Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2026 Aug 5;91(32):10933–10940. doi: 10.1021/acs.joc.6c01097

Molecular Recognition and Chirality Sensing with Metallocene Dichloride Complexes

Yujin Kim 1, Jeffrey S S K Formen 1, Christian Wolf 1,*
PMCID: PMC13488449  PMID: 42599496

Abstract

The utility of well-defined transition-metal coordination complexes for separation-free enantioselective optical analysis has received significant traction due to its promise to speed up chiral compound screening workflows. Herein, chiroptical sensing of a broad selection of carboxylic acids with metallocene dihalides is introduced. Cp2TiCl2 and Cp2MoCl2 undergo smooth chloride exchange under mild conditions toward carboxylate complexes, displaying quantifiable circular dichroism signals at long wavelengths. Spectroscopic titration experiments and crystallographic analysis show that both chlorides in Cp2TiCl2 are readily displaced, while Cp2MoCl2 forms a monocarboxylate complex. In either case, characteristic CD inductions are observed that allow accurate er analysis across a wide range of enantiomeric compositions.

graphic file with name jo6c01097_0011.webp

graphic file with name jo6c01097_0009.webp

Introduction

Metallocene dihalides, Cp2MX2, have been known for a long time and intensively investigated because of their intriguing structures, use as organometallic catalysts or reagents, and medicinal properties, among which anticancer activities have received substantial attention. − Numerous studies have been conducted with bis­(η5-cyclopentadienyl)titanium dichloride − and its molybdocene analog, − showing their ease of handling, unique chemical reactivity at the cyclopentadienyl rings, and facile access to chemically diverse, air-stable structures produced by smooth halide replacement. In particular, the practical access to a large variety of lipophilic metallocenes that are inert in aqueous solutions via halide exchange reactions has unleashed the pursuit of a wide range of biomedical applications. While the readily available metallocene dichlorides Cp2TiCl2 and Cp2MoCl2, which are bright-red and brownish-green solids, have been popular starting materials and sparked widespread interest across the organometallic, bioinorganic, and medicinal chemistry realms for many decades, their striking spectroscopic properties have been scarcely exploited and remain underdeveloped to date.

The formation of metal coordination complexes of chiral compounds has been successfully exploited in many ways for optical enantiomeric ratio (er) sensing. Recently, we showed that piano stool complexes like [Cp*Ru­(CH3CN)3]­PF6 undergo fast and irreversible acetonitrile displacement with chiral aromatic molecules toward sandwich complexes displaying circular dichroism (CD) signals that can be correlated to the absolute configuration and er of the captured analyte, Figure . The strong CD inductions observed with η6-arene coordination complexes suggested to us that metallocenes may have a broader application scope and could be applicable to other compound classes as well. To the best of our knowledge, optical chirality sensing with metallocene dihalides has not been reported. Based on the well-known high oxophilicity of Ti­(IV) and Mo­(IV) compounds, we envisioned that substitution of the chlorides in the corresponding Cp2MCl2 metallocenes with carboxylate groups should be thermodynamically favored and occur under mild conditions. A well-defined stoichiometric ligand exchange was thus expected to create an excellent opportunity for molecular recognition and enantioselective analysis of chiral carboxylic acids in the presence of a weak base to neutralize the HCl byproduct.

1.

1

Open in a new tab

Chirality sensing with piano stool complexes (a) and metallocene dihalides (b).

The search for small-molecule chemosensors suitable for quantitative er analysis is receiving increasing attention. In order to determine the enantiomeric ratio of chiral compounds, chemists tend to resort to chromatographic and nuclear magnetic resonance (NMR) spectroscopic protocols. However, these typically do not match high-throughput screening expectations, i.e., they do not allow fast and preferably parallel analysis of hundreds of samples at once. As a result, a variety of mass spectrometry, UV, fluorescence, − gas-phase rotational resonance, infrared, electronic CD, − fluorescence-detected CD spectroscopy, and biochemical assays have been developed as powerful alternatives. Many CD methods have been tailored toward chiral recognition of α-amino acids − and α-hydroxy acids, − which exhibit two functional groups that can be used in concert for well-defined binding and signal induction and are therefore privileged structures. By contrast, monofunctional carboxylic acids have remained more difficult targets although various assays based on metal coordination, − hydrogen bonding, − and salt bridge formation are known.

