One-pot preparation of pyrazole “turn on” and “turn off” fluorescent sensors for Zn²⁺ and Cd²⁺ directly from chalcones via in situ aromatisation

Abstract

A direct chalcone to pyrazole synthetic route to “turn on” and “turn off” fluorescent sensors for Cd²⁺ and Zn²⁺ was developed using CuCl₂ as an in situ oxidant. This one-pot approach produced eight novel pyridine based pyrazole fluorescent sensors displaying both “turn on” and “turn off” properties dependent on the substutient on the aryl ring (4-F, 4-Cl, 4-Br, 4-I, 4-CN, 4-NO₂, 4-OMe and 3,4-OMe). The results within provide valuable insight for future pyrazole sensor design.

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Introduction

Pyrazole,¹ a five-membered heterocycle with two adjacent nitrogen atoms (red in Fig. 1), is a privileged structure² with a diverse range of biological activities including anti-inflammatory,³ anti-cancer⁴ and anti-infective⁵ properties. 3,5 substituted pyrazoles have unique photophysical properties with applications in luminescent dyes⁶ and fluorescent sensors.⁷ “Turn off” fluorescent sensors display reductions in fluorescent emission (λ_em) with analyte, for example 1 with picric acid⁸ and 2 with Cu²⁺ and Ni²⁺ (Fig. 1).⁹ “Turn on” fluorescent sensors are characterised by increased λ_em with analyte, 3 demonstrates Fe³⁺/Fe²⁺ selectivity¹⁰ and P1 displays a “turn on” response with Zn²⁺ and Cd²⁺ in MeCN (Fig. 1).¹¹

Fig. 1 A selection of 3,5 substituted “turn off” and “turn on” sensors.

Zinc is involved in a variety of biological functions including gene expression,¹² enzyme maintenance¹³ and neurological functions.¹⁴ Cadmium, also a group 12 element sitting below zinc in the periodic table, is a highly toxic pollutant implicated in a variety of cancers.¹⁵3 and P1 demonstrate structural complexity is not a prerequisite for complex functionality and that simple molecular structures can detect biologically important analytes.^10,11

Chalcones,¹⁶ also a privileged structure with numerous biological activities,¹⁷ are popular precursors for pyrazoles due to the range of inexpensive commercially available starting materials. To date, there are few examples of direct chalcone to pyrazole syntheses, often requiring vigorous heating under acidic conditions¹⁸ or use of a catalyst.¹⁹ The traditional two step synthesis involves 1,2 addition of hydrazine to the enone^10,11,20 forming a pyrazoline²¹ which is isolated, purified, and undergoes subsequent aromatisation to a pyrazole (blue and red respectively (Scheme 1).

Scheme 1 A one step approach to synthesise pyrazole (in red) directly from chalcone avoiding the pyrazoline (in blue) intermediate step.

A range of chemical oxidants have been reported to perform this pyrazoline to pyrazole aromatisation including MnO₂,²² FeCl₃,²³ CoCl₂²⁴ and CuCl₂.²⁵ Previous work¹⁰ demonstrated the addition of 8.0 equivalents (eq.) methylhydrazine at room temperature resulted in minor formation of pyrazole (yield 8–18%). Herein we report optimisation of this reaction enabling efficient access to the pyrazole privileged structure directly from chalcone avoiding the requirement to isolate, purify and then aromatise the pyrazoline ring separately. We examined multiple reaction conditions and screened eight different transition metal oxidants. Direct one-pot access to pyrazole sensors facilitated rapid synthesis and screening of eight novel Zn²⁺ and Cd²⁺ “turn on” and “turn off” pyrazole sensors.

Results and discussion

Chalcone C1 is the precursor for P1 and was selected as a model system for reaction screening (Scheme 2).

Scheme 2 Preliminary reaction condition screening.

Previous work¹⁰ was used as a baseline (entry 1, Table 1) and ¹H NMR was used to determine the percentage (%) conversion of C1 to P1 using the ratio of the chemically distinct methyl (CH₃) groups in the pyrazoline P1* at approx. 2.90 ppm and the pyrazole methyl (CH₃) at approx. 4.30 ppm (shown in blue and red in Fig. 2, see ESI† for full study).

