Direct Synthesis of p-Methyl benzaldehyde from Acetaldehyde via An Organic Amine-catalyzed Dehydrogenation Mechanism

Abstract

p-Methyl benzaldehyde (p-MBA) is a class of key chemical intermediates of pharmaceuticals. Conventional industrial processes for p-MBA production involve the consecutive photochlorination, amination, and acid hydrolysis of petroleum-derived p-xylene, while producing vast pollutants and waste water. Herein, we report a direct, green route for selective synthesis of p-MBA from acetaldehyde using a diphenyl prolinol trimethylsilyl ether catalyst. The optimized p-MBA selectivity is up to 90% at an acetaldehyde conversion as high as 99.8%. Intermediate structure and ¹⁸O-isotope data revealed that the conversion of acetaldehyde to p-methylcyclohexadienal intermediates proceeds in an enamine-iminium intermediate mechanism. Then, controlled experiments and D-isotope results indicated that the dehydrogenation of p-methylcyclohexadienal to p-MBA and H2 is catalyzed by the same amines through an iminium intermediate. This is an example that metal-free amines catalyze the dehydrogenation (releasing H2), rather than using metals or stoichiometric oxidants.

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iScience
Article
Direct synthesis of p-methyl benzaldehyde from
acetaldehyde via an organic amine-catalyzed
dehydrogenation mechanism
Qing-Nan Wang,
Xianghui Liu, Kai
Wang, Yan Liu,
Sheng-Mei Lu,
Can Li
canli@dicp.ac.cn
Highlights
A direct route to produce
p-methyl benzaldehyde
from biomass-derived
acetaldehyde
Revealing the reaction
kinetics and mechanism
under reaction conditions
An example of an organic
amine-catalyzed
dehydrogenation-
aromatization reaction
Wang et al., iScience 24,
103028
September 24, 2021 ª2021
The Authors.
https://doi.org/10.1016/
j.isci.2021.103028
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iScience
Article
Direct synthesis of p-methyl benzaldehyde from
acetaldehyde via an organic amine-catalyzed
dehydrogenation mechanism
Qing-Nan Wang,
1,3
Xianghui Liu,
1,2,3
Kai Wang,
1,2
Yan Liu,
1
Sheng-Mei Lu,
1
and Can Li
1,4,
*
SUMMARY
p-Methyl benzaldehyde (p-MBA) is a class of key chemical intermediates of phar-
maceuticals. Conventional industrial processes for p-MBA production involve the
consecutive photochlorination, amination, and acid hydrolysis of petroleum-
derived p-xylene, while producing vast pollutants and waste water. Herein, we
report a direct, green route for selective synthesis of p-MBA from acetaldehyde
using a diphenyl prolinol trimethylsilyl ether catalyst. The optimized p-MBA selec-
tivity is up to 90% at an acetaldehyde conversion as high as 99.8%. Intermediate
structure and
18
O-isotope data revealed that the conversion of acetaldehyde to
p-methylcyclohexadienal intermediates proceeds in an enamine-iminium interme-
diate mechanism. Then, controlled experiments and D-isotope results indicated
that the dehydrogenation of p-methylcyclohexadienal to p-MBA and H
2
is cata-
lyzed by the same amines through an iminium intermediate. This is an example
that metal-free amines catalyze the dehydrogenation (releasing H
2
), rather than
using metals or stoichiometric oxidants.
INTRODUCTION
p-Methyl benzaldehyde (p-MBA) is one of the primary precursors in fine chemicals manufacturing, e.g.,
pharmaceuticals (Yu et al., 2010;Chen et al., 2019). Conventionally, it was produced via a successive
photochlorination, amination, and acid hydrolysis of petroleum-derived p-xylenes (Scheme 1A, Angyal,
2004;Schoch et al., 1982). However, this reaction co-produces vast pollutants and waste acid water
(Schoch et al., 1982), which run counter to the current green development policy. Therefore, this situa-
tion becomes a strong incentive to develop new routes for the energy-efficient and green production of
p-MBA.
Construction of value-added products with aromatic rings from low-molecular weight molecules is a long-
standing research topic (Jiao et al., 2016;Li et al., 2019;Cheng et al., 2017;Tempelman et al., 2015;Moteki
et al., 2016;Hulea, 2018). Extensive researches have reported the production of methyl benzaldehyde from
biomass-derived acetaldehyde over MgO and Ca
10
(OH)
2
(PO
4
)
6
(Wang et al., 2019;Lusardi et al., 2020;
Zhang et al., 2016;Moteki et al., 2017). However, the selectivity of methyl benzaldehydes (MBA) in proceed-
ing was no exceeding 30% (Scheme 1B), among which, p-MBAwaslessthan3%(Moteki et al., 2016;Wang
et al., 2019), far from meeting the industrial production requirements. This insufficient selectivity was attrib-
uted to the complex network of competing reactions in acetaldehyde cascade processes, resulting in
broad product distributions (Moteki et al., 2016;Lusardi et al., 2020).
Organic amines, such as tetrahydropyrrole (THP) and its derivatives, could catalyze enals to yield p-methyl
benzaldehyde derivatives (Hong et al., 2006,2007;Song et al., 2012), although the reaction intermediates
and mechanism have not been investigated. Furthermore, the system that can directly catalyze the self-
condensation of acetaldehyde and then, aromatize enal intermediates to para-aromatic aldehydes has
not been reported yet. Here, we report a direct, green route for the selective synthesis of p-MBA from acet-
aldehyde using a diphenyl prolinol trimethylsilyl ether catalyst (Scheme 1C). The optimized p-MBA selec-
tivity reaches 90% at conversion of 99.8%, yielding a formation rate o f 0.33 mmol
p-MBA
mmol
cat.1
h
1
,which
is about six times of the-state-of-the-art report. This article will focus on the investigation of reaction
intermediates, route, and mechanism to well understand this coupling-aromatization reaction and in
turn, to make an optimization of the reaction rate. Controlled experiments, in situ spectroscopy, and
1
State Key Laboratory of
Catalysis, Dalian Institute of
Chemical Physics, Chinese
Academy of Sciences, Dalian
116023, China
2
University of Chinese
Academy of Sciences, Beijing
100049, China
3
These authors contributed
equally
4
Lead contact
*Correspondence:
canli@dicp.ac.cn
https://doi.org/10.1016/j.isci.
2021.103028
iScience 24, 103028, September 24, 2021 ª2021 The Authors.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1
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18
O/D-isotope studies revealed that acetaldehyde undergoes an enamine-iminium intermediate mecha-
nism and then an organic amine-catalyzed dehydrogenation mechanism to form p-MBA finally. This is
an example that metal-free amines catalyze the dehydrogenation-aromatization (releasing H
2
), rather
than using metals or stoichiometric oxidants. The striking p-MBA selectivity shows the charming merit of
homogeneous catalysts in terms of fine chemicals manufacturing.