Results and Discussion

To assess the suitability of metallocene dihalides for chiral carboxylic acid sensing, we decided to mix either Cp2TiCl2, 1, or Cp2MoCl2, 2, with enantiopure test analytes using a variety of solvents and bases while also exploring the stoichiometry of the proposed halide exchange reaction. These mixtures were then subjected to CD analysis for the initial analysis of successful carboxylate binding and to determine if coordination would indeed result in the induction of strong and potentially quantifiable CD signals. We were pleased to observe strong CD signals, for example, with ibuprofen, 3, that arise in the presence of (i-Pr)2NEt, Et3N, pyridine, K2CO3, or NaOt-Bu in several organic solvents, Figure and Supporting Information. Screening of the reaction conditions revealed that the use of amine bases in chlorinated solvents gives excellent results with the titanocene dihalide 1, and the carboxylate coordination was confirmed by 1H NMR titration experiments, see Supporting Information. Due to the low solubility of the molybdenum compound 2, we resorted to potassium carbonate and N,N-dimethylformamide (DMF) as the solvent. Again, we found that the addition of the enantiomers of ibuprofen generates strong and remarkably red-shifted CD signals, which are generally preferred in the CD sensing field because they avoid complications with potentially present chiral impurities that typically give weak but sometimes not negligible CD curves at shorter wavelengths. We are not aware of previous reports on chiroptical sensing studies with the metallocene dichlorides 1 and 2, but we note that dimolybdenum complexes have previously been demonstrated to allow absolute configuration determination of chiral diols. Interestingly, the CD inductions obtained upon coordination of ibuprofen to 1 and 2 are strikingly different. While chiroptical sensing of (S)-3 with Cp2TiCl2 results in a single positive CD maximum, it yields two negative maxima with Cp2MoCl2. The reverse situation is, as expected, observed when (R)-3 is used, see the spectra shown in blue and red, respectively, in Figure . Although the CD sensing experiments were conducted under different conditions, we suspected that these unexpected outcomes could not simply be attributed to solvent or base effects but may be a result of different binding motifs. Indeed, CD titration experiments showed that the intensity of the produced CD signal nearly doubles when two equiv of base and the chiral analyte were added to 1, suggesting that both chlorides are replaced. By contrast, essentially the same CD spectra were obtained even after several hours when 2 was treated with either one or two equivalents of base and chiral analyte, which indicates that only one chloride is substituted and a monocarboxylate complex is formed, see Supporting Information and below.

2.

2

Open in a new tab

Structures of the sensors and CD inductions obtained by coordination of the enantiomers of ibuprofen, 3, to titanocene dichloride and molybdocene dichloride in the presence of diisopropylethylamine in dichloroethane and K2CO3 in DMF, respectively.

With proof-of-concept results in hand, we continued to evaluate the sensing scope of titanocene dihalide 1 under optimized conditions. For this purpose, we obtained a wide range of chiral substrates including purely aliphatic carboxylic acids but also increasingly complicated, multifunctional compounds and biologically relevant ones like dihydroartemisinic acid, 13, dehydroabietic acid, 14, and isosteviol, 15, see Figure and Supporting Information. In most cases, strong CD signal inductions above 400 nm were measured as exemplified with 5, 11, 15, and 16, which demonstrates the general usefulness of chiral carboxylic acid recognition with this probe. It is noteworthy that substrates carrying an aromatic ring or a rigid scaffold like 3, 5, 6, 11, 16, and 19 generally give quite strong CD effects, whereas structures like 9, 10, 17, and 18 exhibited weak signal inductions.

3.

