β-Carboxyphospholes via carboxylative desilylation: luminophores with a versatile connectivity attached

Abstract

The synthesis of β-carboxyphospholes has been achieved via carboxylative desilylation of their β-TMS-substituted analogues in a CO₂ atmosphere. The title carboxylic acids allow facile transformation into the respective acyl chloride, carboxamide, ester and anhydride, which are compatible with bioconjugation, while the integrity of the phosphole unit is maintained.

---

Phospholes are highly versatile building blocks with interesting features for application in opto-electronic devices,^1–4 for grafting on material surfaces,^5,6 in catalysis^7–10 and for biomedical applications.^11–16 By structural modification of the heterocycle, it is possible to tune the electronic and optical properties in order to achieve optimized characteristics for the targeted field of application.^17–20 However, incorporation of reactive functional groups at the phosphole ring allowing facile modification or bioconjugation is rather limited to date. Previous attempts at incorporating carboxylic groups in the phosphole ring either yielded only unstable products or were limited to α-functionalization.^21–26 A quite unusually functionalized phosphole derivative has been reported by Goicoechea et al.²⁷ Very recently, Imahori et al. presented a synthesis towards β-hydroxymethyl phospholes, which they used for a subsequent intramolecular cyclization reaction albeit in moderate yields.²⁸

Here, we present a simple and highly selective synthetic pathway towards β-carboxyphospholes, which provides high potential for flexible modification. Starting from β-trimethylsilyl phosphole 1, whose synthetic access was described earlier,^29–31 a desilylation is performed using tetramethylammonium fluoride (TMAF) in dry DMF in a CO₂ atmosphere (Scheme 1). The in situ generated, highly reactive carbanion readily reacts with the CO₂ resulting in β-carboxyphosphole 2. In previously reported carboxylative desilylation reactions, aromatic or heteroaromatic scaffolds have been employed with the heteroatom neighboring the silyl group.^32–35 While in these latter cases CsF as the fluoride source and DMF or DMSO as the solvent provided the best results, these conditions are unsuitable in our case, owing to solubility issues in DMF, and the reactivity of DMSO which leads to bicyclic phospholane oxothiolane systems.³⁶ As an alternative, TMAF shows sufficient solubility in DMF, which increases further upon heating the reaction mixture. Strict exclusion from moisture is necessary to prevent hydrolysis of the carbanionic species formed during desilylation, which would result in the formation of the β-unsubstituted phosphole derivative. Upon carboxylation, the initially formed carboxylate 2 is protonated by treatment with water giving the carboxylic acid 3.

Scheme 1 Synthesis of β-carboxylate phosphole 2 starting from β-trimethylsilyl phosphole 1 and subsequent protonation to the corresponding carboxylic acid 3 (TMS = trimethylsilyl, Ph = phenyl, Me = methyl, Et = ethyl, DME = dimethoxyethane, DMF = dimethyl formamide).

Carboxylate 2 is well soluble in alcohols, while carboxylic acid 3 shows the best solubility in THF. The ³¹P-NMR shifts together with the ¹³C-NMR shifts of the carboxyl carbon atom are listed in Table 1. Interestingly, the β-trimethylsilyl phospholes 1a and 1b and the carboxylic acids 3a and 3b respectively show very similar phosphorus shifts, while the signal of the carboxylates 2a and 2b is shifted upfield by 11 ppm. The reverse reaction from 3 to 2 is easily achieved by base treatment, e.g. with LiOH, NaOH or CsOH, which also allows variation of the counter-cation. In terms of NMR shifts, the counter-cation has only a minor impact in the same solvent (see Table 1). In weakly coordinating CD₂Cl₂ solution, carboxylates 2a-Na and 2b-Na show broad ³¹P-NMR resonances at lower field (19.1 ppm (2a-Na) and 18.6 ppm (2b-Na)), which upon addition of crown ether ([15]crown-5, 1 eq.) become sharp and shift to higher field (10.3 ppm (2a-Na) and 9.7 ppm (2b-Na)) close to the values observed in methanol solution, consistent with solvent separation in the latter cases.