RESULTS AND DISCUSSION
Catalytic performance
Figure 1A illustrates the reaction scheme of acetaldehyde to p-MBA and the structure of catalysts used.
Figures 1B and 1C and Table S1 summarize the catalytic activity of acetaldehyde condensation and
aromatization to p-MBA with several organic amines. As shown, the product distributions differ and
change with the type of catalysts, acid additives, and solvents. Notably, among C
8
aromatic oxygenates,
p-MBA is the major product. Reaction in the presence of tetrahydropyrrole (denoted as THP) or 3-pyrro-
lidinol (denoted as THP-OH, considering it as the derivative from THP) generates p-MBA and p-methyl-
cyclohexadienal (p-MCA, Figure 1B), accompanying with undesired o-methyl benzaldehyde (o-MBA) and
massive 2,4,6-octatrienal (C
8
enals) as co-products (see Table S1), i.e., showing broad product distribu-
tions. With L-proline (denoted as THP-COOH), the acetaldehyde is almost completely converted, but
2-butenal is the major product with trace amounts of p-MBA (less than 0.7%, see Table S1). 2-(Diphenyl-
methyl) pyrrolidine (denoted as THP-DPh), grafted with large steric hindrance groups, slightly improves
the selectivity of para-products (p-MBA + p-MCA, 62.6%) compared to those of Py and Py-OH. An encour-
aging result comes from the reaction in the presence of diphenyl prolinol trimethylsilyl ether (denoted as
THP-DPh-OTMS), where p-MBA and p-MCAareformedinaselectivityof 82.5%, whereas the yield of C
8
enals is dramatically reduced to 2.6% (see Table S1). In addition, the enhancement of para-products selec-
tivity from THP to THP-DPh-OTMS (Figure 1B) can be explained by the steric hindrance inducing the pref-
erential formation of intermediates with specific configuration (Mukherjee et al., 2007;Schmid et al., 2010;
Zhang et al., 2012).
Furthermore, we found that organic amines can catalyze the conversion of p-MCA to yield p-MBA (the
details were as below). Thus, more THP-DPh-OTMS was added to the reaction mixture (i.e., a ‘‘one-pot,
Scheme 1. Two routes for synthesis of p-MBA
(A) A conventional industrial route.
(B and C) A biomass-derived acetaldehyde route. o-MBA was reported as a major product using heterogeneous catalysts.
p-MBA was synthesized using amines in this work.
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two-step’’ process), which was then subjected to 60C for more time. Surprisingly, a 90% selectivity of
p-MBA was obtained with a yield of 90% and a formation rate of 0.33 mmol
p-MBA
mmol
cat.1
h
1
,which
is about six times of the report (using 2-butenal as reactants, Hong et al., 2006;Song et al., 2012). Notably,
the ratio of p-MBA to o-MBA is up to 30 (see Table S1),whichismorethantwoordersofmagnitudehigher
than the literature (Moteki et al., 2016;Wang et al., 2019).
Next, the effect of acidic additives on the product distributions was examined. Figure 1Cshowsacidic
groups and their strength playing a determinant role to the selective formation of para-products. To clarify
the role of acidic groups, the OH group of p-NO
2
-PhOH was replaced as COOH.However,thetotal
selectivity of p-MBA and p-MCA is dramatically reduced to 4.4%. To elucidate the effect of acidity, H,
CH
3
,andCOOH substituents were selected to replace the NO
2
group of p-NO
2
-PhOH, respectively.
Correspondingly, only moderate selectivity towards p-MBA and p-MCA was detected, i.e.,33.7, 23.2, and
33.3%. Interestingly, it is noted that there is a volcano-type dependence of the selectivity of p-MBA and
p-MCAontheacidstrength(pK
a
), i.e., 23.2% (p-CH
3
-PhOH, pK
a
= 10.2) < 33.7% (PhOH, pK
a
=9.9)<
82.5% (p-NO
2
-PhOH, pK
a
= 7.15), and then 33.3% (p-COOH-PhOH, pK
a
= 4.6) > 4.4% (p-NO
2
-PhCOOH,
pK
a
= 3.4). The strong acidic group possibly reacts or interacts with the amine group, thus preventing multi-
step C-C coupling, as demonstrated by the high selectivity of 2-butenal (see Table S1). Thus, the synergy
between THP-DPh-OTMS and acidic additives boosts the conversion of acetaldehyde to para-aromatic
aldehyde (Lokesh et al., 2019).
Screening solvents on the product distributions showed that the selectivity of p-MBA and p-MCA increases
in the following order: dimethylsulfoxide (DMSO) zdimethylformamide (DMF) < CH
3
CN < C
2
H
5
OH <
CHCl
3
(see Table S1). This order is almost in parallel to the solvent polarity (ε
r
), i.e., 7.2 (DMSO) > 6.4
(DMF) > 6.2 (CH
3
CN) > 4.3 (C
2
H
5
OH) z4.4 (CHCl
3
). Therefore, the solvent with relative weak polarity favors
the condensation and subsequent aromatization of acetaldehyde.
Figure 1. Reaction scheme and catalytic performance
(A) Reaction scheme of CH
3
CHO to p-MBA.
(B) Effect of catalyst structure on product distributions.
(C) Effect of acidity strength (pKa) on selectivity of para-products. Reaction conditions: CH
3
CHO (1 mmol), solvent (3 mL),
catalyst (0.1 mmol), acidic additives (0.3 mmol), 20C for 2 h under Ar. * More amines were added and the reaction was
kept at 60C for 2 h (see supplemental text for more details).
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Reaction route
To understand the reasons for the selective p-MBA formation from acetaldehyde, the reaction route was
studied by tracking the reaction progress. To distinguish the primary from the secondary products, the ef-
fect of reaction time on the product distributions was investigated (Anbarasan et al., 2012). Product yields
and acetaldehyde conversion were plotted as a function of reaction time (Figure 2A). The steep initial rise in
2-butenal yield with acetaldehyde conversion indicates that the primary product is derived directly from
acetaldehyde aldol-condensation (Wang et al., 2019). In a few minutes, the 2-butenal yield reaches a
maximum and then it is converted to C
8
oxygenates, such as p-MCA and p-MBA, via a secondary reaction.
Furthermore, p-MCA and p-MBA become the major products at reaction time over 10 min. The high initial
slope of p-MCA implies that it is the precursor for p-MBA formation. In addition, C
8
enals and o-MBA were
also simultaneously detected as secondary products but at much lower formation rates. This result sug-
gests that the conversion of 2-butenal to p-MCA/p-MBA and to C
8
enals/o-MBA possibly undergoes par-
allel reaction channels. Thus, acetaldehyde undergoes organic amines-catalyzed condensation, forming
the 2-butenal intermediate (Equation 1), which yields p-MCA and p-MBA through cycloaddition and
aromatization in sequence.