3

Open in a new tab

Structures of carboxylic acids tested and selected ICD spectra obtained with sensor 1. All CD measurements were taken at 5.0 mM in DCE. See Supporting Information for details.

The broad interest in chiroptical CD sensing undoubtedly originates from its unique promise in separation-free enantiomeric-composition-determination applications. We therefore selected t-Boc-protected phenylglycine 19 to investigate the possibility of enantiomeric ratio (er) analysis. Having established that the induced CD signal intensity increases linearly with the enantiomeric excess of 19, we applied nine arbitrarily composed scalemic samples of this acid in our sensing assay and used the intensity of the maximum at 465 nm to determine the corresponding er values via linear regression analysis, Table . Comparison of the actual and experimentally obtained data shows excellent agreement in cases where one enantiomer is in large excess but also at low enantiomeric ratios. For example, the sensing of a 93.7:6.3 (S)/(R) mixture gave a 93.6:6.4 ratio, and the analysis of a sample containing 38.8% of (S)-19 and 61.2% of the (R)-enantiomer gave 39.7% and 60.3%, respectively.

1. Chirality Sensing of Scalemic Mixtures of 19 with 1 .

graphic file with name jo6c01097_0007.webp

sample composition
 sensing results
AC er AC er
S 93.7:6.3 S 93.6:6.4
S 80.0:20.0 S 82.2:17.8
S 63.7:36.3 S 65.0:35.0
S 57.5:42.5 S 57.8:42.2
R 38.8:61.2 R 39.7:60.3
R 32.5:67.5 R 32.0:68.0
R 25.0:75.0 R 24.6:75.4
R 16.2:83.8 R 15.5:84.5
R 8.7:91.3 R 7.4:92.6
Open in a new tab
a

AC is the absolute configuration of the major enantiomer. See Supporting Information for details.

We then turned our attention to molybdocene 2. Following the methodical approach described above with the titanium probe, we first applied a variety of chiral carboxylic acids in the optimized sensing assay and found that Cp2MoCl2 is similarly useful. Using equimolar amounts of 2, an acid, and potassium carbonate in DMF gave strong, red-shifted CD effects as initially observed with ibuprofen. Representative examples of the observed CD inductions obtained with 5–7 and 16 are shown in Figure . We found that carboxylic acids that gave the strongest CD effects with the titanocene sensor also performed the best in this assay.

4.

4

Open in a new tab

Selected ICD spectra obtained with sensor 2. All CD measurements were taken at 5.0 mM in DMF. See Supporting Information for details.

The suitability of 2 for quantitative er determination was examined with 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, 5, as shown in Figure . As expected, we found that the CD amplitudes at 420 and 645 nm increase linearly with the enantiomeric excess of 5. With knowledge of the correlation between the sample composition and the induced CD signal intensities, we then tested our sensing assay using the stronger signals at 645 nm to determine er values of nine nonracemic samples, Table . Again, the actual and experimentally obtained values show very good agreement. For example, the sensing of a 5.0:95.0 (S)/(R) mixture gave a 6.0:94.0 ratio, and the analysis of a sample containing 45.0% of (S)-19 and 55.0% of the (R)-enantiomer gave 43.8% and 56.2%, respectively.

5.

5

Open in a new tab

X-ray structures of Cp2Ti­[(S)-5]2 and Cp2MoCl­(S)-5.

2. Chirality Sensing of Carboxylic Acid 5 Samples with 2 .

graphic file with name jo6c01097_0008.webp

sample composition
 sensing results
AC er AC er
R 5.0:95.0 R 6.0:94.0
R 12.5:87:5 R 12.8:87.2
R 18.8:81.2 R 21.7:78.3
R 25.0:75.0 R 22.2:77.8
R 37.5:62.5 R 34.7:65.3
R 45.0:55.0 R 43.8:56.2
S 56.2:43.8 S 53.9:46.1
S 62.5:37.5 S 60.4:39.7
S 83.7:16.3 S 82.8:17.2
Open in a new tab
a

AC = absolute configuration. See Supporting Information for details.