Table 1 Overview of the ³¹P-NMR shifts, the ¹³C-NMR shifts of the C=O carbon atom and the CO stretching frequencies in the IR spectrum (n.d. = not determined)

	^31P-NMR [ppm]	^13C-NMR C=O [ppm]	IR C=O stretch [cm^−1]
1a (CD2Cl2)	22.3^29	—	—
1b (CD2Cl2)	21.4^30	—	—
2a-Li (MeOH-d4)	11.6	175.8	n.d.
2a-Na (MeOH-d4)	11.5	175.9	1582.39
2a-Cs (MeOH-d4)	12.2	175.5	n.d.
2b-Na (MeOH-d4)	11.1	175.9	n.d.
3a (THF-d8)	22.7	165.4	1669.89
3b (THF-d8)	21.4	165.8	n.d.
4 (CD2Cl2)	28.2	165.3	1768.58
5 (CD2Cl2)	22.5	165.3	1705.38
6 (CD2Cl2)	10.2	168.4	1622.30
7 (CD2Cl2)	26.2	165.1	1772.56, 1711.35

---

The molecular structure of carboxylic acid 3a was investigated via single crystal X-ray diffraction (Fig. 1). The sum of angles at the phosphorus atom amounts to 301.04(8)°. The C23–O1 single bond is 1.315(2) Å, and the C23=O2 double bond is 1.229(2) Å, which is in good agreement with standard values for such bonds.³⁷ Neighboring molecules in the crystal lattice interact via hydrogen bonding of the carboxyl groups with an O⋯O distance of 2.6485(18) Å and an estimated O⋯H distance of 1.8292(12) Å, which classifies it as a moderate and mostly electrostatic hydrogen bond.³⁸

Fig. 1 ORTEP plot of the molecular structure of 3a in the solid state with ellipsoids drawn at the 30% probability level. Hydrogen atoms are omitted for clarity.

To explore the reactivity of the β-carboxy phosphole 3a, we first aimed to obtain the acyl chloride, which is a reactive precursor for many typical modification reactions. However, treatment of 3a with thionyl chloride only resulted in the oxidation of the phosphorus atom. A quantitative and fast transformation towards the desired product 4 could be observed with the less oxidative oxalyl chloride (Scheme 2). The reaction progress can be monitored by UV-light irradiation. The solution of 3a is highly luminescent under UV-light, while the solution of 4 shows no visible fluorescence anymore. The acyl chloride 4 is sensitive towards water, which results in a back reaction to the carboxylic acid 3a. Treatment with an alcohol or a secondary amine, methanol and diethylamine in our case, selectively yields the corresponding ester 5 or amide 6 (Scheme 2). An acid anhydride 7 can be obtained upon mixing 4 with the carboxylate 2a. Solutions of 5, 6 and 7 again show fluorescence under UV-light irradiation.

Scheme 2 Synthesis of the acyl chloride 4 by treatment of 3a with oxalyl chloride and further derivatization towards ester 5, amide 6, acid anhydride 7 and sugar ester 8.

All derivatives 4–7 could be isolated and fully characterized. The ester 5, amide 6 and anhydride 7 are stable for purification via column chromatography. Over time, the phosphorus atom tends to oxidize in air, which can be avoided by storing all compounds under inert conditions. In turn, 3a-O is obtained easily by oxidation of 3a with H₂O₂ (cf. SI). Furthermore, we explored the redox properties of 2a-Na and 3avia CV and CDPV, which indicates irreversible redox behavior of both compounds (cf. SI). Table 1 summarizes the ³¹P-NMR data together with the ¹³C-NMR shifts and IR-frequencies of the [double bond splayed left]C=O units, featuring no peculiarities.³⁹

The molecular structure of acid anhydride 7 was investigated with single crystal X-ray diffraction (Fig. 2). The two phosphorus atoms are stereogenic centers with opposite absolute configurations at P1 (R) and at P2 (S), resulting in the meso form of the molecule in the crystal (Flack-parameter: 0.03(5)). The sum of angles at P1 amounts to 297.45(12)° and that at P2 to 307.74(12)°. However, it is well-known that owing to aromatic stabilization, the inversion barrier of the phosphorus atom in phospholes is sufficiently low to allow constant inversion in solution,^40–42 which is in line with our observation of a single ³¹P-NMR resonance in solution for 7. The two C=O groups are tilted against each other by 54.0(2)°, and the bond lengths are nearly identical at 1.188(3) Å (C23=O1) and 1.184(3) Å (C46=O3), which again is in good agreement with standard values.³⁷

Fig. 2 ORTEP plot of the molecular structure of 7 in the solid state with ellipsoids drawn at the 30% probability level. Hydrogen atoms are omitted for clarity.

Furthermore, we investigated the novel phosphole derivatives 2a-7 with respect to their luminescence properties and in comparison with the already reported data of 1a.³⁰Table 2 provides an overview of the UV-vis absorption and emission data in solution and the solid state, and the respective spectra are depicted in Fig. 3. Maximum absorption and emission wavelengths of the novel carboxyphospholes are mainly red-shifted in comparison to the β-TMS phosphole 1a. The acyl chloride 4 shows the most significant red-shift in absorption, both in solution and solid state, and furthermore, in emission in the solid state. Only in solution, the anhydride 7 shows the most red-shifted emission maximum. The quantum yields in solution of the novel compounds are rather limited at 1–12%. The only exception is the amide 6 with a considerable quantum yield of 43%. In the solid state, the overall quantum yields are much better with 3–29%. However, the values are still far below the extraordinary quantum yield of 1a in the solid state of 82%, which we attributed to aggregation induced emission (AIE) as previously reported for related heterocyclic systems.^30,43–45 To investigate the impact of the counter-cation on the luminescence properties, we measured the absorption and emission spectra of 2a-Li and 2a-Cs but found only minor differences, apart from the very weak emission of 2a-Cs in solution and its absent emission in the solid state, which can be explained by heavy atom-induced quenching owing to the cesium cation.^46–48 Finally, striving for linking a sugar moiety to the carboxy-phosphole scaffold, we attached tetraacetylated glucose via esterification to 4 as a proof of concept (Scheme 2). The spectral data of the resulting sugar ester 8 are in the expected range and selective deprotection will be explored in future work (cf. SI).

Table 2 Overview of the maximum absorption wavelength λ_abs, extinction coefficient ε_max, maximum emission wavelength λ_em, Stokes shift λ_S and quantum yield φ of the phospholes 1a-7 in solution (10⁻⁵ M in dichloromethane) and the solid state

	Solution					Solid
	λ abs [nm]	ε max × 10^4 [L mol^−1 cm^−1]	λ em [nm]	λ S [cm^−1]	φ	λ abs [nm]	λ em [nm]	λ S [cm^−1]	φ
a λ abs is as excitation wavelength and refers to plateau before the sharp decrease in absorption.
1a ^30	362	1.63	473	6483	0.12	375	484	6006	0.82
2a-Na	377	0.98	487	5991	0.08	422	542	5246	0.03
3a	378	1.35	505	6653	0.05	439	532	3982	0.25
4	396	0.81	469	3931	0.03	480^a	574	3412	0.15
5	375	1.39	493	6383	0.07	440^a	542	4277	0.11
6	373	1.81	467	5396	0.43	425^a	512	4278	0.28
7	390	1.99	532	6844	0.01	449	532	3475	0.29

---

Fig. 3 Normalized absorption (dashed lines) and emission (solid lines) spectra of the herein described phospholes 1a-7 in solution (left, 10⁻⁵ M in dichloromethane) and in the solid state (right).

In conclusion, we reported a simple and efficient synthetic route towards β-carboxyphospholes and outlined their reactivity. Transformation into an acid chloride, ester, amide or anhydride is straightforward and allows versatile derivatization of the phosphole core. Moreover, these can be easily tracked with the NMR, IR and UV/vis data provided. All reported compounds show fluorescence in the visible region. In particular, the high reactivity of acyl chloride 4 opens vast flexibility in attaching further functional units or polar moieties such as sugars at the phosphole's β-position, e.g. to increase and tune their hydrophilicity or amphiphilicity. This in combination with bioconjugation offers promising perspectives for phospholes in bio-relevant chemistry which is currently ongoing.