(Equation 1)
In situ infrared spectroscopy (IR) was conducted to confirm whether 2-butenal and other intermediates
were formed (see Figure S1). Figure 2B shows the corresponding IR difference spectra, which were ob-
tained by subtracting a reference spectrum taken soon after the mixture of CH
3
CHO and catalysts from
the real-time spectrum (Chen et al., 2007). An obvious negative peak at 1724 cm
1
, assigned to the C=O
stretching vibration [n(C=O)] of acetaldehyde, was detected. Positive peaks at 1,686, 1,676, 1,642, 1,607,
Figure 2. Reaction route
(A) Dependence of conversion and product yields on the reaction time (1 mmol CH
3
CHO, 3 mL CHCl
3
,0.05mmolTHP-
DPh-OTMS, 0.3 mmol p-NO
2
-PhOH, 20C).
(B) IR difference spectra. The green line in Figure 2B was obtained at 180 min (45 mmol CH
3
CHO, 0.5 mmol THP-DPh-
OTMS, 1.2 mmol p-NO
2
-PhOH, CHCl
3
as solvent, 20C).
(C) Intensity changes of IR peaks in Figure 2Bwithreactiontime.
(D) Evolution of IR peaks using THP as a catalyst with reaction time (see Figure S1). Star: CH
3
CHO, diamond: 2-butenal,
hollow cycle: p-MCA, square: p-MBA, hollow up triangle: o-MBA, hollow down triangle: C
8
enals.
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1,603, 1,593, and 1,577 cm
1
were detected concomitantly. Peaks at 1,686 and 1,642 cm
1
, assigned to the
n(C=O) and n(C=C) modes of 2-butenal (see Figure S1), respectively, became prominent as the reaction
proceeded. A series of IR peaks at 1,676, 1,642, 1,603, and 1,593 cm
1
are characteristic frequencies of
enals with two C=C bonds (Aboaly et al., 1985), indicating the formation of p-MCA in view of the catalytic
data shown in Figure 2A. Characteristic peaks at 1,607 and 1,577 cm
1
are attributed to the n(C=C) modes
of aromatic aldehydes (see Figure S1). Although the C=O stretching vibration peak of aromatic aldehydes
(at 1,686 cm
1
) is overlapped with that of 2-butenal, the characteristic n(C=C) frequencies at 1,607 and
1,577 cm
1
indicate the formation of p-MBA. The peaks at 1724, 1,686, 1,676, and 1,607 cm
1
were used
to track the concentration change of acetaldehyde, 2-butenal, p-MCA, and p-MBA, respectively. Figure 2C
shows the varying tendency of the reactant and products with time. Difference in the initial slope of these
curves indicates acetaldehyde yielding p-MBA via 2-butenal and p-MCA intermediates (Equation 2).
(Equation 2)
CH
3
CHO-IR experiments using THP as catalysts were also conducted (Figures 2DandS1). In contrast,
although products p-MCA (frequencies at 1,676, 1,642, 1,603, and 1,593 cm
1
) are shown, characteristic
n(C=C) peaks of C
8
enals at 1,635, 1,617, and 1,604 cm
1
(Aboaly et al., 1985), also appear and increase
with time. These IR data support the mechanism that 2-butenal derived from acetaldehyde condensation
is the intermediate to yield p-MCA and p-MBA, and prove that the steric hindrance group, i.e., -DPh-OTMS,
contributes to the formation of target products.
Mechanism of acetaldehyde condensation and aromatization
Identification of active sites
To reveal the reaction mechanism, we designed controlled experiments to confirm the active sites. Fig-
ure 3A shows the catalytic activity of THP-DPh-OTMS with its N group grafted to a CH
3
group (Tang
et al., 2004) and that of THP-DPh-OTMS treated with HCl. As shown, the introduction of a –CH
3
group
led to 2-butenal as the only product, i.e., neither p-MCA nor p-MBA detected. When THP-DPh-OTMS hy-
drochloride was used, the major product was 2-butenal, accompanying small amounts of p-MCA and
p-MBA. Both catalysts showed much lower reaction rate than that of THP-DPh-OTMS. Therefore, the basic
R–NH–R’ amine group of THP-DPh-OTMS can indeed be involved in the selective conversion of acetalde-
hyde to p-MCA and p-MBA.
Reaction mechanism of acetaldehyde condensation and cycloaddition
Up to now, several mechanisms were proposed in organic amine-catalyzed condensation and/or cycload-
dition reaction (List et al., 2000;Northrup and MacMillan, 2002;Moyano and Rios, 2011;Erkkila
¨et al., 2007;
Dalko Dr and Moisan, 2004). To clarify the possible intermediates, we tried to track them using H-NMR
technique. However, the change of in situ H-NMR spectra with reaction time hardly provided clear evi-
dence for intermediates formation in this case and typically only show ed mixtures of reactants and products
along with the THP-DPh-OTMS/p-NO
2
-PhOH, even though a high ratio of catalyst to reactant was used
(see Figures S2–S5). This result was consistent with the report of Schnitzer et al. in an addition reaction using
similar organic-amines as catalysts (Schnitzer and Wennemers, 2020). Therefore, we used a Time OfFlight
Mass Spectrometer (TOF-MS) to detect the possible intermediate in the liquid ph aseas s oon as the mixture
of acetaldehyde and THP-DPh-OTMS/p-NO
2
-PhOH. MS data revealed that in addition to the signal of
THP-DPh-OTMS {m/z = 326.1863, [M + H]
+
,ESI
+
}, the peaks at 431.2567 and 430.2489 were also detected
(Figure 3B), which can be assigned to the diene iminium and trienamine, respectively, derived from the suc-
cessive condensation and cycloaddition reaction between amines and 2-butenal (Scheme 2).
To confirm the possible enamine-iminium mechanism, an
18
O-isotope experiment was conducted. If the
condensation and aromatization of acetaldehyde takes place in the presence of
18
O-enriched water, incor-
poration of
18
O at the carbonyl group of reactants and products would be expected (List et al., 2004)
because of the final hydrolysis step in the iminium catalysis cycle (Scheme 2). Thus, prior to this experiment,
the reaction order of H
2
O was determined by adding water (0–4 mmol) into the reaction system. The reac-
tion rate and product distributions almost remain constant (see Figure S6), indicating a zero-order depen-
dence on H
2
O under the controlled conditions. Then we detected the product distributions in the presence
of 2 mmol
18
O-enriched water (97 mol%, Aladdin). Scheme 2 and Figure S7 showed that
18
O-contained re-
actants and products are observed.
