Iridium-Catalyzed Aerobic α,β-Dehydrogenation of γ,δ-Unsaturated Amides and Acids: Activation of Both α- And β-C-H bonds through an Allyl-Iridium Intermediate

Article abstract of DOI:10.1021/jacs.7b11351

Direct aerobic α,β-dehydrogenation of γ, δ-unsaturated amides and acids using a simple iridium/copper relay catalysis system is described. We developed a new strategy that overcomes the challenging issue associated with the low α-acidity of amides and acids. Instead of α-C-H metalation, this reaction proceeds by β-C-H activation, which results in enhanced α-acidity. Conjugated dienamides and dienoic acids were synthesized in excellent yield with this reaction, which uses a simple reaction protocol. Mechanistic experiments suggest a catalyst resting state mechanism in which both α-C-H and β-C-H cleavage is accelerated.

Full text of DOI:10.1021/jacs.7b11351

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Article
Iridium Catalyzed Aerobic #,#-Dehydrogenation of #,#-
Unsaturated Amides and Acids: Activation of Both #-
and #-C-H bonds through an Allyl-Iridium Intermediate.
Zhen Wang, Zhiqi He, Linrui Zhang, and Yong Huang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11351 • Publication Date (Web): 18 Dec 2017
Downloaded from http://pubs.acs.org on December 18, 2017
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Iridium Catalyzed Aerobic α,βꢀDehydrogenation of γ,δꢀUnsaturated
Amides and Acids: Activation of Both αꢀ and βꢀCꢀH bonds through
an AllylꢀIridium Intermediate
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Zhen Wang‡, Zhiqi He‡, Linrui Zhang and Yong Huang*
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University, Shenzhen
Graduate School, Shenzhen, 518055, China
Supporting Information Placeholder
ABSTRACT: Direct aerobic α,βꢀdehydrogenation of γ,δꢀunsaturated amides and acids using a simple iridium/copper relay catalysis sysꢀ
tem is described. We developed a new strategy that overcomes the challenging issue associated with the low αꢀacidity of amides and acids.
Instead of αꢀCꢀH metalation, this reaction proceeds by βꢀCꢀH activation, which results in enhanced αꢀacidity. Conjugated dienamides and
dienoic acids were synthesized in excellent yield with this reaction, which uses a simple reaction protocol. Mechanistic experiments sugꢀ
gest a catalyst resting state mechanism in which both αꢀCꢀH and βꢀCꢀH cleavage is accelerated.
the direct dehydrogenation of challenging amide, nitrile and ester
substrates. Very recently, Dong reported Lewisꢀacid assisted deꢀ
hydrogenation of imides5e but primary amides or acids are generꢀ
ally not tolerated in these reactions due to the presence of an acidꢀ
ic residue that interferes with enolate formation (Figure 1A). In
this paper, we report our findings in direct, aerobic, dehydrogenaꢀ
tion of γ,δꢀunsaturated amides and acids under conditions of Ir/Cu
relay catalysis.