Finally, we decided to further corroborate the different binding stoichiometries with the two metallocenes, 1 and 2. A literature survey revealed that Cp2TiCl2 indeed produces dicarboxylates under conditions similar to our assay, thus confirming that both chlorides are replaced, which was demonstrated by single-crystal analysis of a dibenzoate complex. This encouraged us to attempt single-crystal growth with chiral carboxylate complexes of the two metallocene probes. For this purpose, we chose 5, because we expected that the relatively small size and rigid structure of this carboxylic acid would facilitate effective solid-state packing and therefore be more promising than the others. We were successful with producing a single crystal of Cp2Ti­[(S)-5]2 suitable for crystallographic analysis, and we were pleased to find that this was also possible with the molybdenum compound. The molybdocene dichloride and two equivalents of (S)-5 and K2CO3 were stirred at room temperature in DMF to closely mimic our sensing protocol and to allow formation of both Cp2MoCl­(S)-5 and Cp2Mo­[(S)-5]2. After 2 h, the mixture was filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2, and pentane was carefully layered onto the resulting solution to afford single crystals. Despite the excess of base and carboxylate present in solution, the monocarboxylate complex showing one remaining chloride was obtained, as shown in Figure . The crystallographic analyses of the isolated single crystals are thus in agreement with CD titration experiments.

Attempts to generate a molybdenum dicarboxylate complex under significantly harsher conditions were unsuccessful. When Cp2MoCl2 was treated with excess of 5 and base at 70 °C for 2 h, the resulting CD signal was identical to that of the monocarboxylate complex, confirming that the second substitution does not occur under these conditions. The addition of silver triflate to abstract the remaining chloride from the molybdenum center did coincide with the expected AgCl precipitation but we were not able to identify a molybdenum dicarboxylate complex and the resulting solution gave only a weak CD signal.

To determine if the carboxylate binding is reversible and if formation of heterochiral titanium complexes is possible, we conducted several CD titration experiments. We prepared the homochiral complex Cp2Ti­[(S)-20]2 following our general assay protocol. This gave the expected CD induction with a strong positive signal, as shown in Figure . One equivalent of the (R)-acid was then added, and after stirring for several hours, the CD amplitude decreased to the value predicted for a fully equilibrated 33% ee mixture. The CD essentially disappeared upon addition of a second (R)-20 equivalent, as expected for a racemic mixture at equilibrium. This was reproduced with the opposite homochiral Cp2Ti­[(R)-20]2 complex. These titration experiments clearly demonstrate that the system is dynamic and undergoes a reversible ligand exchange. The CD changes are in agreement with a mechanism involving a heterochiral dicarboxylate complex that is formed by stepwise replacement of one carboxylate at a time, as simultaneous displacement of two (S)-ligands from the titanium­(IV) center by two (R)-carboxylates is unlikely.

6.

6

Open in a new tab

CD titration experiments with Cp2Ti­[(S)-20]2 (left) and Cp2Ti­[(R)-20]2 (right).

In summary, the possibility of enantioselective chiral compound CD sensing with metallocene dihalides has been demonstrated for the first time. Cp2TiCl2 and Cp2MoCl2 undergo chloride exchange in the presence of base and chiral carboxylic acids under mild conditions, and the corresponding carboxylate complexes display distinct CD signals at long wavelengths. Spectroscopic titration experiments and crystallographic analysis showed that both chlorides in Cp2TiCl2 are readily displaced, while Cp2MoCl2 forms a monocarboxylate complex. The screening of a broad selection of analytes, including profens and other biologically active compounds, showed that these sensors are generally useful. The strong CD inductions obtained simply by mixing the metallocene dihalides with base and acid can be used for accurate er analysis, which was demonstrated with a total of 18 samples covering a wide range of enantiomeric compositions. All assay components are commercially available, which further highlights the practicality of this optical method. It is noteworthy that this type of assay is amenable to commercial multiwell plate readers, which would allow high-throughput analysis of large numbers of samples and avoid the use of time-consuming, one-at-a-time chromatographic separation methods unless molecular interferents that compete with the complex formation are present.

