Visual detection of formaldehyde by highly selective fluorophore labeling via gold(iii) complex-mediated three-component coupling reaction

Article abstract of DOI:10.1039/c5ob00966a

A novel method for visual detection of formaldehyde with excellent selectivity via a gold(iii) complex-mediated three-component coupling reaction of resin-linked sterically bulky amines and fluorescent alkynes has been developed.

Full text of DOI:10.1039/c5ob00966a

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Visual Detection of Formaldehyde by Highly Selective
Fluorophore Labeling via Gold(III) Complex-Mediated
Three-Component Coupling Reaction
Cite this: DOI: 10.1039/x0xx00000x
Kong-Fan Wong,a Jie-Ren Deng,a Xiao-Qun Wei,b Shi-Ping Shao,b Da-Peng Xiang*b
and Man-Kin Wong*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Gold-catalyzed three-component coupling reaction of
aldehydes, amines, and alkynes (A3-coupling reaction) has
become a convenient approach for propargylamine synthesis.7
Along with our ongoing efforts on the development of gold(III)
catalysis for A3-coupling reaction,8 we have developed a bis-
cyclometallated gold(III) complex with distorted square planar
geometry as an efficient catalyst for propargylamine
synthesis.8e The generally accepted reaction mechanism of the
A3-coupling reaction involves iminium ion generation from
amines and aldehydes followed by gold-catalyzed alkylation of
alkynes to give propargylamines. Formaldehyde is an aldehyde
of the smallest size in nature. In principle, we are able to
employ sterically bulky amines that could exclusively generate
iminium ions with formaldehyde even in the presence of other
aldehydes of larger sizes. Subsequent catalytic alkylation of the
iminium ions by fluorescent alkynes would give fluorescent
propargylamines. Accordingly, the amount of formaldehyde
could be determined by the fluorescent intensity of the
propargylamines.
A novel method for visual detection of formaldehyde with
excellent selectivity via a gold(III) complex-mediated three-
component coupling reaction of resin-linked sterically bulky
amines and fluorescent alkynes has been developed.
Formaldehyde is a reactive organic compound ubiquitously
found in the environment1 and present in food mainly due to
natural occurrence and/or release from food packaging
materials.2 Common food contains formaldehyde with an
average level of 1-98 mg/kg.2 However, formaldehyde has been
illegally added to food for preservation and bleaching with
extreme cases of over 4,250 mg/kg.2
Serious exposure to formaldehyde may induce acute
poisoning, dermal allergy, and irritation problems.2 According
to International Agency for Research on Cancer (IARC),
formaldehyde is carcinogenic to humans in causing
nasopharyngeal cancer.2b Chronic toxicities of formaldehyde
include neurotoxicity, reproductive toxicity, hematotoxicity and
genotoxicity. World Health Organization (WHO) establishes a
tolerable daily intake of 0.15 mg/kg/day for formaldehyde.
United States Environmental Protection Agency (USEPA) also
defines an oral reference dose of 0.2 mg/kg/day.2
Standard analytical methods for formaldehyde measurement
include gas chromatography3 and liquid chromatography.4
However, these methods require expensive instruments and
sophisticated operational skills are not suitable for on-site
detection. Significant advances have been achieved for rapid
detection of gaseous formaldehyde.5 Yet, the development of
rapid formaldehyde detection for food samples remains sparse.
Without chromatographic separation and structural
characterization by instruments, the key challenge of rapid
detection methods is to achieve excellent specificity towards
the target analytes. Hantzsch pyridine synthesis featuring multi-
component coupling reaction of formaldehyde with 2,4-
pentanedione and ammonium acetate affording 3,5-diacetyl-
2,6-dihydrolutidine has been used as a highly selective reaction
for formaldehyde detection since 1950s.6 However, no major
breakthrough in the development of highly selective chemical
reactions amendable for rapid formaldehyde detection under
mild reaction conditions has been made for decades.1a
Herein we first report a visual detection method with
excellent selectivity for formaldehyde based on the gold(III)-
mediated A3-coupling reaction (Scheme 1). Using resin-linked
sterically bulky amines, formaldehyde can be exclusively
linked to fluorescent alkynes through propargylamine
formation. A good linearity (R2 = 0.9937) between the
formaldehyde concentration and propargylamine formation was
found by LC–MS/MS analysis. Using a hand-held UV lamp,
the formaldehyde concentration (as low as 10 ppm) could be
qualitatively determined by naked eyes. Excellent selectivity
and tolerance have been demonstrated by application on
formaldehyde detection of crude mushroom water extracts.