Funding by Deutsche Forschungsgemeinschaft (468464668 and CRC 1319) is gratefully acknowledged.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: NMR-, HR-MS-, IR-, UV/vis-, CV-, and crystallographic data (CCDC 2481891 and 2481892).⁴⁹ See DOI: https://doi.org/10.1039/d5cc04850h.

Notes and references

1. M. Hissler, P. W. Dyer and R. Reau, Top. Curr. Chem., 2005, 250, 127–163.
2. T. Baumgartner and R. Réau, Chem. Rev., 2006, 106, 4681–4727.
3. M. P. Duffy, W. Delaunay, P. A. Bouit and M. Hissler, Chem. Soc. Rev., 2016, 45, 5296–5310.
4. M. A. Shameem and A. Orthaber, Chem. – Eur. J., 2016, 22, 10718–10735.
5. F. Roesler, B. Kaban, D. Klintuch, U. M. Ha, C. Bruhn, H. Hillmer and R. Pietschnig, Eur. J. Inorg. Chem., 2019, 4820–4825.
6. D. Klintuch, M. V. Höfler, T. Wissel, C. Bruhn, T. Gutmann and R. Pietschnig, Inorg. Chem., 2021, 60, 14263–14274.
7. D. Carmichael, in Phosphorus(III) Ligands in Homogeneous Catalysis: Design and Synthesis, ed P. C. J. Kamer and P. W. N. M. van Leeuwen, John Wiley & Sons, Ltd., West Sussex, United Kingdom, 2012, ch. 7.
8. K. Fourmy, D. H. Nguyen, O. Dechy-Cabaret and M. Gouygou, Catal. Sci. Technol., 2015, 5, 4289–4323.
9. T. Johannsen, C. Golz and M. Alcarazo, Angew. Chem., int. Ed., 2020, 59, 22779–22784.
10. J. Guaramato, F. Fuentes, R. Rivera, D. Oliveros, J. R. Mora, A. Reiber, E. Avila, Y. Otero and J. M. Garcia-Garfido, J. Organomet. Chem., 2024, 1008, 123063.
11. C. G. Wang, A. Fukazawa, M. Taki, Y. Sato, T. Higashiyama and S. Yamaguchi, Angew. Chem., int. Ed., 2015, 54, 15213–15217.
12. E. Öberg, H. Appelqvist and K. P. R. Nilsson, Front. Chem., 2017, 5, 28.
13. C. G. Wang, M. Taki, Y. Sato, A. Fukazawa, T. Higashiyama and S. Yamaguchi, J. Am. Chem. Soc., 2017, 139, 10374–10381.
14. M. Schenk, N. König, E. Hey-Hawkins and A. G. Beck-Sickinger, ChemBioChem, 2024, 25, e202300857.
15. C. Romero-Nieto, K. Kamada, D. T. Cramb, S. Merino, J. Rodríguez-López and T. Baumgartner, Eur. J. Org. Chem., 2010, 5225–5231.
16. N. König, J. Mahnke, Y. Godinez-Loyola, H. Weiske, J. Appel, P. Lönnecke, C. A. Strassert and E. Hey-Hawkins, J. Mater. Chem. C, 2024, 12, 7797–7806.
17. C. Hay, M. Hissler, C. Fischmeister, J. Rault-Berthelot, L. Toupet, L. Nyulaszi and R. Reau, Chem. – Eur. J., 2001, 7, 4222–4236.
18. T. Baumgartner, T. Neumann and B. Wirges, Angew. Chem., Int. Ed., 2004, 43, 6197–6201.
19. X. M. He and T. Baumgartner, RSC Adv., 2013, 3, 11334–11350.
20. Y. Ren, A. Orthaber, R. Pietschnig and T. Baumgartner, Dalton Trans., 2013, 42, 5314–5321.
21. L. D. Quin and S. G. Borleske, Tetrahedron Lett., 1972, 4, 299–302.
22. L. D. Quin, S. G. Borleske and J. F. Engel, J. Org. Chem., 1973, 38, 1858–1866.