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Please note that the formation of iminium ions and their tautomerization to enamine species, see Scheme 2,
need the assistance of acidic additives via a proton transfer process (List et al., 2000). Figure 1C showed that
the functional group type and strength of acidic additives greatly influence the product distributions.
Furthermore, Figures 3C and 3D showed that the selectivity of products dramatically changes with the vari-
ationintheamountofp-NO
2
-PhOH. Without acidic additives, neither p-MBA nor p-MCA was detected,
but a 96.3% selectivity of 2-butenal. Other minor products were C
6
enals (0.3%), C
8
enals (2.4%), and
o-MBA (1%). Interestingly, the p-MBA and p-MCA became the dominant products, when 0.15 mmol acidic
additive was added (i.e., n
p-NO2-PhOH
/n
cat.
= 1.5 mmol/mmol). Meanwhile, a dramatically declined selec-
tivity of 2-butenal and an increased conversion were obtained. In the absence of THP-DPh-OTMS, no
obvious reaction occurred. Therefore, the result of
18
O-isotope studies and the dependence of products
selectivity on acid amounts support that both the aldol condensation of acetaldehyde to 2-butenal and
the following cycloaddition of 2-butenal to p-MCA undergo an enamine-iminium intermediate mechanism.
In addition, in Figure 3D, p-MCA and p-MBA were the major products, accompanying with less C
6
/C
8
enals
and their derivatives o-MBA (<5% in selectivity). This result suggests that the cycloaddition and subsequent
aromatization of 2-butenal are thermodynamically more favorable than its chain growth (forming long-
chain enals), as verified by the much lower Gibbs energy of the former reaction, i.e., 110 vs. 10 kJ/mol.
It is proven that 2-butenal is in a trans-configuration based on the in situ H-NMR data (see Figure S5). To
reveal its cycloaddition course, the activation behavior of trans-2-butenal was investigated. We firstly adop-
ted n-butyraldehyde as reactants to examine product distributions. Figure S8 showed that only aliphatic
aldol-condensation products were detected from C
4
saturated aldehydes. Branched chains at a-C sites
Figure 3. Reaction mechanism of acetaldehyde condensation and cycloaddition
(A) Comparison of catalytic performance with THP-DPh-OTMS, THP(–CH
3
)-DPh-OTMS, and (THP-DPh-OTMS)H
+
Cl

(Reaction conditions: 1 mmol CH
3
CHO, 3 mL CHCl
3
,0.1mmolcatalyst,0.3mmolp-NO
2
-PhOH, 20Cfor2h,Ar
atmosphere).
(B) A TOF-MS spectrum of the reaction liquid after the mixture of acetaldehyde and THP-DPh-OTMS/p-NO
2
-PhOH.
(C and D) Effect of p-NO
2
-PhOH amounts on conversion and product distributions (Reaction conditions: 1 mmol
CH
3
CHO, 3 mL CHCl
3
, 0.1 mmol THP-DPh-OTMS, 20C for 2 h, Ar atmosphere). Star: CH
3
CHO, diamond: 2-butenal,
hollow cycle: p-MCA, square: p-MBA, hollow up triangle: o-MBA, hollow down triangle: C
8
enals.
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of the dimer products convincingly indicate that the nucleophilic attack by the a-C of the aldehydes at the
carbonyl C of others takes place. Next, when trans-2-butenal was used as reactants, aromatic aldehydes
were obtained as main products. However, when the a-C site of 2-butenal was grafted with a methyl sub-
stituent, neither aldol dimers nor aromatic aldehydes were detected. This can be explained by the CH
3
at
the a-C site of 2-methyl-2-butenal hindering the nucleophilic attack by this site, because this site is tetra-
coordination without a-H. Therefore, these controlled experiments illustrated that the activation of the a-C
site of trans-dienamines (or trans-2-butenal) results in the selective formation of p-MCA (Scheme 3).
Note that, on a heterogeneous CaO catalyst, trans-2-butenal was preferentially deprotonated at the g-C
position because of allylic stabilization of the resulting anion (Wang et al., 2019). Nucleophilic attack by
the g-C of the anion at the carbonyl C of trans-2-butenal formed 2,4,6-octatrienal, which underwent cycli-
zation and dehydrogenation to form o-MBA as the major product (Scheme 1B).Therefore,itiscrucialto
control the activation of the a-C site of trans-2-butenal for the selective synthesis of p-MBA.
Combination of the detected enamine and iminium intermediates and the viewpoint of the a-C site acti-
vation of trans-2-butenal, the possible cycloaddition mechanism, is proposed. Before the aldol condensa-
tion to form cyclic products (Scheme 3), dienamine species possibly serve as Michael donors for the
conjugate addition to form iminium ions, i.e., forming the first C-C bond for p-MCA (Hong et al., 2006).
Next, the resulting Michael adduct possibly proceeds in hydrolysis, intramolecular condensation (Hammer
et al., 2020), and dehydration in sequence to form trienamine and diene iminium intermediates, which can
hydrolyze to form p-MCA.
Aromatization reaction of p-methylcyclohexadienal (p-MCA)
The aromatization of p-MCA to p-MBA is thermodynamically favorable (DG
(25–60

C)
=50 kJ/mol) and its
mechanism is further investigated. Figure 4A showed that the selectivity of p-MBA and p-MCA is almost
independent of air, O
2
, or Ar, even though prolonging reaction time (under Air or Ar, see Table S2). In addi-
tion, although both degassed CHCl
3
solvent and Ar were used, product distributions were the same as that
Scheme 2. Proposed enamine/iminium catalytic cycle
The detected fragment ions of
18
O/
16
O-incorporated aldehydes were marked in red/black.
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of its counterpart (Figure 4A). A similar experiment result was reported using 2-butenal as a reactant (Hong
et al., 2006,2007), but the reason had not been revealed yet. There were two possible explanations for
these findings: (1) the hydrogen species abstracted from p-MCA were captured by certain acceptors or
(2) a dehydrogenation process takes place by releasing H
2
. Nitro groups in p-NO
2
-PhOH could be reduced
to form corresponding hydroxylamine and amino units (Serna and Corma, 2015). To substantiate this hy-
pothesis, PhOH and its derivatives (for example, with a COOH or CH
3
group at the para site), were
used as acidic additives, respectively, but p-MBA was still formed (3.2%–8.5% in selectivity, see Table
S1). Please note that, when no acids were used (Figure 3D), o-MBA was detected in a selectivity of 1%.
Furthermore, no obvious alcohols and enols, possibly formed from a selective transfer hydrogenation of
aldehydes and/or enals (Shi et al., 2010), were detected. Based on these data of controlled experiments,
the possibility of the first hypothesis could be ruled out.