Experimental Section

Bis­(cyclopentadienyl)­titanium dichloride is a moisture-sensitive compound, while bis­(cyclopentadienyl)molybdenum dichloride is stable to water. However, both chemicals were stored under an inert atmosphere in a glovebox. All sensing reactions were carried out under an inert atmosphere with anhydrous solvents. The solutions of the corresponding carboxylate complexes are stable under air for several hours and were subjected to CD analysis without additional precautions.

General Remarks

All commercially available reagents were used without any further purification. All of the sensing reactions were carried out under nitrogen. The CD spectra were collected with a standard sensitivity of 100 mdeg, a data pitch of 0.5 nm, and a bandwidth of 1.0 nm in a continuous scanning mode with a scanning speed of 500 nm/min and a response of 1 s (1 cm path length). The data were baseline-corrected and smoothed using a binomial equation.

CD Sensing

Carboxylic Acid Sensing with Sensor 1

To 0.20 mL of a 0.10 M stock solution of the acid in 1,2-dichloroethane (DCE) was added 44.0 μL of a 0.50 M (i-Pr)2NEt stock solution in DCE. Then, 1.6 mL of a 6.25 mM sensor 1 stock solution in DCE and 0.156 mL of the same solvent were added to each vial. The solutions were stirred for 3 h at 25 °C, and CD analysis was performed directly with the reaction mixtures (5.0 mM) without further dilution.

Carboxylic Acid Sensing with Sensor 2

Into a glass vial, 0.40 mL of a 25.0 mM solution of the acid in DMF was added, followed by 1.1 equiv of K2CO3. Then, 1.6 mL of a 6.25 mM sensor 2 stock solution in DMF was added. The mixtures (5.0 mM) were stirred for 1 h at 25 °C, and CD analysis was performed without further dilution.

The carboxylate complexes are stable for several hours in solution under air, which gives sufficient time to conduct the sensing experiments. However, racemization of the carboxylic acid can occur when the basic solutions are concentrated.

Supplementary Material

jo6c01097_si_001.pdf (2.8MB, pdf)

Acknowledgments

We gratefully acknowledge financial support from the NSF (CHE-2246747).

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.6c01097.

  • Assay development, optimization, and crystallographic and analytical details (PDF)

The manuscript was written through contributions of all authors.

The authors declare no competing financial interest.