Scheme 1. Bis-cyclometallated gold(III) complex-mediated
three-component coupling reaction for exclusive fluorescent
detection of formaldehyde.
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We hypothesized that sterically bulky amines would µmol), amine 1b (50 µmol), alkyne 2b (100 µmol), and gold(III)
achieve excellent selectivity for formaldehyde in the step of complex 3a (50 µmol) in 1,2-dichloroethane (450 µL).
iminium ion formation. Thus, sterically bulky 2,2,6,6-
To achieve fluorescent detection of formaldehyde, we
tetramethyl-piperidine (1a) bearing four alpha-methyl groups decided to attach a fluorophore to the alkyne component. The
was chosen for the studies (Scheme 2). As a rapid detection amount of formaldehyde can then be determined by measuring
method, we set out to conduct the A3-coupling reaction for 1 h. the fluorescent intensity of the resulting propargylamines. On
Heating of formaldehyde (0.1 mmol), amine 1a (0.11 mmol), the other hand, to minimize the background fluorescent signal
phenylacetylene 2a (0.15 mmol) and gold(III) complex 3a (0.01 coming from the unreacted fluorescent alkynes, excess reagents
have to be removed after the A3-coupling reaction. To facilitate
mmol) in water (0.6 mL) at 50 °C for 1 h gave propargylamine
the washing step, the sterically bulky amines were attached to
polymer-bound 2-chlorotrityl chloride resins to give resin-
linked sterically bulky amine 1e according to literature.9 The
A3-coupling reaction of formaldehyde, resin-linked sterically
4a in 6% isolated yield (ESI†). Under the same reaction
conditions, no propargylamine formation for acetaldehyde,
isobutyraldehyde, benzaldehyde, and acetone was detected by
ESI-MS analysis of the reaction mixtures (ESI†). These
findings indicated the excellent formaldehyde selectivity of
bulky amine 1e, and coumarin-linked alkyne 2c gave
fluorescent propargylamines (Scheme 4).
sterically bulky 2,2,6,6-tetramethyl-piperidine 1a
.
O
O
O
Cl
NH
O
+
+
NH
N
N
H
H
NH
2c
1e
O
O
O
Cl
NH
3a
NH
H2O/ClCH2CH2Cl
50 oC, 1 h
Scheme 2. Seletivity study of A3-coupling reaction with
N
O
O
N
different carbonyl-containing compounds.
4c
O
NH
After identifying the sterically bulky amine component for
exclusive formaldehyde selectivity, we studied the effects of
different reaction parameters on the formation of
propargylamine 4b by HPLC analysis using formaldehyde,
amine 1b, and alkyne 2b (Scheme 3). A calibration curve of
propargylamine 4b with excellent linearity (R2 = 0.9996) was
constructed for quantification (Figure S2, ESI†).
Cl
+
TFA/CH2Cl2
H2N
H
N
5a
Scheme 4. A3-coupling reaction of formaldehyde, resin-linked
sterically bulky amine 1e and coumarin-linked alkyne 2c via
propargylamine formation and cleavage of propargylamine 5a
from the resin 4c
.
The A3-coupling reactions of formaldehyde (0.02 mmol),
resin-linked sterically bulky amine 1e (15 mg), coumarin-linked
alkyne 2c (0.02 mmol) and bis-cyclometallated gold(III)
catalyst 3a (0.01 mmol) were conducted in 1,2-dichloroethane
at 50
°C for 1 h to give resin-bound propargylamine 4c
(Scheme 4). To confirm the product formation, propargylamine
5a was cleaved from the respective resins by treatment with
TFA/CH2Cl29 and confirmed by ESI-MS analysis (ESI†). Upon
excitation at 355 nm, propargylamine 5a exhibited a maximum
emission wavelength at 461 nm that is consistent with a
coumarin chromophore (Figure 1A).