To verify the validity of the second hypothesis, we used MS to detect the gas products in a batch reactor.
Interestingly, in line with prediction, H
2
was quantitatively obtained in a yield of 0.05 mmol/2 h (Figure 4B).
Furthermore, CD
3
CDO (chemical purity, Aladdin) were employed as reactants, and HD/D
2
were qualita-
tively detected (Figure 4B), which were originated from the dehydrogenation of D-substituted and H/D-
substituted p-MCA (see Figure S9). Therefore, the direct dehydrogenation of p-MCA to p-MBA and H
2
takes place indeed. This can be explained by the fact that the carbonyl and vinyl groups in cyclic p-MCA
possibly induce the acidity (pK
a
) enhancement of their a/g-CHsites(Bordwell pKa Table, 2020), suggest-
ing the easy CH activation and dissociation.
The nucleophilic N center in the NH
x
group of organic amines activates the C-H bond of aldehydes and
then catalyzes the subsequent condensation (Moyano and Rios, 2011;Erkkila
¨et al., 2007). Thus, we thought
that the basic R-NH-R0group of THP-DPh-OTMS possibly catalyzes the dehydrogenation of p-MCA via an
H-abstract process. Therefore, we used HCl to poison the R-NH-R0group ( forming a hydrochloride) to verify
this hypothesis. The poisoning experiment was performed by adding HCl (n
HCl
/n
Cat.
= 1 mmol/mmol) into
the mixture after reaction 2 h under normal conditions. The product distributions were then tracked with
Scheme 3. Proposed reaction mechanism for the selective p-MCA formation from trans-2-butenal
Theactivationofthea-C site (marked in blue) of trans-2-butenal is crucial for the selective synthesis of p-MBA.
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reaction time. Figure 4C showed the selectivity of p-MBA and p-MCA remaining almost constant, i.e., 24%
and 58%, respectively, in 60 h after HCl addition. In comparison, controlled experiments without HCl addi-
tion showed that p-MBA selectivity slowly increases to 60% from 24% in 80 h, whereas that of p-MCA grad-
ually decreases.
Furthermore, we found that the selectivity of p-MBA increased, though in different degree, when more pri-
mary-, secondary-, and tertiary-amines [such as H
2
N-(CH
2
)
6
-NH
2
, NH(C
2
H
5
)
2
/THP-DPh-OTMS, and
N(C
2
H
5
)
3
] were added (Figure 4D). With the aid of secondary amines, the selectivity of p-MBA is about 2
times higher than those of other amines. For example, a 90% selectivity of p-MBA and a formation rate
of 0.33 mmol
p-MBA
mmol
NHx1
h
1
were obtained, when more THP-DPh-OTMS (0.1 mmol) was added
(i.e., a ‘‘one-pot, two-step’’ process) and the reaction was conducted at 60C for 2 h. In comparison, the
Figure 4. Aromatization mechanism of p-MCA to p-MBA
(A) Product distributions under different atmospheres.
(B) Detection of gaseous products by MS (CH
3
CHO and CD
3
CDO as reactants).
(C) HCl poisoning experiments. Hollow: with HCl. Star (green): CH
3
CHO, cycle (red): p-MCA, square (blue): p-MBA.
(D) Effect of the type of organic amines on the selectivity and formation rate of p-MBA (reaction conditions: 1 mmol
CH
3
CHO, 3 mL CHCl
3
, 0.1 mmol THP-DPh-OTMS, 0.3 mmol p-NO
2
-PhOH, 20C for 2 h; then amines were added and
stirredfor1or2hat60
C under Ar).
(E) Effect of the amounts of acidic additives on the dehydrogenation rate of p-MCA (reaction conditions: 0.04 mmol p-
MCA, 0.04 mmol amines, 3 mL CHCl
3
,60
C for 1.5 h under Ar).
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selectivity of p-MBA under H
2
N-(CH
2
)
6
-NH
2
and N(C
2
H
5
)
3
is 47.1% and 40.3%, respectively. When 0.2 mmol
THP-DPh-OTMS was added into the reaction liquid at the beginning of the reaction (conducted at 60C),
however, 62% selectivity towards p-MBA was obtained with a carbon balance of as low as 58.7% (see Table
S3, Entry 16). It indicates that acetaldehyde more easily undergoes over-polymerization to form high mo-
lecular weight products at high reaction temperatures. Therefore, this reaction was carried out in a ‘‘one-
pot, two-steps’’ process, i.e., the conversion of CH
3
CHO to p-MCA at 20C and then, the aromatization of
p-MCA to p-MBA at 60C. In this case, the carbon balance remains to 90% (see Table S3). Note that under
these conditions, the molar ratio of p-MBA formed to catalyst is about 1.2–1.5, which further suggests that
the amines catalyze the dehydrogenation of p-MCA to p-MBA and H
2
.
Next, cyclohexane was used to separate the p-MCA from the p-NO
2
-PhOH and THP-DPh-OTMS, which of-
fers an unmissable chance to directly use it as a reactant to investigate the dehydrogenation mechanism.
Figure 4E showed the dehydrogenation rate of p-MCA using THP-DPh-OTMS with or without acidic addi-
tives. p-MBA is the only product, i.e., a 100% selectivity. Amazingly, the reaction rate increases from 0.05 to
0.64 mmol
p-MCA
mmol
Cat.1
h
1
when varying the ratio of n
(p-NO2-PhOH)
/n
(THP-DPh-OTMS)
from 0 to 3 (mmol/
mmol). No reaction occurred with only acidic additives. This drastic difference suggests that the existence
of acids, i.e., H-proton, possibly changed the dehydrogenative intermediates and reaction mechanism.
However, a poor dehydrogenation rate was detected using acidic additives and H
2
N-(CH
2
)
6
-NH
2
or
N(C
2
H
5
)
3
(Figure 4E). Please note that, iminium species are easily formed from aldehydes under the co-ex-
istence of acids and secondary amines (Scheme 2). These results guide us to presume that the p-MCA first
converts to diene iminium, and then undergoes an amine-catalyzed dehydrogenation reaction to form
p-MBA finally (Scheme 4). During this process, abstracting the first H from the acidic d(g)-C sites (pK
a
)
should be crucial. This pK
a
in aldehydes is about 25 because of the activation effect by C=O (Bordwell
pKa Table, 2020), thus possibly showing a low C-H activation barrier, about 6 kJ/mol (Liu et al., 2015).
Compared to C=O, the electron-deficient C=N
+
group in iminium will further decrease the pK
a
(Kitamura
et al., 2014). This may explain the increased reaction rate of p-MCA when acids co-existed. In comparison,
the electron-rich C-N group in enamine shows a negative effect for the C-H activation, which will not be
discussed in the following sections.