References

  1. Köpf H., Köpf-Maier P.. Titanocene Dichloride - The First Metallocene with Cancerostatic Activity. Angew. Chem., Int. Ed. Engl. 1979;18:477–478. doi: 10.1002/anie.197904771. [DOI] [PubMed] [Google Scholar]
  2. Toney J. H., Marks T. J.. Hydrolysis Chemistry of the Metallocene Dichlorides M­(η5-C5H5)2Cl2, M = Titanium, Vanadium, or Zirconium. Aqueous Kinetics, Equilibria, and Mechanistic Implications for a New Class of Antitumor Agents. J. Am. Chem. Soc. 1985;107:947–953. doi: 10.1021/ja00290a033. [DOI] [Google Scholar]
  3. McLaughlin M. L., Cronan J. M. Jr., Schaller T. R., Snelling R. D.. DNA-metal Binding by Antitumor-Active Metallocene Dichlorides from Inductively Coupled Plasma Spectroscopy Analysis: Titanocene Dichloride Forms DNA-Cp2Ti or DNA-CpTi Adducts Depending on pH. J. Am. Chem. Soc. 1990;112:8949–8952. doi: 10.1021/ja00180a046. [DOI] [Google Scholar]
  4. Niu H., Yao J., Wang Y., Wang G.. Cp2TiCl2 Used as a Catalyst for the Transesterification Between Dimethyl Carbonate and Phenol to Diphenyl Carbonate. J. Mol. Catal. A:Chem. 2005;235:240–243. doi: 10.1016/j.molcata.2005.03.023. [DOI] [Google Scholar]
  5. Allen O. R., Croll L., Gott A. L., Knox R. J., McGowan P. C.. Functionalized Cyclopentadienyl Titanium Organometallic Compounds as New Antitumor Drugs. Organometallics. 2004;23:288–292. doi: 10.1021/om030403i. [DOI] [Google Scholar]
  6. Causey P. W., Baird M. C., Cole S. P. C.. Synthesis, Characterization, and Assessment of Cytotoxic Properties of a Series of Titanocene Dichloride Derivatives. Organometallics. 2004;23:4486–4494. doi: 10.1021/om049679w. [DOI] [Google Scholar]
  7. Profitt L. A., Baxter R. H. G., Valentine A. M.. Superstoichiometric Binding of the Anticancer Agent Titanocene Dichloride by Human Serum Transferrin and the Accompanying Lobe Closure. Biochemistry. 2022;61:795–803. doi: 10.1021/acs.biochem.1c00813. [DOI] [PubMed] [Google Scholar]
  8. Kumar N., Kaushal R., Awasthi P.. A Comprehensive Review on the Development of Titanium Complexes as Cytotoxic Agents. Curr. Top. Med. Chem. 2024;24:2117–2128. doi: 10.2174/0115680266317770240718080512. [DOI] [PubMed] [Google Scholar]
  9. Mouriki O., Passeri G., Singh K., Lamorte S. D., Singh K., Suntharalingam K., Kilpatrick A. F. R.. Anti-breast Cancer Stem Cell Activity of Titanocene Complexes of Non-steroidal Anti-inflammatory Drugs. Dalton Trans. 2025;54:15389–15394. doi: 10.1039/D5DT01491C. [DOI] [PubMed] [Google Scholar]
  10. Waern J. B., Harding M. M.. Coordination Chemistry of the Antitumor Metallocene Molybdocene Dichloride with Biological Ligands. Inorg. Chem. 2004;43:206–213. doi: 10.1021/ic034892q. [DOI] [PubMed] [Google Scholar]
  11. Waern J. B., Turner P., Harding M. M.. Synthesis and Hydrolysis of Thiol Derivatives of Molybdocene Dichloride Incorporating Electron-Withdrawing Substituents. Organometallics. 2006;25:3417–3421. doi: 10.1021/om060133e. [DOI] [Google Scholar]
  12. Meléndez E.. Bioorganometallic Chemistry of Molybdenocene Dichloride and Its Derivatives. J. Organomet. Chem. 2012;706–707:4–12. doi: 10.1016/j.jorganchem.2012.02.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kandioller W., Reikersdorfer M., Theiner S., Roller A., Hejl M., Jakupec M. A., Malarek M. S., Keppler B. K.. The Impact of Leaving Group Variation on the Anticancer Activity of Molybdenocenes. Organometallics. 2018;37:3909–3916. doi: 10.1021/acs.organomet.8b00582. [DOI] [Google Scholar]