INTRODUCTION
α,βꢀUnsaturated carbonyl compounds are arguably the most diꢀ
verse synthetic building blocks with remarkable chemical versatilꢀ
ity. Direct α,βꢀdehydrogenation takes advantage of the ubiquity of
alkyl aldehydes, ketones, esters, acids or amides, and is the most
straightforward strategy with which to access this important class
of α,βꢀunsaturated carbonyl compounds. Common strategies used
to affect direct dehydrogenation of carbonyl compounds are cenꢀ
tered on enolate chemistry.1 Earlier studies used stoichiometric
strong oxidants such as SeO2
(A) Genaral strategy for the
-dehydrogenation of carbonyl compounds
1aꢀ1d
or 1,4ꢀbenzoquinone derivaꢀ
O
H
O
O
H
tives1eꢀ1g for direct oxidization of ketones and aldehydes. The
reaction conditions involved are harsh and the reactions themꢀ
selves have limited substrate scopes. In 2000, Nicolaou developed
a general and mild method using oꢀiodoxybenzoic acid (IBX) as a
stoichiometric oxidant.2 More recently, environmental pressures
have prompted chemists to upgrade these methods with more
atomꢀeconomical and byproductꢀfree processes.3 As a result, inꢀ
vestigations have been focused on development of mild catalytic
conditions using air or molecular oxygen as the terminal oxidant.4
-elimination
M
X
R
X
R
X
R
deprotonation
oxidant
M
H
aldehyde > ketone > ester ~ nitrile > 2 amide > 1 amide ~ acid
decreasing -acidity
more challenging
1) Li-N base; 2) ZnCl2
3) Pd, allyl oxidant
Newhouse
Pd/ligand O2
Stahl, Huang
Wang, Kang et. al
[Cp*IrCl]BF4, Cu(OAc)2, air
This work
(B) Directed -C-H activation prohibits dehydrogenation
O
H
O
M
M
locked conformation
RHN
-C-H activation
prohibits hydride elimination
RHN
H
H
Recent reports by Stahl,4bꢀ4h Wang,4i,j Kang4k and us4l provide a
general solution to aerobic dehydrogenation of alkyl aldehydes
and ketones, using palladium catalysis. This reaction generates the
important α,βꢀunsaturated aldehyde and ketone products with high
efficiency under mild conditions. Aerobic dehydrogenation of
amides and acids is however, far more challenging,5 notwithstandꢀ
ing the prevalence of such compounds in biomass and industrial
feedstocks. The mechanism of aerobic dehydrogenation of aldeꢀ
hydes and ketones shares a common intermediate: the palladium
enolate. Due to the weak acidity of the αꢀCꢀH of amides and acids,
it is difficult to identify catalytic conditions that can promote metꢀ
al enolate formation, the subsequent βꢀhydride elimination and
catalyst reꢀoxidation, all at the same time. Recently, Newhouse
reported palladiumꢀcatalyzed, direct α,βꢀdehydrogenation of amꢀ
ides, esters and nitriles via a zinc enolate intermediate.5c,d The
palladium turnover was accomplished using allyl acetate as the
terminal oxidant. Despite the use of stoichiometric lithium amide
base and allyl acetate, this strategy represents a major advance in
(C) Activation of both
and C-H using Ir (this work)
M
O
O
O
M
O
H
O
O
R
N
Y
H
H
H
H
Cu, air
Y = NHR, NR2, OH
Directed C-H activation followed by
accelerated -deprotonation
O
Y
O
O
O
O
OH
O
OH
N
Me
Sorbic acid
H
Me
Trichostatin A
N
Me
Me
Me
Me
OH
O
Me
O
O
O
H
O
OH
HO
H
O
N
Cl
Tylactone
O
O
Piperine
Radicicol
Figure 1. Direct dehydrogenation of carbonyl compounds
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Our group has long sought catalytic conditions for aerobic deꢀ
RESULTS AND DISCUSSION
hydrogenation of amides, esters and acids. Due to the limited α–
acidity of these compounds, use of various Lewis acid activators
to form a sufficient concentration of the metal enolates was largeꢀ
ly unsuccessful. Accordingly, we examined alternative strategies
whose rateꢀlimiting step does not require formation of metal enoꢀ
lates. Amides and acids have been well documented as excellent
directing groups for selective βꢀCꢀH insertion by various transiꢀ
tion metals6 but, in spite of significant advances in CꢀH functionꢀ
alization reactions in recent years, βꢀCꢀH activation has not been
applied to dehydrogenation reactions.7 The use of a directing
group locks the transition metal into a cyclic metal complex (Figꢀ
ure 1B), in a conformation that disfavors hydride elimination,
both sterically and electronically. In order to solve this problem,
we proposed a means of releasing transition metals from the diꢀ
recting group by forming metalꢀallyl complexes. Metalꢀallyl comꢀ
plexes are classical electronꢀdeficient species that react readily
with various nucleophiles under mild conditions.8 Despite a pioꢀ
neering report by White on dehydrogenation of terminal olefins,
direct dehydrogenation of olefinic amides and acids remains eluꢀ
sive.9 We hypothesized that the electronꢀwithdrawing property of
metalꢀallyl complexes can be harnessed by enhancing the α–
acidity of amides and acids to forge a new protocol for aerobic
α,βꢀdehydrogenation of γ,δꢀunsaturated amides and acids. The
enhanced α–acidity of the metalꢀallyl intermediate resembles that
of 1,3ꢀdicarbonyl compounds, whose enolates are stabilized by an
additional π* orbital from the second carbonyl (Figure 1C). The
resulting conjugated dienyl carbonyl products are versatile synꢀ
thetic intermediates and often exist as key fragments in various
natural products and their metabolites.