Table 1 Preliminary reaction condition screening for pyrazole P1, % conversion determined by ¹H NMR from duplicate experiments (see ESI). Bold indicates the optimum selection per parameter

Entry	Solvent	Temperature (°C)	Eq. H2NNHMe	P1 % conversion
1	MeOH	20	8.0	18
2	EtOH	20	8.0	10
3	iPrOH	20	8.0	3
4	MeCN	20	8.0	11
5	THF	20	8.0	7
6	CH2Cl2	20	8.0	10
7	CHCl3	20	8.0	13
8	Hexane	20	8.0	2
9	MeOH	40	8.0	30
10	MeOH	60	8.0	40
11	MeOH	60	1.5	38
12	MeOH	60	2.0	40
13	MeOH	60	4.0	35
14	MeOH	60	16	32

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Fig. 2 Representative example of ¹H NMR study to determine the % conversion of methyl group A in P1* (in blue, entry 18, Table 2, i) to methyl group B in P1 (in red, entry 19, Table 2, ii).

Preliminary conditions produced 18% conversion of C1 to P1 with pyrazoline P1* the residual component (Table 1). Solvent, consisting of the bulk of the reaction mixture, was initially screened using a variety of polar/nonpolar and protic/nonprotic solvents.

Polar protic solvents MeOH, EtOH and iPrOH (entries 1–3, Table 1) were initially investigated with MeOH providing the best % conversion of 18%. Polar aprotic solvents (MeCN and THF, entry 4 and 5, Table 1) reduced % conversion to 11% and 7% respectively. Chlorinated solvents CH₂Cl₂ and CHCl₃ (entries 6 and 7, Table 1) failed to provide an improvement with 10% and 13% P1 conversion. Interestingly the use of the nonpolar aprotic solvent hexane was highly detrimental to P1 formation with 98% conversion to P1* and only 2% P1 (entry 8, Table 1). Hexane would be an excellent choice for pyrazoline only targeted synthesis. Eight solvents were screened and the preferred solvent for pyrazole formation was MeOH, this was fixed and used for all subsequent reactions. The reaction temperature was varied to 40 °C and then 60 °C with a further improvement on P1% conversion to 30% and 40% respectively (entry 9 and 10, Table 1). The temperature was fixed at 60 °C to provide the best P1 conversion while remaining below both the boiling points of MeOH and methylhydrazine (H₂NNHMe). The number of equivalents (eq.) H₂NNHMe was varied, surprisingly reducing the eq. of H₂NNHMe to 2.0 did not significantly reduce the P1% conversion (entry 12, Table 1). Further increases in eq. H₂NNHMe did not yield an improvement therefore according to the principle of atom efficiency and green chemistry²⁶ 2.0 eq. H₂NNHMe was used for all further reactions.

The initial reaction condition optimisation (Table 1) resulted in a significant increase in P1 pyrazole formation from 18% to 40%, we then investigated if the presence of an oxidant would improve the in situ aromatisation of the pyrazoline to a pyrazole (Scheme 3 and Table 2).

Scheme 3 Oxidant screening.

Table 2 In situ oxidant screening for P1 using the optimum conditions from entry 12, Table 2 (2 eq. H₂NNHMe, MeOH, 60 °C, 24 h) with the addition of the indicated oxidant, bold indicates optimum condition for each parameter, % conversion determined via¹H NMR and is from duplicate experiments (see ESI). Bold indicates the optimum selection

Entry	Oxidant	Eq.	P1 % conversion
12	—	—	40
15	MnO2	1.0	25
16	FeCl3	1.0	17
17	CoCl2	1.0	12
18	NiCl2	1.0	2
19	CuCl2	1.0	83
20	ZnCl2	1.0	45
21	CuSO4	1.0	64
22	Cu(OAc)2	1.0	78
23	CuCl2	0.5	61
24	CuCl2	0.25	19