Combination of the catalytic data, in situ spectroscopic evidence, and isotope experiments described
above, we propose a possible pathway for p-MBA synthesis from acetaldehyde using THP-DPh-OTMS
as catalysts (Scheme 5). First, fast condensation converts acetaldehyde into trans-2-butenal, which then
successively proceeds in Michael addition, aldol condensation (cycloaddition), and dehydrogenation to
form para-site aromatic aldehydes, i.e., CH
3
CHO /trans-2-butenal /p-MCA /p-MBA. Among this
course, the formed diene iminium species, derived from trans-2-butenal cycloaddition, proceed in a dehy-
drogenation process to form p-MBA and H
2
. This reaction follows an organic amine-catalyzed dehydroge-
nation mechanism via diene iminium intermediates. This process is different to the dehydrogenation-
aromatization of N-heterocycles, in which potassium salt catalyzes the cleavage of N-H and C-H, thus re-
sulting into H
2
formation (Liu et al., 2019). In addition, the overall reaction rate remains constant when
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a commonly used radical-trapping reagent (Tang, et al.,
2021), was added in the reaction system, indicating that the conversion of acetaldehyde to p-MBA does
Scheme 4. Aromatization reaction route of p-MCA to p-MBA.
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not undergo a free radical route (see Figure S10). No transition metals were involved in this reaction (see
ICP analysis in Method Details), thus excluding the possible existence of a red oxmec hanism. Therefore, the
overallreactionproceedsinamechanismofionicreaction.THP-DPH-OTMS(withacidicadditives)alsocat-
alyzes the self-condensation of 2-butenal followed by dehydrogenation to form o-MBA, but in small
amounts.
Overall, this direct conversion of acetaldehyde to p-MBA is performed under mild reaction conditions with
a remarkable yield. Further scale-up studies for p-MBA synthesis were carried out to demonstrate the utility
of this method. For example, 440 mg CH
3
CHO (98%) was fed as reactants and, finally, 206.5 mg of p-MBA
was obtained via an extraction-rotary evaporation technique (see Figure S11). In contrast, the commercial
process for converting p-xylene to p-methyl benzaldehyde yields massive chlorides as by-products and
produces waste strong acid water (Schoch et al., 1982). In addition, the inevitable chlorine residues in prod-
ucts further limits its application for pharmaceuticals. Therefore, this work represents a step change in
developing a direct, green synthesisroute for para-aromatic aldehydes and guides the design of more effi-
cient heterogeneous catalysts for this reaction. More importantly, this report shows an experimental
example of an organic amine-catalyzed dehydrogenation reaction, which is different to the reported
metal-dehydrogenation and stoichiometric-dehydrogenation processes (Gnaim et al., 2021;Teskey
et al., 2019;Mukaiyama et al., 2000).
The synthesis of aromatic aldehydes from low-carbon aliphatic aldehydes (n %6) was explored under
the optimal conditions (Figure 5). When formaldehyde or acrolein were co-fed with acetaldehyde, a
10–12% selectivity of benzaldehyde was obtained, which was attributed to the complex network
of competing reactions in these coupling-aromatization processes, leading to broad product distribu-
tions (Zhou et al., 2020). Interestingly, p-MBA could be selectively synthesized from acetaldehyde or
2-butenal. The butyraldehyde yielded the corresponding aldol-condensation product. Both C
5
and C
6
enals underwent the coupling-aromatization reaction yielding aromatic aldehydes with selectivity of
over 94%.
Conclusions
In this work, we developed a direct route for the selective synthesis of p-methyl benzaldehyde from acet-
aldehyde via condensation, cycloaddition, and dehydrogenation in consequence, using organic amines as
catalysts. The optimized p-MBA selectivity reached 90% at an acetaldehyde conversion of 99.8%, leading to
a product formation rate of 0.33 mmol
p-MBA
mmol
cat.1
h
1
, which is about six times of the report. The basic
R-NH-R0group of THP-DPh-OTMS was proved to be the active site for acetaldehyde condensation, cyclo-
addition, and aromatization. Kinetic and in situ IR studies indicated that acetaldehyde undergoes aldol
condensation to yield 2-butenal, which further forms p-MCA through cycloaddition and then to p-MBA
via dehydrogenation. Intermediate structure and
18
O-isotope data revealed that the conversion of acetal-
dehyde to p-MCA proceeds in an enamine-iminium intermediate mechanism. Then, the dehydrogenation
of p-MCA to p-MBA was catalyzed by the same organic amine through an iminium intermediate. This is an
Scheme 5. Reaction pathways for aromatic aldehydes formation from acetaldehyde
All the reactants, intermediates, and products were detected except the one in the yellow panel.
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experimental example that an organic amine catalyzes the dehydrogenation-aromatization reaction.
Furthermore, this report proves that it is possible to selectively synthesize p-MBA from acetaldehyde by
controlling the activation of the a-C site of 2-butenal intermediates.
Limitations of the study
We reported that the organic amine catalyzes the dehydrogenation of p-methylcyclohexadienal to
p-methyl benzaldehyde with H
2
releasing. This process was verified by controlled experiments and
D-isotope results. However, during this dehydrogenation-aromatization process, the H-abstract, recombi-
nation, and H
2
releasing were not clear yet. We preliminary tried to reveal these processes using DFT calcu-
lation, but failed, because it was a complex molecular system (involving 129 atoms with 381 parameters,
including bond lengths, angels, and dihedrals). More rational models and feasible methods would be
used to address these in future studies.
STAR+METHODS
Detailed methods are provided in the online version of this paper and include the following:
dKEY RESOURCES TABLE
dRESOURCE AVAILABILITY
BLead contact
BMaterials availability
BData and code availability
dMETHOD DETAILS
BCatalytic reaction test
BMethods for characterization
SUPPLEMENTAL INFORMATION
Supplemental information can be found online at https://doi.org/10.1016/j.isci.2021.103028.
Figure 5. Selectivity of aromatic aldehydes from several aliphatic aldehydes (For [a], as shown in Scheme 3,thed-
C site of iminium intermediates involved in the cycloaddition step is indispensable; however, this site can’t be
formed from CH
2
OorC
3
H
4
O, thus 1 mmol acetaldehyde was co-fed).
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12 iScience 24, 103028, September 24, 2021
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ACKNOWLEDGMENTS
This work was supported by the Youth Program of National Natural Science Foundation of China (No.
22002161). This work was also conducted by the Fundamental Research Center of Artificial Photosynthesis
(FReCAP), financially supported by National Natural Science Foundation of China (NSFC) under grant No.
22088102. We thank Prof. Dr. Zhaochi Feng and Zhendong Feng (Dalian Institute of Chemical Physics, Chi-
nese Academy of Sciences) for their help in in situ IR experiments. We also thank Dr. Guanna Li (Wagenin-
gen University & Research, Netherlands) for her help to make a preliminary attempt in theoretical
calculation.