To test this proposal, we began our investigation by exploring
the use of transition metals for the α,βꢀdehydrogenation of Nꢀ(4ꢀ
methoxybenzyl)pentꢀ4ꢀenamide (1) in 1,2ꢀdichloroethylene
(DCE). Initially, 2.2 equivalents of Cu(OAc)2 hydrate were used
as the terminal oxidant. Most palladium catalysts were found to be
ineffective in promoting the dehydrogenation. The intramolecular
Wacker oxidation was the major side reaction that resulted in a
cyclization product (Table 1, entry 1).10 No dehydrogenation
occurs with nickel, cobalt and rhodium (entries 2ꢀ4) but use of 10
mol% ([Cp*IrCl2]2) and 25 mol% AgBF4 produced the desired
dienamide (2) in 54% yield at 60 ºC (entry 5).11,12 Solvent screenꢀ
ing led to the identification of dioxane as the optimum medium
for this reaction. Product 2 was formed in 80% NMR yield (entry
5ꢀ11). Considering the undesirable use of super stoichiometric
copper acetate as the terminal oxidant, we examined coꢀcatalysts
to turnover the previous Ir using molecular oxygen or air. Copper
acetate hydrate was found to be a unique coꢀcatalyst that turns
over the iridium under air (entry 5, 12ꢀ15). The loading of both
[Cp*IrCl2]2 and Cu(OAc)2•H2O can be lowered to 2 mol% and 4
mol%, respectively without compromising the yield (entry 16,
see SI for detailed optimization of conditions). Although the loadꢀ
ing of Cu can be further lower to 1 mol%, for the convenience of
weighing, 4 mol% was used for the substrate scope study. Control
experiments showed that Ir, Ag and Cu are essential for the aeroꢀ
bic dehydrogenation (entry 17ꢀ18). The reaction is remarkably
clean, the only byproduct being water. Simple filtration through a
short plug of silica gel affords the product in high purity as judged
by NMR. No column chromatography is necessary.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Screening of conditions of the dehydrogenation reactiona,b
entry
1c
2
catalyst
Pd(OAc)2
additive
DAF
solvent
DCE
oxidant
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
BQ
yield(%)b
0
0
Ni(acac)2
/
DCE
3
[Cp*Co(CO)I2]
[Cp*RhCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
/
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
/
DCE
0
4
DCE
0
5
DCE
54
76
0
6
DMF
7
DMSO
MeCN
toluene
MTBE
dioxane
DCE
8
17
54
32
80
0
9
10
11
12
13
14
15
16d
17
18
DCE
PhI(OAc)2
24
10
<5
>99e
0
DCE
Ag2O
DCE
O2
Cu(OAc)2•H2O /air
Cu(OAc)2•H2O /air
Cu(OAc)2•H2O /air
dioxane
dioxane
dioxane
[Cp*IrCl2]2
8%
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[Cp*IrCl2]2
AgBF4
dioxane
air
<5
3
4
5
6
a Reactions were conducted using 0.1 mmol 1, 10 mol% catalyst, 25 mol% additive or ligand, 0.22 mmol oxidant, in 1 mL solvent under
b
c
Ar at 60 °C for 12 h. The yield was determined by NMR integration using 1,4ꢀdinitrobenzene as the internal standard. 12 mol% 4,5ꢀ
d
diazafluorenone (DAF) was used under O2. Reactions were conducted using 2 mol% [Cp*IrCl2] 2, 5 mol% AgBF4, 4 mol%
Cu(OAc)2•H2O under air. e Isolated yield.