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MnO₂ has been reported to be a useful oxidant for pyrazole formation²² however it reduced conversion to 25% (entry 15, Table 2). A similar effect was observed with FeCl₃, CoCl₂ with the presence of 1.0 eq. NiCl₂ highly detrimental to pyrazole formation (entries 16–18, Table 2). 1.0 eq. ZnCl₂ produced a slight increase in conversion to 45% (entry 20, Table 2) however the addition of CuCl₂ was the most promising with a more than doubling of conversion to 83% (entry 19, Table 2). Encouraged by this result, we investigated two different copper salts, CuSO₄ and Cu(OAc)₂ which yielded 64% and 78% conversion suggesting the Cu²⁺ primarily is responsible for the oxidation with CuCl₂ the preferred oxidant (entries 21 and 22, Table 2). Reducing the amount of CuCl₂ to 0.5 eq. and 0.25 eq. reduced the conversion to 61% and 19% respectively (entries 23 and 24, Table 2) suggesting a full 1.0 eq. is required for maximum conversion. Copper salts are cheap, easily accessible and their ease of handling and low toxicity profile have found widespread use in organic catalysis. Cu²⁺ mediated aromatisation of cyclohexanone derivatives to phenols,²⁷ Cu²⁺ catalysed aromatisation of tetrahydrocarbazole to carbazole alkaloids²⁸ and the synthesis of pyrazoles via copper-catalysed relay oxidation have also been reported.²⁹ In summary, we screen eight transition metal as in situ oxidants with Cu²⁺ based oxidants the most significant with CuCl₂ providing the best option for in situ aromatisation. An LC-MS study was conducted to further examine this synthesis under entry 19 conditions (with CuCl₂) to monitor the conversion of C1 to P1via the in situP1* intermediate (Fig. 3 and Table 3).

Fig. 3 LC-MS study using entry 19 conditions (Table 2).

Table 3 LC-MS study % conversion using entry 19 conditions from Table 2

Timepoint (h)	P1* (%)	P1 (%)	C1 (%)
0.0	—	27	57
4.0	4.0	60	2.6
6.0	1	84	—
24.0	—	83	—

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After 4.0 hours all chalcone C1 was consumed with P1 the major component with detectable P1*. After 6.0 hours all P1* was aromatised to P1 (Fig. 3 and Table 3). A second LC-MS study was conducted as a negative control using the NiCl₂ conditions with contrasting results (Fig. 4 and Table 4).

Fig. 4 LC-MS study using entry 18 conditions (Table 2).

Table 4 LC-MS study percentage % conversion using entry 18 conditions

Timepoint (h)	P1* (%)	P1 (%)	C1 (%)
0.0	—	—	96.0
2.0	18	7.0	62.0
4.0	31.0	11.0	45.0
6.0	36.0	14.0	39

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After 2.0 and 4.0 hours there was still significant C1 with P1* and trace amounts of the desired P1 present (Fig. 4 and Table 4). Sampling the mixture at 6.0 hrs showed a minor P1 improvement but with substantial unreacted C1 still remaining, in contrast to the same timepoint with CuCl₂. Further sampling at 8.0 and 24.0 hours failed to show improvement (ESI†) in P1 demonstrating the choice of transition metal oxidant was critical to the aromatisation process with CuCl₂ the superior choice. With a suitable one-pot method to generate pyrazoles selected we validated it by applying it to chalcones with both electron withdrawing and donating aryl units. Chalcones C1–C9 were prepared via literature methods³⁰ in good to excellent yield (38–92%). The CuCl₂ method was applied to P1 with an isolated yield of 57% which is comparable on the overall yield of 58% over two steps previously reported.¹⁰ This method was also successfully applied to novel pyrazoles P2–P9 in acceptable yield (38–77%, Scheme 4 and Table 5).

Scheme 4 Synthesis of P1–P9 using optimised conditions.

