Logic gate copolymers of cinchona alkaloid-ferrocene derivatives

Abstract

The cinchona alkaloids quinidine, quinine, cinchonine and cinchonidine were derivatised with ferrocene by Steglich-type esterification and subsequently polymerised with acrylamide by free radical polymerization. The copolymers were characterised by ¹H NMR, FT-IR and UV-vis absorbance spectroscopy. The logic-based computing properties in emission mode are consistent with H⁺, X⁻-driven combinatorial OR-INHIBIT logic (where X = Cl⁻, Br⁻ or I⁻). The maximum fluorescence quantum yields are compromised by the presence of the ferrocene moiety due to photoinduced electron transfer from the ferrocene derivative to the quinoline fluorophore. Attempts to revive the fluorescence with a chemical oxidant were constrained due to inner filter effects or collisional anion quenching. In absorbance mode, the copolymers function as rapid naked-eye colorimetric H⁺, I⁻-driven AND logic gates in 4 : 6 (v/v) THF/water. The colour change from colorless to yellow is attributed to a π–anion non-covalent charge transfer interaction between I⁻ and the quinolium fragment of the alkaloids.

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Introduction

The cinchona alkaloids are fluorescent natural products used extensively in various scientific and medical fields.^1–3 Quinine has been used as a treatment for malaria since the 1600s.⁴ It is the key ingredient of ‘tonic water’, an invention patented by Erasmus Bond, the owner of Pitt & Co. in Islington, England, in 1858.⁵ The first proposed synthesis of quinine was reported in 1944, although with some controversy.⁶ Photochemists came to know of quinine as an off-the-shelf fluorescence quantum yield standard.⁷ Recently, molecular logic enthusiasts have shown interest in this unique genre of molecule.^8–11 Since its inception in 1993, the field of molecular logic^12–18 has spread throughout hundreds of chemistry labs around the world,¹⁹ predominantly in the form of synthetic molecules that initially applied the principles of photoinduced electron transfer (PET)²⁰ and photoinduced internal charge transfer (ICT).²¹ Indeed, the first AND²² and INHIBIT²³ molecular logic gates were human creations developed in organic synthetic laboratories. Rather intriguingly, it had gone unnoticed that Nature had long ago engineered the cinchona alkaloids with the hallmarks of PET and ICT fluorescent indicators with a receptor₁–fluorophore–spacer–receptor₂ arrangement.²⁴ The fluorophore is the quinoline unit and the spacer is the hydroxylated ethylene moiety. The proton receptors are the nitrogen atom of the quinoline and the azabicyclic amine (Fig. 1).

Fig. 1 The four cinchona alkaloid copolymers and their modular design.

Our group has developed the concept of Pourbaix sensors.²⁵ These are fluorescent molecular logic gates responsive to acidic and oxidizing conditions.²⁶ A themed functional component has been the incorporation of ferrocene as an oxidant responsive moiety. We have examined this class of sensor within polyacrylamide hydrogels,²⁷ polyurethane coatings²⁸ and covalently attached to TentaGel® polystyrene beads.^29,30 In the presence of high oxidant and high H⁺ levels, an enhanced fluorescent signal is observed according to an AND logic gate²⁹ and in some cases, as an INHIBIT logic gate.³⁰

In this study, cinchona alkaloids were functionalised at the hydroxyl unit with ferrocenecarboxylic acid, and subsequently, polymerised with acrylamide to yield ferrocene-containing cinchona copolymers 1–4 (Fig. 1). The copolymers have a receptor₁–fluorophore–spacer–electron-donor–spacer–receptor₂–linker–backbone format. We examine the copolymers in the context of molecular logic using H⁺, oxidants and anions as inputs and fluorescence as the output. We demonstrate the copolymers as colorimetric AND logic gates and fluorometric INHIBIT logic gates. Notably, these smart materials are selective for I⁻, an essential dietary mineral required for good health.³¹

Results and discussion

Synthesis

Scheme 1 illustrates the synthetic strategy for copolymers 1–4. The cinchona alkaloids were functionalised with ferrocene by reaction of ferrocenecarboxylic acid with N,N′-dicyclohexylcarbodiimide (DCC) using Steglich-type esterification.³² The cinchona-ferrocene esters were then reacted with acrylamide in the presence of the radical initiator 2,2′-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (VA-044) in 1 : 1 (v/v) H₂O/EtOH.⁸ The identity and composition of the copolymers were accessed by ¹H NMR and FTIR. The characterisation data are available in the Experimental section and the spectra in the ESI† (Fig. S1–S8).