7
8
9
Table 2. Substrate Scope a,b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[IrCp*Cl2]2 (2 mol%)
AgBF4 (5 mol%)
O
H
O
Cu(OAc)2.H2O (4 mol%)
R1
R1
X
R4
X
R4
air, 1,4-dioxane
60 or 90 °C
R2
H
O
R3
R2
R3
Amides:
O
O
Br
O
O
N
H
N
H
N
H
N
H
n-Pr
S
N
n-Pr
H
MeO
MeOOC
2, >99%
3, 99%
4, 99%
5, 95%c
6, 97%
F3C
O
O
O
O
O
Ph
N
n-Pr
N
H
n-Pr
HO
N
H
n-Pr
N
n-Pr
N
H
n-Pr
H
H
7, 81%c
8, 78%d
9, 98%f
10, 90%c
11, 97%f
O
O
O
O
O
O
N
H
N
n-Pr
N
n-Pr
N
H
N
n-Pr
O
O
MeO
O
12,73%e,g,h
13, 81%f,g,h
14, 75%e,g,h
15, 92%c
16, >99%
O
n-Pr
O
O
Ph
Br
Ph
Cl
Ph
Ph
N
N
H
N
N
H
H
H
17, 94%f
18,
19, 99%e
20, 98%e
96%e
O
O
O
O
O
Ph
PMB
OMOM
Ph
OAc Ph
N
H
OTBDPS
N
N
H
N
N
Ph
H
H
H
21, >99%e
22, 98%e
23, 97%e
24, 71%d
O
O
O
O
O
PMB
PMB
PMB
PMB
PMB
N
N
H
N
N
N
H
H
H
H
COOMe
Br
F
Cl
29, 85%e,g,h
26, 75%e,g,h
27, 74%e,g,h
28, 75%e,g,h
25, 73%e,g,h
O
O
O
O
Ph
Ph
Ph
Ph
N
CN
n
N
N
N
O
H
30a, n=1, 96%c
30b, n=2, 97%c
H
H
H
31, 80%e
32, 96%c
Acids:
O
O
O
O
O
HO
HO
OTBDPS
HO
Br
HO
HO
33, 64% (77%)i,j
34, 67% (76%)i,j
35, 40% (55%)g,j
36, 66% (73%)i,j
37, 68% (79%)g,j
Cl
Ketone:
O
O
O
O
O
Me
HO
HO
HO
Br
38, 83% (86%)g,j
39, 75% (89%)g,j
40, (52%)i,j
41, 55% (63%)g,j
42, (76%)g,j
Other substrates:
O
O
Ph
O
O
Ph
N
N
N
H
Ph
N
H
+
H
H
MeO
MeO
MeO
43, 0%g
44, 0%g
45a, (34%)g
45b, 44%g
Nitrile:
O
Ester:
O
O
Ph
N
NC
Ph
O
H
O
Me
MeO
46, <1%g
47, (15%)g,j
48, (10%)g,j
49, 0%g,j
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aUnless specified, reactions were performed using 0.1 mmol of substituted amides, 2 mol% of [Cp*IrCl2]2, 5 mol% of AgBF4, 4 mol%
Cu(OAc)2•H2O in 1 mL dioxane under air atmosphere at 60 oC for 12 h. b Isolated yield. Numbers in parentheses are NMR yield. c Run for
20 h. d Run for 36 h. e Run for 14 h. f Run for 24 h. g Run at 90 oC. h 4 mol% of [Cp*IrCl2]2, 10 mol% of AgBF4, 4 mol% Cu(OAc)2•H2O
were used. i Run at 50 oC. j 4 mol% of [Cp*IrCl2]2, 7.5 mol% of AgBF4, 4 mol% Cu(OAc)2•H2O was used.