AUTHOR CONTRIBUTIONS
C. L. directed this work. C. L., Q. -N. W., and X. L. conceived this work. Q. -N. W. performed the catalytic
experiments and proposed the dehydrogenation mechanism. X. L. prepared the (in situ)NMRexperiments
and investigation. K. W. participated in the discussion of dehydrogenation mechanism and gave some sug-
gestions.Y.L.proposedthecycloadditionreactionfrom acetaldehyde. S. -M. L. discussed the results and
offered some suggestionsabout the dehydrogenation mechanism. C. L., Q.-N. W., and X. L. wrote the
article with edits and approval from all authors.
DECLARATION OF INTERESTS
C. L., Q.-N. W., and X. L. applied for a China patent based on the technology described in this work at Da-
lian Institute of Chemical Physics, Chinese Academy of Sciences (Application number: 202011448529.1).
The other authors declare no competing interests.
Received: May 24, 2021
Revised: July 25, 2021
Accepted: August 19, 2021
Published: September 24, 2021
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STAR+METHODS
KEY RESOURCES TABLE
RESOURCE AVAILABILITY
Lead contact
Further information and requests for resources and reagents should be directed to and will be fulfilled by
the Lead Contact, Can Li (canli@dicp.ac.cn).
Materials availability
This study did not generate new unique reagents.
Data and code availability
dAll data reported in this paper will be shared by the lead contact upon request.
dThis paper dose not report original code.
REAGENT or RESOURCE SOURCE IDENTIFIER
Chemicals
Tetrahydropyrrole (THP) Bidepharm CAS: 123-75-1
3-pyrrolidinol (THP-OH) ACMEC biochemical CAS: 40499-83-0
L-Proline (THP-COOH) Bidepharm CAS: 147-85-3
2-(Diphenylmethyl) pyrrolidine
(THP-DPh)
Daicel CAS: 23627-61-4
(S)-2-(diphenyl((trimethylsilyl)oxy)Methyl)pyrrolidine (THP-DPh-OTMS) Bidepharm CAS: 848821-58-9
CHCl
3
Sinopharm CAS: 67-66-3
p-NO
2
-Ph-OH Macklin CAS: 100-02-7
HCHO Sinopharm CAS: 50-00-0
CH
3
CHO Aladdin CAS: 75-07-0
CD
3
CDO (Chemical purity) Aladdin CAS: 1632-89-9
Trans-C
3
H
4
O Aladdin CAS: 107-02-8
Trans-C
4
H
6
O Aladdin CAS: 4170-30-3
n-C
4
H
8
O Aladdin CAS: 123-72-8
p-MBA Aladdin CAS: 104-87-0
H
218
O Aladdin CAS: 14314-42-2
Cyclopentanol Aladdin CAS: 96-41-3
Trans-C
5
H
8
O (95%) TCI CAS: 1576-87-0
Trans-C
6
H
10
O (98%) D&B CAS: 6728-26-3
Software and algorithms
ChemDraw Professional 17.0 PerkinElmer https://www.perkinelmer.com/
Origin Pro 9.0 OriginLab https://www.originlab.com/
MathType 6.9 WIRIS https://www.wiris.com/en/mathtype/
Other
7890A GC/GC-MS (5975C) Agilent Technologies https://www.agilent.com/
TOF-MS (6540 UHD Q-TOF) Agilent Technologies https://www.agilent.com/
Avance 400 MHz NMR/HD 700 MHz NMR spectrometer Bruker https://www.bruker.com/
ICP-OES (7300DV) PerkinElmer https://www.thermofisher.cn/
NEXUS 470 FT-IR Thermo Nicolet https://www.thermofisher.cn/
Mass spectrometer (DECRA) Hiden Analytical https://www.hidenanalytical.com/
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dAny additional information required to analyze the data reported in this paper is available from the lead
contact upon request.
METHOD DETAILS
Catalytic reaction test
All commercially available reagents were reagent grade and used without further purification unless other-
wise specified. CHCl
3
were further degassed before use for controlled experiments according to a stan-
dard freeze-pump-thaw method. Normally, reactions were carried out under Ar atmosphere in new, fire
dried Schlenk tube (35 mL, Synthware). The amount of transition metals in amines was detected by ICP,
and their content is negligible.
General procedure: a solution of acetaldehyde (1 mmol) in solvent (for example, CHCl
3
,3mL)wastreated
with p-nitrophenol (0.3 mmol) and catalysts(0.1 mmol). The reaction mixture was stirred in a tube at 20Cfor
a certain period. Cyclopentanol is co-added and used as an internal standard to calculate formation rate
and carbon balance (Table S3). To accelerate the conversion of p-MCA to p-MBA, after the reaction carried
out at 20C for 2 h under normal conditions, more organic amines (0.1-0.45 mmol -NH- groups) were added
and then the mixture was stirred for more time (1-20 h) at a certain temperature (20, 40, or 60C). The re-
action under Air, Ar, and O
2
atmosphere was carried out using a batch reactor (75 mL). After reaction, a
gas chromatograph (GC) with a flame ionization detector, equipped with a HP-5 column (30 m 3
0.320 mm 30.25 mm), was used to quantify the products. Their identities were confirmed by GC-MS analysis
(Agilent 7890A GC, interfaced with 5975C MS, USA), and NMR spectrometer (
1
H spectra, BrukerAvance 400
NMR spectrometer). Time of Flight Mass Spectrometer (TOF-MS, Agilent, USA) was used to capture the
possible reaction intermediates in the liquid mixture. Gaseous products (such as H
2
)wereanalyzedbya
mass spectroscopy (Hiden Analytical). All conversion and selectivity were calculated on basis of moles of
carbon in the reactants and products, as follows:
Acetaldehyde conversion:
Conv:ðC%Þ=1N13A13f1
N13A13f+PiR2Ni3Ai3fi3100%
Product selectivity:
Selec:ðC%Þ=Ni3Ai3fi
PiR2Ni3Ai3fi
3100%
The carbon number, FID peak area, and response factor of each product are designated N
i
,A
i
,andf
i
,
respectively.
Product yield:
Yield ðC%Þ=Conv:ðC%Þ3Selec:ðC%Þ3100%
Aromatization of p-MCA to p-MBA: Cyclohex ane was used to separate p-methylcyclohexadienal from acidic
additives an d catalysts. Briefly, ace taldehyde reaction was fir stly carried out at 20C for 2 h under Ar. Then, t he
CHCl
3
was removed by a rotary evaporator at 20C. 25 mL (5 mL35 times ) cyclohexane was added to the y el-
low viscous residues to dissolve the methylcyclohexadienal intermediates. Please note that cyclohexane
doesn’t dissolve the p-NO
2
-PhOH and THP-DPh-OTMS. Yellowish products were obtained by removing
the cyclohexane from the extraction liquid. Although methylcyclohexadienal was co-existed with methyl
benzaldehyde, reaction rate can be calculated by using cyclopentanol as an internal standard.
Scale-up experiments: A solution of acetaldehyde (10 mmmol) in CHCl
3
(30 mL) was treated with p-nitro-
phenol (3 mmol) and THP-DPh-OTMS (1 mmol). The reaction mixture was stirred in a glass reactor
(100 mL) at 20Cfor2h;thenmoreTHP-DPh-OTMS(1mmol)wasaddedandstirredfor2hat60
Cunder
Ar. After reaction, a GC was used to quantify the products. Hexane was used to obtain the products in a
similar method described above, i.e., an extraction-rotary evaporation technique.
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16 iScience 24, 103028, September 24, 2021
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Synthesis of several aromatic aldehydes: C
1
-C
6
aliphatic aldehydes (CH
2
O, C
2
H
4
O, trans-C
3
H
4
O, trans-
C
4
H
6
O, C
4
H
8
O, trans-C
5
H
8
O, and trans-C
6
H
10
O) were used to as reactants. A solution of aldehydes
(1 mmmol C
1
-C
3
/0.5 mmol C
4
-C
6
aldehydes) in CHCl
3
(3 mL) was treated with p-nitrophenol (0.3 mmol)
and THP-DPh-OTMS (0.1 mmol). The reaction mixture was stirred in a tube at 20Cfor2h;thenmore
THP-DPh-OTMS (0.1 mmol) were added and stirred for 2 h at 60C under Ar. The product structure was
analyzed and identified by GC-MS. Cyclopentanol is co-added and used as an internal standard to calcu-
late formation rate and carbon balance (Table S3).
18
O-isotope experiments: H
218
O (97 atom%) was supplied by Aladdin. Prior to adding acetaldehyde,
2mmolH
218
O was firstly added into the mixture liquid of catalyst (0.1 mmol) and solvent (CHCl
3
,3mL).
The reaction mixture was stirred in a vial at 20C for 2 h. After reaction, a GC-MS was used to analyze
the fragment peaks (m/z) of reactants and products.
D-isotope experiments: A solution of CD
3
CDO (4 mmmol) in CHCl
3
(10 mL) was treated with p-nitrophenol
(0.6 mmol) and THP-DPh-OTMS (0.2 mmol). The reactionmixturewasstirredinabatchreactorat20
Cfor
2 h; then more THP-DPh-OTMS (0.2 mmol) were added and stirred for 2 hr at 60C under Ar. Aldehyde con-
version and product selectivity were quantified by GC. The product structure was identified by GC-MS.
Gaseous products (such as H
2
,HD,andD
2
) were qualitatively analyzed by a mass spectroscopy (Hiden
Analytical DECRA). In comparison, experiments used CH
3
CHO as reactants were also conducted in a
similar procedure. And the gaseous products were also analyzed.
In situ HCl poisoning experiments: A solution of acetaldehyde (1 mmol) in CHCl
3
was treated with p-nitro-
phenol (0.3 mmol) and THP-DPh-OTMS (0.1 mmol). The reaction mixture was stirred in a vial at 20Cfor2h
under Ar. Then, 0.1 mmol HCl was added into the reaction mixture, which was continued to be treated at
20C. The product distributions were detected with reaction time.
In situ IR experiments: CH
3
CHO-IR was carried out on a Thermo Nicolet spectrometer (NEXUS 470) equip-
ped with a liquid reaction cell (Omni-Cell) and a deuterated triglycine sulfate (DTGS) detector. This liquid
cell was equipped with a pair of CaF
2
windows and sealed by Teflon, forming a cavity of about 120 mL. The
reaction mixture was injected into the cell via one of the circular holes (2 mm in diameter) located at the
CaF
2
window (see Figure S1E).Afterthecellsealed,thereactionmixturewasmaintainedat20
Ctocollect
the spectrum. The evolution of reactants and products was monitored by IR in a transmission mode by aver-
aging 32 scans at a resolution of 4 cm
-1
. Standard IR spectra of acetaldehyde, 2-butenal, p-MBA, THP-DPh-
OTMS, and p-NO
2
-PhOH in CHCl
3
were also conducted using the same cell, respectively.
NMR investigation: to confirm the synthesis of p-MBA, products were separated from reaction mixtures by
a method of column chromatography with EtOAc-light petroleum (volume ratio = 1:10) to obtain a light-
yellow oil. Merck 60 silica gel was used for chromatography.
1
Hand
13
C NMR spectra were obtained on
an Avance 400 MHz NMR spectrometer. NMR peaks, assigned to p-MBA, were shown, as follows:
1
H
NMR (400 MHz, CDCl
3
)d9.96 (s, 1H), 7.77 (d, J= 8.1 Hz, 2H), 7.32 (d, J= 8.0 Hz, 2H), 2.43 (s, 3H);
13
C
NMR (101 MHz, CDCl
3
)d191.97, 145.54, 134.22, 129.84, 129.71, 21.87. THP-DPh-OTMS:
1
H NMR (400
MHz, CDCl
3
)d7.58–7.52 (m, 2H), 7.47–7.41 (m, 2H), 7.41–7.27 (m, 7H), 4.15 (t, J= 7.4 Hz, 1H), 3.02–2.81
(m, 2H), 2.25 (s, 1H), 1.76–1.61 (m, 3H), 1.52–1.41 (m, 1H), 0.00 (s, 9H). In situ
1
H spectra were recorded
on a 700 MHz spectrometer (Bruker) at 20C. 40 spectra were collected at an interval of 80s within about
1 h. Chemical shifts are given in ppm. Standard H-NMR spectra of acetaldehyde, 2-butenal, p-MBA,
THP-DPh-OTMS, and p-NO
2
-PhOH in CHCl
3
were also conducted as references. Reaction conditions
were shown in Figure S4.
Methods for characterization
ICP analysis: Inductively Coupled Plasma-Optical Emission Spectrometry (ICP-OES, ICPS-8100, Japan) was
used to analyze the content of transition metals. Briefly, 90 mg THP-DPh-OTMS was dissolved into 3 mL
aqua regia (Take care: this oxidation is a strong exothermic reaction!) to obtain a clear aqueous solution.
Then, the content of Pd, Ir, and Pt (which are reported active for oxidative dehydrogenation, Gnaim, et al.,
2021) was analyzed by ICP-OES. The amount was calculated on basis of the peak area. The amount of Pt is
0.01 ppm, and no Pd and Ir were detected. These results are within the uncertainty of the measurement;
therefore, the metal amount is negligible.
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