Scheme 3. A3-coupling reaction of formaldehyde with amines
and alkynes catalyzed by different gold(III) complexes.
A
B
2.50E+06
2.00E+06
1.50E+06
1.00E+06
5.00E+05
0.00E+00
160
140
120
100
80
Three cyclometallated gold(III) complexes 3a-c commonly
R² = 0.9937
used by our research group8d-e were screened to study their
catalytic activities on the formation of propargylamine 4b
(Scheme 3) (Table S2, ESI†). Bis-cyclometallated gold(III)
complex 3a gave the highest yield among the three catalysts
that is in line with our previous work.8e In addition, we studied
the effects of different solvents, solvent ratio, temperature and
amounts of formaldehyde, amine 1b, alkyne 2b and bis-
cyclometallated gold(III) complex 3a on the yield of
propargylamine 4b (Tables S3-S6, ESI†). Up to 56% yield
60
40
20
0
390
440
490
540
590
0
20
40
60
80
100
Formaldehyde concentration (ppm)
Wavelength (nm)
Figure 1. (A) Fluorescent spectrum of propargylamine 5a; (B)
good linearity (R2 = 0.9937) between formaldehyde
concentration (4-103 ppm) and the peak area of the
propargylamine 5a determined by LC MS/MS.
A
could be achieved at 50 °C in 1 h using formaldehyde (10
–
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5OB00966A
LC–
MS/MS was used to determine the amount of the
This work was supported by Guangzhou Science and
propargylamine 5a. The peak area, which represented the Technology Fund (12S496140081), Hong Kong Research
amount of propargylamine 5a, increased with the concentration Grants Council (PolyU 5031/11p), State Key Laboratory of
of formaldehyde (from 4 to 103 ppm) (Figure 1B). A good Chirosciences, and The Hong Kong Polytechnic University
linear relationship (R2 = 0.9937) between the peak area and (SEG PolyU01).
formaldehyde concentrations was observed, suggesting the
readout from the LC–MS/MS can be used for quantification.
Under irradiation by a hand-held UV lamp at 365 nm, the
brightness of the resin-bound propargylamine 4c was related to
Notes and references
a Food Safety and Technology Research Centre, State Key Laboratory of
Chirosciences, and Department of Applied Biology and Chemical
the formaldehyde concentrations. The observable change of the Technology, The Hong Kong Polytechnic University, Hung Hom, Hong
Kong, China. Fax: +852-2364-9932; Email: mankin.wong@polyu.edu.hk
b Guangdong Inspection and Quarantine Technology Center, Guangdong
Entry-Exit Inspection and Quarantine Bureau, Tower B, 66 Huacheng
Avenue, Zhujiang Xincheng, Guangzhou, China. +86-20-3829-0537;
brightness could be straightforwardly differentiated by naked
eyes to qualitatively detect the formaldehyde concentration as
low as 10 ppm (Figure 2).
Email: xiangdp@iqtc.cn
.
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
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with acetaldehyde (250 µmol, ~18,400 ppm), isobutyraldehyde
(250 µmol, ~30,000 ppm) and benzaldehyde (125 µmol,
~26,500 ppm), respectively (ESI†). No propargylamine was
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indicated the excellent formaldehyde selectivity of this method.
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mushroom was used. It was found that formaldehyde in the
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In summary, a visual detection method for formaldehyde
e
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a gold(III) complex-mediated three-component
K. Y. Kung, J. F. Cui and M. K. Wong, Chem. Commun., 2013, 49
,
coupling reaction of formaldehyde, amines and alkynes has
been developed. No expensive instruments and sophisticated
operation skills are required with fast reaction time of 1 h at 50
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°
C. Exclusive formaldehyde selectivity was achieved by using
resin-linked sterically bulky amines. Signal readout can be
achieved by using LC MS/MS analysis or naked eyes.
–
Excellent tolerance in complex reaction mixtures has been
demonstrated by formaldehyde detection of crude mushroom
water extracts. This highly selective method opens up a new
direction for the development of rapid on-site detection of
formaldehyde with diverse applications.
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DOI: 10.1039/C5OB00966A
Visual fluorescent detection of formaldehyde by a highly selective gold(III) complex-
mediated three component coupling reaction