5
With the optimized dehydrogenation conditions in hand, we
next surveyed the substrate scope and the functional group comꢀ
patibility associated with this transformation (Table 2). Various
Nꢀalkyl amides and Nꢀaryl amides were examined. NꢀBenzyl and
Nꢀaryl amides bearing either electronꢀdonating or electronꢀ
withdrawing groups are well tolerated. Notably, the bromide (6)
and compounds with free hydroxyl groups (7) are unaffected. The
primary (9), secondary (10) and tertiary (11) Nꢀalkyl amides afꢀ
ford excellent yields. N,NꢀDialkyl amides react more slowly, reꢀ
quiring 90°C and 4 mol% [Cp*IrCl2]2. The increased steric crowdꢀ
ing of the carbonyl might weaken its coordination to the Ir cataꢀ
lyst in this case. Interestingly, the carbamate derivative (14) can
also be dehydrogenated in high yield.
terminal olefins fail to undergo the dehydrogenation under the
standard conditions.5b,9
6
7
8
9
O
O
[IrCp*Cl2]2 (2 mol%)
AgBF4 (5 mol%)
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
N
n-Pr
N
n-Pr
Cu(OAc)2.H2O (4 mol%)
air, 1,4-dioxane, 60 °C
H
H
50
9
Variations in the acyl chain were also investigated. Substitution
at the γꢀ, and δꢀatoms and beyond does not affect the dehydroꢀ
genation (15, 16) and the olefin geometry of the starting material
is preserved. Excellent yields are obtained of the Zꢀolefinic amide
(17). Low conversion is observed for αꢀ substituted substrates (46).
βꢀSubstituted olefin amides undergo smooth dehydrogenation.
The corresponding dienamides are prone to isomerization and a
mixture of olefin isomers were obtained (45a and 45b). Functionꢀ
al groups including alkyl halides (18, 19), alkenes (20), silyl
ethers (21), ethers (22), esters (23) and amides (24, 31) are all
tolerated and high to quantitative yields are obtained for these
substrates. Substrates with a styrene functionality react smoothly
at 90°C (25ꢀ29). Exclusive regioselectivity is observed for subꢀ
strates containing two carbonyl groups. Side chains with an addiꢀ
tional carbonyl group for example, amide (31), aldehyde (32) and
nitrile (30), are unaffected. The dehydrogenation occurs excluꢀ
sively between the αꢀ and βꢀcarbons of the Nꢀalkyl amides. The
γ,δꢀ olefin is essential for this reaction. No conversion to 43 and
44 was observed using saturated alkyl amide substrates. The startꢀ
ing materials were recovered quantitatively. Most of the products
listed in Table 2 can be isolated by simple filtration as mentioned
above. The NMR spectroscopic data shown in the Supporting
Information were collected without additional purification. The
reactions performed at 90 °C generate small amounts of oligomerꢀ
ic side products, which can be removed by column chromatogꢀ
raphy.
Figure 2. Dehydrogenation profile. Blue dot: [9], red dot:
[50]. Data were fit (R2 = 0.99) to linear relationship.
Preliminary kinetics studies were carried out. The correlation of
[50] and [9] vs time was measured. From 0 to 12 hours, the
change of substrate and product concentration maintains a linear
relationship to time. The reaction rate remains constant regardless
of [50]. This data support pseudo zeroꢀorder with respect to the
amide substrate (resting state approximation, Figure 2). We specꢀ
ulate a substrateꢀbound catalyst resting state might be responsible
for this observation.
Scheme 1. Control Experiments and KIE Studies
In addition to amide groups, carboxylic acid has also been
demonstrated to be an effective directing group promoting the βꢀ
CꢀH insertion reaction.13 After minor modifications of the reaction
conditions, we found the reaction using (E)ꢀoctꢀ4ꢀenoic acid perꢀ
forms well with 4 mol% [Cp*IrCl2]2, 7.5 mol% silver and 4 mol%
copper. The dienoic acid (33) was obtained in 64% yield. A numꢀ
ber of olefinic acids react under the dehydrogenation reaction
conditions. Silyl ethers (34), alkenes (35), alkyl halides (36), aryl
groups (37 to 39) and aryl halides (37, 39) are all tolerated and
return moderate to good yields of the product. Interestingly, γ,δꢀ
enones also undergo the desired α,βꢀdehydrogenation with similar
efficiency as acids (41, 42). Previous conditions of ketone dehyꢀ
drogenation reported by Stahl4c and us4lare restricted to βꢀaryl
ketones and cyclic ketones. In these cases, long chain ketones
suffer from double and multiple dehydrogenation, outcomes that
cannot be controlled. In this case, the dienone is obtained without
these complications. Reactions involving ester (47, 48) and nitrile
(49) are sluggish, suggesting that the metal binding affinity of the
directing group is important for the βꢀCꢀH metalation step. Simple
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a Cu loading
Supporting Information
O
O
standard conditions
3
4
Ph
Experimental procedures, analytical and spectroscopic data for
new compounds, copies of NMR spectra. This material is availaꢀ
ble free of charge via the Internet at http://pubs.acs.org
Ph
N
H
n-Pr
N
H
n-Pr
Cu (x mol%), 2.5 hr
50
9
0.1 mol%, 2%
2 mol%, 18%
1 mol%, 18%
4 mol%, 18%
x =
5
6
7
8
9
b Ir/Ag ratio
AUTHOR INFORMATION
[IrCp*Cl2]2 (2 mol%)
AgBF4 (x mol%)
O
O
O
Ph
Ph
Ph
N
H
n-Pr
x = 4, 61%
N
H
n-Pr
Cu(OAc)2.H2O (4 mol%.)
Corresponding Author
50
air, 1,4-dioxane, 60 °C, 12 hr
9
huangyong@pkusz.edu.cn
x = 8, 26%
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c Air vs O2
Author Contributions
‡Z. Wang and Z. He contributed equally.
O
standard conditions
Ph
N
H
n-Pr
n-Pr
N
H
n-Pr
air or O2, 12 hr
50
9, air: 61% yield; O2: 43% yield
Notes
The authors declare no competing financial interests.
d KIE experiment
O
O
[IrCp*Cl2]2 (2 mol%)
AgBF4 (5 mol%)
Ph
Ph
N
N
n-Pr
ACKNOWLEDGMENT
Cu(OAc)2.H2O (4 mol%.)
air, 1,4-dioxane, 60 °C
H
H
50
9
This work is financially supported by the National Natural Sciꢀ
ence Foundation of China (21372013), the Guangdong Natural
Science Foundation (2014A030312004), and the Shenzhen muꢀ
nicipality (JCYJ20160226105602871).
O
>99% D
D
D
O
O
D
D >99% D
Ph
Ph
Ph
N
n-Pr
D 90% D
N
n-Pr
D
90% D
N
n-Pr
H
H
H
D
D
50- -D, KIE value: 1.23
50- -D, KIE value: 1.18
50- -D, KIE value: 1.04
REFERENCES
The Ir turnover is believed to be catalyzed by copper. In the abꢀ
sence of copper, only a trace amount of the product was formed.
The loading of Cu was examined, and the reaction showed a satuꢀ
ration kinetics at 1 mol% copper. Under the standard reaction
conditions (4 mol% Cu), the turnover of the Ir catalyst is not the
rateꢀlimiting step. This step becomes slow only at very low copper
loading (Scheme 1a). The optimum Ir/Ag ratio was found to be
1/1. Changing Ir/Ag to 1/2 resulted a significantly more sluggish
reaction, suggesting [Cp*IrCl]+ might be the most active species
(Scheme 1b). Reactions using air and oxygen were compared.
Noticeably, higher yield was obtained using air than molecular
oxygen (Scheme 1c). The lower yield using 1 atm oxygen is a
result of over oxidation of the product, not substrate decomposiꢀ
tion.
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