Table 5 Chemical yields for P1–P9 using CuCl₂ as an in situ oxidant

Entry	X	CuCl2 method yield (%)
P1	4-H	57
P2	4-F	77
P3	4-Cl	61
P4	4-Br	40
P5	4-I	32
P6	4-CN	57
P7	4-NO2	47
P8	4-OMe	48
P9	3,4-OMe	38

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With eight novel potential sensors in hand, we investigated their potential as Zn²⁺ and Cd²⁺ fluorescent sensors in MeCN (Fig. 5), this solvent was selected to allow direct comparison with two previous studies on related pyrazoles.^10,11 Standard protocols for screening fluorescent sensors in organic solvents were followed throughout.³¹

Fig. 5 Fluorescence studies of P2–P5 (20 μM, MeCN, λ_ex 295 nm) with 5.0 eq. Zn²⁺ or Cd²⁺, insets are pyrazoles at λ_ex 365 nm with the indicated metal, cps is counts per second.

Halogenated pyrazole P2–P5 all display a “turn on” fluorescent response in the presence of both Zn²⁺ and Cd²⁺ with a higher λ_em at 465 nm with Cd²⁺/Zn²⁺ (Fig. 5). A similar result was observed with the previously reported sensor¹¹ also displaying λ_em at 465 nm with Cd²⁺/Zn²⁺. The nature of the electronegative halogen influenced “turn on” intensity when X = 4-F P2 (Fig. 5A) and 4-Cl P3 (Fig. 5B) the response is almost identical but as halogen size is increased to 4-Br P4 (Fig. 5C) and 4-I P5 (Fig. 5D) the magnitude of λ_em is reduced. The halogen series can be summarised as λ_em intensity at 465 nm: F ≈ Cl > Br < I. These preliminary results suggest the presence of an electronegative group results in a “turn on” response. To test this hypothesis, two additional electronegative pyrazoles were produced pyrazole P6 bearing a strong electronegative cyano (4-CN) group, which is often compared to F, and a highly electronegative nitro (4-NO₂ group) pyrazole (Fig. 6A and B).

Fig. 6 Fluorescence studies of P6–P9 (20 μM, MeCN, λ_ex 295 nm) with 5.0 eq. Zn²⁺ and Cd²⁺, insets at λ_ex 365 nm with the indicated metals, cps is counts per second.

As predicted, pyrazole P6 with a 4-CN group (Fig. 6A) did display a “turn on” response with both Cd²⁺ and Zn²⁺ analogous to the halogenated pyrazoles P2–P5 however with reduced intensity at λ_em 460 nm. Comparing P6 directly with P2, both of which have similar electronegative withdrawing groups, demonstrates that F is the preferred substituent, and that electronegativity alone is not solely responsible for the “turn on” response. This is further confirmed for P7 with a NO₂ group displaying “turn on” properties in the presence of Zn²⁺ and Cd²⁺ (Fig. 6B) but with λ_em 350 nm in contrast to λ_em 460 nm observed in P2–P6 and P8. This indicates the 4-NO₂ group is exerting a significant influence on the photophysical properties of this sensor. An interesting observation was the presence of the electron donating 4-OMe group in P8 resulted in a minor “turn off” response with both Zn²⁺ and Cd²⁺ (Fig. 6C). A further electron donating pyrazole bearing a 3,4-Dimethyloxyl group P9 was synthesized, this followed the trend of P8 displaying minor “turn off” response in the presence of Zn²⁺ and Cd²⁺ (Fig. 6D). In summary this preliminary screen of eight novel pyrazoles suggests the presence of electron withdrawing groups at the 4-position of the aryl ring result in a “turn on” response in the presence of Zn²⁺ and Cd²⁺ with the chemistry of the group influencing photophysical properties. Electron donating groups on the aryl ring result in a minor “turn off” response also with Zn²⁺ and Cd²⁺. “Turn on” sensors are typically preferred over “turn off” therefore P2 was selected for further investigation with Zn²⁺ titration experiments confirming an increased λ_em at 465 nm with Zn²⁺ reaching a maximum at 5.0 eq. metal with sensor with further increases in Zn²⁺ resulting in very minor increased fluorescent intensity (Fig. 7).

Fig. 7 Fluorescence studies of P2 (20 μM, MeCN, λ_ex 295 nm) with increasing eq. of Zn²⁺ 0.125, 0.25, 0.50, 1.0, 2.0, 3.0, 4.0, 5.0, 7.0, 10.0 and 20.0 eq. Inset is λ_em at 465 nm, cps is counts per second.