  14. Guk D. A., Gibadullina K. R., Burlutskiy R. O., Pavlov K. G., Moiseeva A. A., Tafeenko V. A., Lyssenko K. A., Gandalipov E. R., Shtil A. A., Beloglazkina E. K.. New Titanocene­(IV) Dicarboxylates with Potential Cytotoxicity: Synthesis, Structure, Stability and Electrochemistry. Int. J. Mol. Sci. 2023;24:3340. doi: 10.3390/ijms24043340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fuchs V., Cseh K., Hejl M., Vician P., Neuditschko B., Meier-Menches S. M., Janker L., Bileck A., Gajic N., Kronberger J., Schaier M., Neumayer S., Köllensperger G., Gerner C., Berger W., Jakupec M. A., Malarek M. S., Keppler B. K.. Highly Cytotoxic Molybdenocenes with Strong Metabolic Effects Inhibit Tumour Growth in Mice. Chem.Eur. J. 2023;29:e202202648. doi: 10.1002/chem.202202648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Herrera B. T., Pilicer S. L., Anslyn E. V., Joyce L. A., Wolf C.. Optical Analysis of Reaction Yield and Enantiomeric Excess. A New Paradigm Ready for Prime Time. J. Am. Chem. Soc. 2018;140:10385–10401. doi: 10.1021/jacs.8b06607. [DOI] [PubMed] [Google Scholar]
  17. Nelson E., Bertke J. A., Thanzeel F. Y., Wolf C.. Organometallic Chirality Sensing via “Click”-like η6-Arene Coordination with an Achiral Cp*Ru­(II) Piano Stool Complex. Angew. Chem., Int. Ed. 2024;63:e202404594. doi: 10.1002/anie.202404594. [DOI] [PubMed] [Google Scholar]
  18. Piovesana S., Samperi R., Laganà A., Bella M.. Determination of Enantioselectivity and Enantiomeric Excess by Mass Spectrometry in the Absence of Chiral Chromatographic Separation: An Overview. Chem.Eur. J. 2013;19:11478–11494. doi: 10.1002/chem.201300233. [DOI] [PubMed] [Google Scholar]
  19. Leung D., Kang S. O., Anslyn E. V.. Rapid Determination of Enantiomeric Excess: A Focus on Optical Approaches. Chem. Soc. Rev. 2012;41:448–479. doi: 10.1039/C1CS15135E. [DOI] [PubMed] [Google Scholar]
  20. Pu L.. Fluorescence of Organic Molecules in Chiral Recognition. Chem. Rev. 2004;104:1687–1716. doi: 10.1021/cr030052h. [DOI] [PubMed] [Google Scholar]
  21. Shcherbakova E. G., Minami T., Brega V., James T. D., Anzenbacher P. Jr.. Determination of Enantiomeric Excess in Amine Derivatives with Molecular Self-Assemblies. Angew. Chem., Int. Ed. 2015;54:7130–7133. doi: 10.1002/anie.201501736. [DOI] [PubMed] [Google Scholar]
  22. Akdeniz A., Minami T., Watanabe S., Yokoyama M., Ema T., Anzenbacher P.. Determination of enantiomeric excess of carboxylates by fluorescent macrocyclic sensors. Chem. Sci. 2016;7:2016–2022. doi: 10.1039/c5sc04235f. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sonstrom R. E., Neill J. L., Mikhonin A. V., Doetzer R., Pate B. H.. Chiral Analysis of Pantolactone with Molecular Rotational Resonance Spectroscopy. Chirality. 2022;34:114–125. doi: 10.1002/chir.23379. [DOI] [PubMed] [Google Scholar]
  24. Tielmann P., Boese M., Luft M., Reetz M. T.. A Practical High-throughput Screening System for Enantioselectivity by Using FTIR Spectroscopy. Chem.Eur. J. 2003;9:3882–3887. doi: 10.1002/chem.200304885. [DOI] [PubMed] [Google Scholar]
  25. Berova N., Di Bari L., Pescitelli G.. Application of Electronic Circular Dichroism in Configurational and Conformational Analysis of Organic Compounds. Chem. Soc. Rev. 2007;36:914–931. doi: 10.1039/b515476f. [DOI] [PubMed] [Google Scholar]
  26. Berova N., Pescitelli G., Petrovic A. G., Proni G.. Probing Molecular Chirality by CD-sensitive Dimeric Metalloporphyrin Hosts. Chem. Commun. 2009;45:5958–5980. doi: 10.1039/b909582a. [DOI] [PubMed] [Google Scholar]
  27. Wolf C., Bentley K. W.. Chirality Sensing Using Stereodynamic Probes with Distinct Electronic Circular Dichroism Output. Chem. Soc. Rev. 2013;42:5408–5424. doi: 10.1039/c3cs35498a. [DOI] [PubMed] [Google Scholar]
  28. