
0
0
4
37
74
37
65
25
______________________
a
isolated yields
Inspection of the data in Table 3 reveals that the presence of the carbonyl group (substrates i and j)
significantly lowers diquinone yield compared to the amine-bearing substrates (k and l). Of course, this
does not prove the existence or significance of intermediates such as 10, since the alkoxy groups in
substrates i and j are also electronically different from those on substrates k and l, and that could also be
playing a role. Further investigation is required before the proposed explanation for the difference in
diquinone yields can be verified. One might also note, however, that diquinone yields for substrates 7k,
7l, 8k and 8l are all lower than those obtained for the corresponding methoxy-substituted substrates 7b
and 8b. Though still quite speculative, the possibility exists that the tertiary amines on the alkoxy group
7

can also stabilize the radical cation intermediate, only to a lesser extent than the corresponding amide.
Further studies aimed at clarifying the nature of this substituent effect will be undertaken.
In summary, investigation of the oxidation of a number of 2-alkyl-1,4-dialkoxybenzene
derivatives by CAN reveals that the overall hydrophilicity of the substrate does not appear to have a
significant effect on the isolated yields of diquinone products from such reactions. Additionally, it has
been found that increased steric size of the alkyl group and the presence of an appropriately placed
coordinating atom on an alkoxy group both contribute to lowering yields of the diquinone product by as
of yet undetermined mechanisms.
Acknowledgements
Work was supported by the Burroughs-Wellcome Fund, ECU Department of Chemistry, and
ECU’s Undergraduate Research/Creative Activity Award.
References and notes
1) Jacob III, P.; Callery, P. S.; Shulgin, A. T.; Castagnoli, Jr., N. J. Org. Chem. 1976, 41, 3627-3629.
2) Ali, M. H.; Niedbalski, M.; Bohnert, G.; Bryant, D. Synth. Commun. 2006, 36, 1751-1759.
3) Srikrishna, A.; Ravikumar, P. C.; Krishnan, H. S. Synthesis 2008, 1527-1534.
4) While diquinone products from such reactions were typically isolated in a high state of purity, the
analogous quinones were nearly always impure and were difficult to purify by standard means. Therefore
we’ve found it useful and more reliable to report data from these experiments in terms of diquinone yield
rather than quinone/diquinone mole ratios.
5) Love, B. E.; Bonner-Stewart, J.; Forrest, L. A. Synlett 2009, 813-817.
6) Love, B. E.; Duffy, B. C.; Simmons, Alexander L. Tetrahedron Lett. 2014, 55, 1994-1997.
7) Commercial BHA is actually a mixture of isomers, but samples we used were found to be almost
entirely the isomer shown as 7a.
8

8) Standard reaction conditions: a 1.0 mmol sample of the aryl ether was dissolved in 1.8 mL of
acetonitrile and was added slowly over several minutes to a rapidly stirred solution of CAN (1.92 g, 3.5
mmol) which had been dissolved in 1.8 mL of distilled water in a 10 mL round-bottom flask. After the
addition was complete, the mixture was stirred for an additional 1 hour at room temperature open to the
air. The mixture was diluted with 25 mL of water, and the resulting precipitate collected by suction
filtration. The precipitate was washed with several 10 mL portions of water and then finally with
approximately 5 mL of ice cold ethanol. The resulting yellow solid (diquinone) was dried at room
temperature under vacuum.
9) Reactions were conducted using twice the volume of solvent as described in “Standard reaction
conditions.”
10) The diquinone in this case was not isolated in pure form. Yield was estimated by NMR analysis of a
mixture of the quinone and diquinone.
11) Ikkanda, B. A.; Iverson, B. L. Chem. Commun. 2016, 52, 7752-7759.
9

Graphical Abstract
Effects of the nature of alkyl and alkoxy groups upon diquinone formation in reactions of 2-alkyl-1,4-
dialkoxybenzenes with ceric ammonium nitrate have been investigated.
10

Highlights
• Increasing size of alkyl group on aromatic substrate decreases diquinone yield
• Steric effect most significant at benzylic carbon
• Presence of a coordinating group decreases diquinone yield
• Hydrophobicity of substrate has little effect on diquinone yield
11