A similar response was observed with Cd²⁺ however with increased λ_em at 465 nm at the same concentration suggesting P2 would be more suited as a Cd²⁺ sensor (Fig. 8).

Fig. 8 Fluorescence studies of P2 (20 μM, MeCN, λ_ex 295 nm) with increasing eq. of Cd²⁺ 0.125, 0.25, 0.50, 1.0, 2.0, 3.0, 4.0, 5.0, 7.0, 10.0 and 20.0 eq. Inset is λ_em at 465 nm, cps is counts per second.

The maximum emission was observed at 5.0 eq. Cd²⁺ with further increases resulting in minor increase in emission. A limit of detection (LoD) of 1.97 μM for Zn²⁺ and 0.077 μM for Cd²⁺ was measured for P2 which is an improvement on the 0.34 μM LoD for P1 with Cd²⁺ reported previously.¹¹ A proposed binding mechanism for P2 with Zn²⁺ is shown in Fig. 9 and agrees with the previously reported crystal structure for P1 with Zn²⁺.¹¹

Fig. 9 Proposed binding mechanism of P2 with Zn²⁺.

A competition assay was performed to assess P2λ_em in the presence of a range of competing metals (Fig. 10).

Fig. 10 Competition experiments for P2. The white bar represents P2 (20 μM, MeCN, λ_ex 295 nm, λ_em 465 nm) with 5.0 eq. of the indicated cation; the black bars is the same with 5.0 eq. Cd²⁺ after equilibrating for 3 min.

Quenching of the “turn on” response was observed with a range of paramagnetic metals including Ni²⁺, Mn²⁺, Cu²⁺, Ru³⁺ and Co²⁺ and this has been observed with similar sensors.^10,11 Interestingly the presence of diamagnetic metals Zn²⁺ and Pb²⁺ and the group 1 and 2 metals Na⁺, K⁺, Ca²⁺ and Mg²⁺ did not result in a significant reduction in λ_em. This suggests P2 could be a useful sensor for the detection of Cd²⁺ in biological samples containing group 1 and 2 metals once a suitable aqueous based derivative of P2 is developed. The results from the eight novel pyrazoles indicate the 4-position of the aryl ring to be an excellent location for introducing electronegative water solubilising groups to accomplish this. This is the primary focus of the next generation of sensors under development and will be resulted in due course. The one-pot route enables rapid access to novel pyrazoles directly from chalcones greatly accelerating future pyrazole sensors development alongside expediting pyrazole-based molecules with a diverse and wide range of valuable applications.³²

Conclusions

A new one pot method to synthesize pyrazoles directly from chalcones was developed using CuCl₂ as an in situ oxidant which was validated against a range of electron donating and withdrawing chalcones resulting in eight novel pyrazole based sensors. These sensors were confirmed to display both “turn on” and “turn off” properties dependent on aryl ring substitution. The presence of electronegative groups at the 4-position resulted in a “turn on” sensor with the chemistry of the group influencing the extent of λ_em wavelength. Electro donating groups displayed a very mild “turn off” response. The 4-position is well suited to a variety of substitution and would be an excellent position for the introduction of water solubilising groups to transition away from a purely organic solvent-based sensor to an aqueous one, this is an ongoing objective and will be reported shortly. This simple modular scaffold would be highly amenable to a multi-sensor approach incorporating multiple chelation sites with valuable applications in real world monitoring. While the focus of this study was efficient access to pyrazoles for the design screening of sensors, this direct one pot approach also enables efficient access to future pyrazoles with applications in anti-cancer, anti-infective and anti-inflammatory screening studies and will be of benefit to the wider chemistry community.³²

Author contributions

Alexander Ciupa designed, synthesized, characterised, performed all spectroscopy studies and authored the manuscript.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The author acknowledges Steven Robinson for assistance with time-of-flight high resolution mass spectrometry, Glyn Connolly for NMR spectroscopy guidance and Krzysztof Pawlak with fluorescence spectroscopy. This work made use of shared equipment located at the Materials Innovation Factory; created as part of the UK Research Partnership Innovation Fund (Research England) and co-funded by the Sir Henry Royce Institute.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4nj02433h

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