23. E. Deschamps, L. Ricard and F. Mathey, Angew. Chem., Int. Ed. Engl., 1994, 33, 1158–1161.
24. E. Deschamps and F. Mathey, C. R. Acad. Sci. Paris, 1998, 1, 715–717.
25. M. Melaimi, L. Ricard, F. Mathey and P. Le Floch, Org. Lett., 2002, 4, 1245–1247.
26. S. van Zutphen, G. Mora, V. J. Margarit, X. F. Le Goff, D. Carmichael and P. Le Floch, Tetrahedron Lett., 2008, 49, 1734–1737.
27. T. P. Robinson and J. M. Goicoechea, Chem. – Eur. J., 2015, 21, 5727–5731.
28. T. Higashino, R. Minobe, T. Machino and H. Imahori, Chem. Commun., 2025, 61, 9420–9423.
29. D. Klintuch, K. Krekic, C. Bruhn, Z. Benko and R. Pietschnig, Eur. J. Inorg. Chem., 2016, 718–725.
30. D. Klintuch, A. Kirchmeier, C. Bruhn and R. Pietschnig, Dyes Pigm., 2020, 180.
31. F. Roesler, M. Kovacs, C. Bruhn, Z. Kelemen and R. Pietschnig, Chem. – Eur. J., 2021, 27, 9782–9790.
32. M. Yonemoto-Kobayashi, K. Inamoto, Y. Tanaka and Y. Kondo, Org. Biomol. Chem., 2013, 11, 3773–3775.
33. X. Frogneux, N. von Wolff, P. Thuéry, G. Lefèvre and T. Cantat, Chem. – Eur. J., 2016, 22, 2930–2934.
34. T. V. Q. Nguyen, W. J. Yoo and S. Kobayashi, Asian J. Org. Chem., 2018, 7, 116–118.
35. W. Xu, A. G. Ebadi, M. Toughani and E. Vessally, J. CO2 Util., 2021, 43.
36. K. Getfert, F. Roesler, C. Bruhn and R. Pietschnig, Adv. Synth. Catal., 2024, 366, 2764–2774.
37. F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen and R. Taylor, J. Chem. Soc. Perkin Trans. II, 1987, S1–S19.
38. T. Steiner, Angew. Chem., Int. Ed., 2002, 41, 48–76.
39. M. Hesse, H. Meier, B. Zeeh, R. Dunmur and M. Murray, Spectroscopic Methods in Organic Chemistry, Georg Thieme Verlag KG, Stuttgart, 2nd edn, 2008.
40. W. Egan, R. Tang, G. Zon and K. Mislow, J. Am. Chem. Soc., 1971, 93, 6205–6216.
41. F. Mathey, Chem. Rev., 1988, 88, 429–453.
42. L. D. Quin, G. Keglevich, A. S. Ionkin, R. Kalgutkar and G. Szalontai, J. Org. Chem., 1996, 61, 7801–7807.
43. K. Shiraishi, T. Kashiwabara, T. Sanji and M. Tanaka, New J. Chem., 2009, 33, 1680–1684.
44. Z. J. Zhao, B. R. He and B. Tang, Chem. Sci., 2015, 6, 5347–5365.
45. P. Bolle, Y. Chéret, C. Roiland, L. Sanguinet, E. Faulques, H. Serier-Brault, P. A. Bouit, M. Hissler and R. Dessapt, Chem. – Asian J., 2019, 14, 1642–1646.
46. L. K. Patterson and S. J. Rzad, Chem. Phys. Lett., 1974, 31, 254–256.
47. I. R. Gould, P. L. Kuo and N. J. Turro, J. Phys. Chem., 1985, 89, 3030–3034.
48. B. Radaram, T. Mako and M. Levine, Dalton Trans., 2013, 42, 16276–16278.
49. (a) CCDC 2481891: Experimental Crystal Structure Determination, 2025 DOI:10.5517/ccdc.csd.cc2p9m0n; (b) CCDC 2481892: Experimental Crystal Structure Determination, 2025 DOI:10.5517/ccdc.csd.cc2p9m1p.

---