Scheme 1 The synthesis of cinchona alkaloid-ferrocene copolymers 1–4 where R = OCH₃ in 1 and 2, and R = H in 3 and 4. Reaction conditions: (i) ferrocenecarboxylic acid, DCC, triethylamine, THF; (ii) acrylamide, VA-044, 1 : 1 (v/v) ethanol/water, Δ.

The ¹H NMR spectra of copolymers 1–4 in DMSO-d₆ are broad due to the slower correlation time for rotational diffusion of polymers (Fig. S1–S4, ESI†).³³ Proton coupling constants within the aromatic region could be determined for the monomer alkaloids, in some cases, but could not be determined for the copolymers. The disappearance of the vinyl ABX pattern of the monomers at 5.0–6.2 ppm supported the completion of the radical polymerisation reaction.⁸ The FTIR spectra of the copolymers (Fig. S5–S8, ESI†) are broad in the fingerprint region with an intense band at 1680 cm⁻¹ indicative of the acrylamide primary amide C=O stretch. The composition ratio of alkaloid/acrylamide units was determined by ¹H NMR by integrating the area of the quinoline proton at 8.70 ppm and the broad amide band at 6.80 ppm. The percentage of alkaloid in each copolymer was 15 ± 5% while the remaining acrylamide units made up 85 ± 5% (Table 1).

Table 1 Percent ratio of repeat units in copolymers 1–4^a

	1 QD^b	2 QN^c	3 CN^d	4 CD^e
a Determined by ^1H NMR from the quinoline H at 8.70 ppm and the broad NH2 singlet at 6.80 ppm in DMSO-d6. b Quinidine (QD). c Quinine (QN). d Cinchonine (CN). e Cinchonidine (CD).
Cinchona alkaloid (x)	15	20	20	10
Acrylamide (y)	85	80	80	90

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Spectroscopic results

The UV-visible absorption spectra (Fig. 2) of 1–4 were examined in water. In acidic media, pH 2, the maximum absorption band of the 6-methoxyquinoline of 1 and 2 is observed at 340 nm whilst the quinoline of 3 and 4 is observed at shorter wavelengths of 316 nm and 315 nm. The difference in the peak maxima between 1 and 2 to 3 and 4 is due to the electron-donating methoxy group at the 6-position of the quinoline ring. In alkaline media, pH 11, the maximum absorption band shifts to 271 nm and 269 nm for 1 and 2, and 274 nm and 275 nm for 3 and 4.

Fig. 2 The UV-vis absorption spectra of 1–4 in water at pH 1, 4 and 11. The concentrations are 0.20 g L⁻¹1, 0.70 g L⁻¹2, 0.11 g L⁻¹3, and 0.036 g L⁻¹4.

The absorptivity (a) at pH 2 for 1–4 is 0.33 L g⁻¹ cm⁻¹, 1.25 L g⁻¹ cm⁻¹, 0.42 L g⁻¹ cm⁻¹, and 1.58 L g⁻¹ cm⁻¹, respectively. At pH 11, the absorptivity (a) increases to 0.55 L g⁻¹ cm⁻¹, 2.34 L g⁻¹ cm⁻¹, 1.50 L g⁻¹ cm⁻¹ and 4.64 L g⁻¹ cm⁻¹. Between pH 6 and 11, the peak maximum remains constant for both the parent cinchona alkaloids and the acrylamide copolymers. This is consistent with a PET mechanism from the azabicyclic amine.⁹ However, between pH 2 and 6, the bands are pH dependent due to an ICT mechanism associated with the quinoline group as evidenced by isosbestic points about 262 nm and 302 nm. The UV-vis absorbance data are summarized in Table 2.

Table 2 Photophysical properties of copolymers 1–4 in water^a

	1 QD	2 QN	3 CN	4 CD
a 0.20 g L^−11, 0.70 g L^−12, 0.11 g L^−13, and 0.036 g L^−14. b pH adjusted with 0.10 M (CH3)4NOH. c Units of L g^−1 cm^−1. d pH adjusted with 0.10 M CH3SO3H. e Excited state pKas determined by log[(Imax − I)/(I − Imin)] = −log[H^+] + log βH+ from emission spectra in 0.1 μM Na2EDTA. Excited at λIso. f Only one inflection point in the I–pH plot. g H^+-induced switching ratio IFpH2/IFpH11.
λ Abs pH11/nm^b	271	269	274	275
log εpH11^c	0.55	2.34	1.50	4.64
λ Abs pH2/nm^d	341	338	316	315
log εpH2^c	0.33	1.25	0.42	1.58
λ Abs(iso)/nm	260, 294, 345	263, 305, 336	262, 306	265, 302
λ Flu pH11/nm	382	390	380	400
λ Flu pH2/nm	446	449	438	416
λ Flu(iso)/nm	391	394	397	374
	3.97, 9.00	4.02, 8.30	3.64, 8.79	3.99^f
FE^g	115	77	7	3

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The emission spectra of 1–4 in water are shown in Fig. 3 as a function of pH. The bands are broad, ranging between 320 and 600 nm. The fluorescence is high in acidic media and low in basic media. At pH 2, the emission peak maxima are observed at 446 nm, 449 nm, 438 nm, and 416 nm, respectively, for 1–4. At pH 11, a hypsochromic shift occurs accompanied by a decrease in the fluorescence intensity. The fluorescence enhancement (FE) ratios of 1 and 2 are large at 115 and 77, while 3 and 4 have lower comparable FEs of 7 and 3. These results are lower than those of the cinchona alkaloids⁹ due to the ferrocene moiety, which decreases the fluorescence intensity by ca. 30% of the cinchona alkaloids (vide infra).

Fig. 3 The emission spectra of 1–4 in water with increasing [H⁺]. The spectra were recorded while exciting at the isosbestic point (see Table 2).

The excited state pK_a were obtained by analysis of pH-intensity plots (Fig. 4) according to a modified Henderson–Hasselbalch equation (see footnote, Table 2). Copolymers 1–3 have a two-step sigmoidal profile explained by double protonation at the azabicyclic and quinoline nitrogen atoms. A substantial FE results from the protonation of the quinoline nitrogen atom. The are 3.99 ± 0.03 (excluding 3) and 8.70 ± 0.40 (excluding 4). Copolymer 4 has only one noticeable inflection point as observed with cinchonidine.⁹ The for the copolymers are ∼0.3 log units lower than the parent cinchona alkaloids. This difference is due to the lesser polar microenvironment of the acrylamide copolymer framework.

Fig. 4 Maximum peak emission intensity–pH plots of copolymers 1–4 in water excited at 350 nm, 350 nm, 316 nm and 315 nm.

Molecular logic by fluorescence

The copolymers 1–4 were next studied within the context of molecular logic-based computation.¹² The chemical inputs chosen were initially H⁺ and Cl⁻ while fluorescence is the output. At high H⁺ levels, the fluorescence is high, and at basic pH values, the fluorescence is low, as shown in Fig. 3, in the absence of Cl⁻. The low emission at low H⁺ levels is attributed to PET from azabicyclic amine or carboxyferrocene to (6-methoxy)quinoline.

Spectroscopic demonstration of INHIBIT logic is exemplified in Fig. 5. Chloride anions disable the fluorescence irrespective of the concentration of H⁺. The copolymers are non-emissive when there are no inputs (the absence of H⁺ and Cl⁻). This is the (0,0) input state. The copolymers are also non-emissive with Cl⁻ only (0,1), or with both H⁺ and Cl⁻ (1,1). A high emission is only observed when the copolymers are doubly protonated under high H⁺ conditions (1,0). This input–output behaviour is H⁺, Cl⁻-driven INHIBIT logic. The corresponding truth tables for copolymers 1–4 are provided in Table 3.

Fig. 5 The emission spectra of 1–4 in water for H⁺, Cl⁻-driven INHIBIT logic.

Table 3 Truth tables for H⁺, Cl⁻-driven INHIBIT logic gates 1–4 in water^ab

Input1 (H^+)^c	Input2 (Cl^−)^d	Output 1 (ΦF)^e	Output 2 (ΦF)^e	Output 3 (ΦF)^e	Output 4 (ΦF)^e
a 0.20 g L^−11, 0.70 g L^−12, 0.11 g L^−13, and 0.036 g L^−14. b Excited at 352 nm, 345 nm, 316 nm, and 315 nm. c High input1 10^−2 M H^+ and low input1 H^+ 10^−11 M adjusted with CH3SO3H and (CH3)4NOH. d High input2 100 mM Cl^− and low input2 no Cl^− added as NaCl. e Relative ΦFversus 10^−6 M quinine sulfate in aerated 0.1 M H2SO (Φf = 0.55). High threshold output level set at ΦFmax/2.
0 (low)	0 (low)	0 (0.002)	0 (0.005)	0 (0.006)	0 (0.003)
1 (high)	0 (low)	1 (0.163)	1 (0.139)	1 (0.030)	1 (0.013)
0 (low)	1 (high)	0 (0.002)	0 (0.004)	0 (0.005)	0 (0.002)
1 (high)	1 (high)	0 (0.042)	0 (0.037)	0 (0.006)	0 (0.004)

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The bright blue emission from 1 and 2 is quantified with fluorescence quantum yields (Φ_F) of 0.163 and 0.139. The dimmer blue emission from 3 and 4 have Φ_F values of 0.030 and 0.013. Fig. 6 nicely illustrates that, in each case, a blue fluorescence is only observed with high H⁺ levels. It should be noted that these Φ_F values are lower than those observed with analogue cinchona-acrylamide copolymers, which had Φ_F = 0.55 in the cases of 1 and 2, and 0.046 and 0.025 for 3 and 4.⁸ The carboxyferrocene exhibits a lower Φ_F value due to PET to the protonated quinoline but does not fully turn off the emission.

Fig. 6 Copolymers 1–4 in glass vials irradiated with 365 nm UV light in water in the presence of 0.1 μM Na₂EDTA. Conditions (A) 10⁻¹¹ H⁺, (B) 10⁻² H⁺, (C) 10⁻¹¹ H⁺ and 100 mM Cl⁻ and (D) 10⁻² H⁺ and 100 mM Cl⁻.

The ferrocene moiety was incorporated into the cinchona monomer unit with the intent of modulating the emission by an oxidant.^25,26 The driving force for PET is calculated from ΔG_PET = E_Ox − E_Red − E_S − e²/εr.³⁴ The oxidation potential of the carboxyferrocene is estimated at 0.75 eV vs. SCE,³⁵ which is 300 mV greater than ferrocene. The reduction potential of quinine was estimated to be −1.33 eV at pH 10, which decreases with increasing pH.³⁶ The singlet energy at 341 nm, for quinidine, is −3.64 eV. The calculated ΔG_PET is −1.66 eV. This highly exothermic value suggests that PET is within the Marcus inverted region.²⁵ In efficient PET logic gate systems in the normal Marcus region with a less exothermic driving force, fluorescence would not be observed.³⁷

With a suitable oxidant, it was hypothesised that the ferrocene moiety would be converted to its +3 state, which would prevent the PET and revive the fluorescence output. We tested ammonium persulfate, iron(III) sulfate, iron(III) perchlorate and cerium(III) nitrate as oxidants. In all cases, the emission tended to decrease to various extents attributed to the anion as well as the fact that Fe³⁺ is notorious for quenching short wavelength fluorophores by inner filter and paramagnetic effects.³⁸

Br⁻ and I⁻ also act as disabling inputs.^8,9 Regardless of the pH, the presence of 100 mM Br⁻ or I⁻ quenches the emission. The logic outcome on consideration of two (or more) anions as additional inputs is a multi-input disabled OR logic gate linked to the disabling input of an INHIBIT logic gate.⁹

Molecular logic by absorbance

Copolymers 1–4 were examined in water in the presence of I⁻ at 10⁻² M H⁺. A colour change from colourless to yellow was observed after 48 hours with new peaks in the UV-vis spectrum at 288 nm and 356 nm (Fig. S9, ESI†). This observation was seen with the parent cinchona alkaloids⁹ and acrylamide copolymers,⁸ which undergo a similar colour change. We surmised that the colour change results from an intermolecular charge transfer complex between I⁻ and the fluorophore as witnessed with nitrogen rich chemosensors containing pyridine,³⁹ benzimidazole,⁴⁰ or acridine.⁴¹ Two previous studies with heterocyclic polymers also reported iodide sensing in aqueous THF solutions.⁴² We observed a faster colorimetric response in 9 : 1 (v/v) THF/water such that the UV-vis spectrometer detector was saturated (Fig. S10, ESI†).

By adjusting the solvent conditions, the logic function can be reconfigured. In 9 : 1 (v/v) THF/water, a dark yellow colour change was observed with 10 μM I⁻ and 10⁻² H⁺ after 1 min as well as with 10 μM I⁻ and 10⁻⁹ M H⁺. This situation where a colour change was observed irrespective of the pH is in agreement with H⁺, I⁻-driven TRANSFER logic gates where I⁻ is the enabling input (Table 4).

Table 4 Truth tables for H⁺, I⁻ driven logic gate 1 as a solvent reconfigurable AND and TRANSFER logic gate with the absorbance (Abs) output monitored at 360 nm^a

Label	Input1 (H^+)^b	Input2 (I^−)^c	Output Abs (4 : 6 THF/H2O)^d	Output Abs (9 : 1 THF/H2O)^d
a 0.29 g L^−12. b High and low input1 is 10^−2 M and 10^−9 M H^+ adjusted with CH3SO3H and TMAH. c High input2 in 4 : 6 THF/H2O is 0.15 mM I^−. High input2 in 9 : 1 THF/H2O is 10 μM. I^− added as KI. d High threshold output level set at Abs > 0.6.
A	0 (low)	0 (low)	0 (low, 0.094)	0 (low, 0.016)
B	1 (high)	0 (low)	0 (low, 0.068)	0 (low, 0.40)
C	0 (low)	1 (high)	0 (low, 0.53)	1 (high, 3.92)
D	1 (high)	1 (high)	1 (high, 2.80)	1 (high, 3.92)

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Tuning the solvent polarity to 4 : 6 (v/v) THF/water, a different response was observed. A yellow color change was observed in the presence of 10⁻² M H⁺ and 0.15 mM I⁻ after 5 min. In contrast, no color change was observed with 10⁻⁹ M H⁺ and 0.15 mM I⁻, or in the presence of only 10⁻⁹ M H⁺, or only 0.15 mM I⁻. These results are consistent with the copolymers functioning as AND logic gates as exemplified by the quinidine copolymer 1 (Fig. 7). The AND logic truth table is collated in Table 4.

Fig. 7 UV-vis absorbance spectra (solvent subtracted) of 0.20 g L⁻¹ of copolymer 1 in 4 : 6 (v/v) THF/water after 5 min: (A) 10⁻⁹ M H⁺, (B) 10⁻² M H⁺, (C) 10⁻⁹ M H⁺ and 0.15 mM I⁻ and (D) 10⁻² M H⁺ and 0.15 mM I⁻. The copolymer operates as a H⁺, I⁻-driven AND logic gate. See Table 4 for the truth table.

The mechanism of action is rationalized by a π–anion non-covalent charge transfer mechanism facilitated by an electrostatic attraction between I⁻ and the positively charged π-system, and an anion-induced polarization of the π-system. Iodide is a more electron-rich halide, than F⁻, Cl⁻ and Br⁻, which hold onto their electron density tighter. I⁻ ions share electron density more readily with electron-deficient π-systems, such as the positively charged quinolinium units, of the cinchona alkaloids. This approach contrasts with the use of pH probes as fluorescent “turn-on” receptors for anions.⁴³

The limit of detection for I⁻ in 4 : 6 (v/v) THF/water with 10⁻² H⁺ was determined to be 3.5 μM whilst the limit of quantification was determined to be 40 μM I⁻. It should be noted that the copolymers selectively differentiate I⁻ from F⁻, Cl⁻ and Br⁻ in absorbance mode.^8,42

Conclusions

Cinchona alkaloids were functionalised with ferrocene and copolymerised with acrylamide. The copolymers are examples of fluorescent H⁺, Cl⁻-driven INHIBIT fluorescent logic gates. High fluorescence is observed only under high H⁺ conditions. The anions Br⁻, I⁻ and S₂O₈²⁻, among others, also quench the emission. Hence, the copolymers are examples of H⁺, X⁻-driven combinatorial OR-INHIBIT logic gates. The spectroscopic properties of the copolymers in water were generally preserved except for the fluorescence quantum yields, which are lower than for the alkaloid-acrylamide copolymers⁸ and cinchona monomers.⁹ Photoinduced electron transfer from the azabicyclic amine or carboxyferrocene decreases the fluorescence, the latter with an extremely exothermic PET driving force predicted within the Marcus inverted region. Attempts to revive the fluorescence to the maximum output with a chemical oxidant were not successful due to interference from an inner filter effect with Fe³⁺ or quenching from the counter anion.

In absorbance mode, the copolymers operate as rapid, selective, naked-eye H⁺, I⁻-driven AND logic gates. Potential future applications of cinchona-ferrocene copolymers could be as antibacterial⁴⁴ and antimalarial⁴⁵ agents, and as cellular imaging tools.^46,47

Experimental

Synthesis of ferrocenecarboxylic acid³⁴

Ferrocene carboxaldehyde (1.0 g, 4.7 mmol) was dissolved in 20 mL of acetone. Potassium permanganate (3.0 g, 19 mmol) was dissolved in 100 mL of water. The KMnO₄ solution was added dropwise to the ferrocene carboxaldehyde solution over an ice bath and stirred at room temperature for 2 hours. Then, 10% (w/v) of NaOH was added and the mixture was stirred for 30 minutes. The brown solution was filtered through Celite to remove MnO₂ resulting in a deep orange solution. The filtrate was extracted with diethyl ether (3 × 150 mL) and the aqueous layer was acidified with dilute HCl solution. An orange powder was obtained after the removal of the solvent by rotary evaporation. The product was dissolved in DCM, loaded onto silica gel and dried. The loaded silica gel was transferred to the top of a silica gel column and eluted with pentane, and then DCM to obtain 0.65 g of orange powder. 60% yield; m.p. 204–206 °C; ¹H NMR (DMSO-d₆, ppm): δ 4.73 (s, 2H), 4.48 (s, 2H), 4.25 (s, 5H); ¹³C NMR (DMSO-d₆, ppm): δ 172.60 (C), 71.94 (C), 71.36 (2C), 70.14 (2C), 69.75 (5C); IR (ATR, cm⁻¹): 3110–2554, 1650, 1480, 1415, 1400, 1363, 1346, 1264, 1220, 1160, 1109, 1068, 1053, 1031, 1007, 939, 915, 836, 829, 784, 741, 699.

The reaction procedure for the cinchona alkaloid-ferrocene esters was identical to that described for quinidine-ferrocene ester 5.

Synthesis of quinidine-ferrocene ester 5

In a 100 mL round-bottom flask, quinidine sulfate dihydrate (0.70 g, 0.89 mmol), DCC (0.45 g, 2.2 mmol) and ferrocenecarboxylic acid (0.45 g, 1.9 mmol) were dissolved in 10 mL of dry tetrahydrofuran (THF) by stirring over ice. After one hour, 4 mL of triethylamine was added. The reaction was continued for 2.5 days at room temperature. The mixture was filtered, and the THF was removed by rotary evaporation. The orange oil was dissolved in acetone and 1,3-dicyclohexylurea precipitated from the solution. Recrystallization from acetonitrile gave 1.1 g of solid product (98% yield). ¹H NMR (DMSO-d₆, ppm): δ 8.68 (d, 1H, J = 4.6 Hz), 7.93 (d, 1H, J = 9.2 Hz), 7.50 (d, 1H, J = 4.6 Hz), 7.46 (d, 1H, J = 2.6 Hz), 7.40 (dd, 1H, J = 2.6 Hz, 9.2 Hz), 6.09 (m, 1H), 5.30 (m, 1H), 5.08 (m, 1H), 4.63 (s, 2H), 4.33 (s, 2H), 4.16 (s, 5H), 3.91 (s, 3H), 2.83–0.97 (m, 11H).

Synthesis of quinine-ferrocene ester 6

Quinine (0.70 g, 2.2 mmol), DCC (0.45 g, 2.2 mmol) and ferrocenecarboxylic acid (0.45 g, 2.0 mmol) were reacted in 10 mL of dry THF. Recrystallization from acetonitrile gave 1.1 g of the product (98% yield). ¹H NMR (DMSO-d₆, ppm): δ 8.68 (d, 1H, J = 4.6 Hz), 7.93 (d, 1H, J = 9.2 Hz), 7.50 (dd, 2H, J = 2.6, 4.1 Hz), 7.39 (dd, 1H, J = 2.6 Hz, 9.2 Hz), 5.87 (m, 2H), 5.24 (m, 1H), 4.92 (m, 2H), 4.64 (s, 2H), 4.34 (s, 2H), 4.15 (s, 5H), 3.92 (s, 3H), 2.32–0.87 (m, 10H).

Synthesis of cinchonine-ferrocene ester 7

Cinchonine (0.70 g, 2.4 mmol), DCC (0.45 g, 2.2 mmol) and ferrocenecarboxylic acid (0.45 g, 2.0 mmol) were reacted in 10 mL of dry THF. Recrystallization from acetonitrile gave 0.66 g of the product (63% yield). ¹H NMR (DMSO-d₆, ppm): δ 8.84 (d, 1H, J = 4.4 Hz), 8.24 (d, 1H, J = 8.2 Hz), 8.02 (d, 1H, J = 7.5 Hz), 7.73 (t, 1H, J = 7.0 Hz), 7.61 (t, 1H, J = 7.7 Hz), 7.55 (d, 1H, J = 8.9 Hz), 6.08 (m, 2H), 5.85 (s, 1H), 5.09 (m, 2H), 4.71 (s, 2H), 4.42 (s, 2H), 4.16 (s, 5H), 2.39–0.87 (m, 10H).

Synthesis of cinchonidine-ferrocene ester 8

Cinchonidine (0.70 g, 2.4 mmol), DCC (0.45 g, 2.2 mmol) and ferrocenecarboxylic acid (0.45 g, 2.0 mmol) were reacted in 10 mL of dry THF. Recrystallization from acetonitrile gave 0.37 g of the product (35% yield). ¹H NMR (DMSO-d₆, ppm): δ 8.91 (d, 1H, J = 4.6 Hz), 8.36 (d, 1H, J = 7.9 Hz), 8.10 (d, 1H, J = 8.4 Hz), 7.80 (t, 1H, J = 7.2 Hz), 7.61–7.70 (m, 2H), 5.90 (m, 1H), 5.65 (m, 1H), 5.52 (m, 1H), 5.04 (m, 2H), 4.74 (s, 2H), 4.49 (s, 2H), 4.24 (s, 5H), 2.37–0.96 (m, 10H).

Synthesis of poly(QD-Fe-co-Am) 1

In a two-necked flask, quinidine-ferrocene ester (1.1 g, 2.8 mmol), acrylamide (0.50 g, 7.0 mmol) and VA-044 (0.12 g, 1.0 mmol) were dissolved in 5 mL of 1 : 1 H₂O/EtOH. The solution was purged with nitrogen and stirred at 70 °C. After 4 days, another aliquot of VA-044 (0.22 g, 0.68 mmol) was added. The mixture was stirred for up to 7 days. The solvent was removed by rotary evaporation to give a brown oil. A minimal amount of EtOH, ethyl acetate and acetone were subsequently added, and the polymer precipitated as a light brown powder (0.90 g). R_f = 0.10 (9 : 1 (v/v) CH₂Cl₂/MeOH); ¹H NMR (DMSO-d₆, ppm): δ 8.80–8.69 (1H), 8.00–7.94 (1H), 7.66–6.99 (br, 3H), 6.99–6.60 (2H), 5.27–5.13 (1H), 4.63 (s, 3H), 4.33 (s, 2H), 4.15 (s, 2H), 4.10–3.90 (3H), 2.24–1.09 (backbone H); IR (KBr, cm⁻¹): 3200, 2902, 1678, 1649, 1600, 1471, 976, 623.

Synthesis of poly(QN-Fe-co-Am) 2

Quinine-ferrocene ester (1.1 g, 2.1 mmol), acrylamide (0.40 g, 5.6 mmol) and VA-044 (0.12 g, 0.37 mmol) were dissolved in 5 mL of 1 : 1 H₂O/EtOH. After 4 and 7 days, more VA-044 (0.22 g, 0.68 mmol) was added. The reaction time was 21 days. The work-up was the same as 1 to give a light brown powder (0.87 g). R_f = 0.11 (9 : 1 (v/v) CH₂Cl₂/MeOH); ¹H NMR (DMSO-d₆, ppm): δ 8.84–8.65 (1H), 8.05–6.98 (4H), 6.98–6.60 (2H), 5.54–5.32 (1H), 4.35–4.14 (9H), 4.06–3.95 (3H), 2.24–0.84 (backbone H); IR (KBr, cm⁻¹): 3161, 2956, 1693, 1654, 1578, 1466, 1079, 976, 623.

Synthesis of poly(CN-Fe-co-Am) 3

Cinchonine-ferrocene ester (0.65 g, 1.3 mmol), acrylamide (0.20 g, 2.8 mmol) and VA-044 (0.10 g, 0.31 mmol) were dissolved in 5 mL of 1 : 1 H₂O/EtOH. After 4 days, VA-044 (0.22 g, 0.68 mmol) was added. The reaction time was 14 days. The work-up was the same as 1 to give a light brown powder (0.61 g). R_f = 0.11 (9 : 1 (v/v) CH₂Cl₂/MeOH); ¹H NMR (DMSO-d₆, ppm): δ 9.03–8.86 (1H), 8.50–8.37 (1H), 8.11–6.98 (4H), 6.98–6.61 (2H), 5.30–5.11 (1H), 4.57–4.19 (9H), 2.30–0.91 (backbone H); IR (KBr, cm⁻¹): 3170, 2922, 1683, 1598, 1449, 1091, 967, 643.

Synthesis of poly(CD-Fe-co-Am) 4

Cinchonidine-ferrocene ester (0.29 g, 0.57 mmol), acrylamide (0.10 g, 1.4 mmol) and VA-044 (0.12 g, 0.37 mmol) were dissolved in 5 mL of 1 : 1 H₂O/EtOH. After 4 days, more VA-044 (0.22 g, 0.68 mmol) was added. The reaction time was 7 days. The work-up was the same as 1 to give a light brown powder (0.20 g). R_f = 0.10 (9 : 1 (v/v) CH₂Cl₂/MeOH); ¹H NMR (DMSO-d₆, ppm): δ 8.99–8.91 (1H), 8.66–8.52 (1H), 8.28–6.98 (4H), 6.98–6.61 (2H), 5.63 (1H), 4.52–4.23 (9H), 2.19–1.13 (backbone H); IR (KBr, cm⁻¹): 3170, 2922, 1683, 1598, 1449, 1091, 967, 623.

Author contributions

Conceptualization: DCM, formal analysis: NA, funding acquisition: DCM, investigation: NA, methodology: DCM, supervision: DCM, writing – original draft: NA and DCM, and writing – review & editing: DCM.

Data availability

Experimental details, NMR, FTIR and UV-vis spectra are provided in the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The University of Malta is thanked for financial support. Dr Duncan Micallef is acknowledged for NMR support. This project was financed by Xjenza Malta through the FUSION: R&I Research Excellence Programme 2023, grant agreement number REP-2023-023.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, NMR, FTIR and UV-vis spectra. See DOI: https://doi.org/10.1039/d5nj00415b

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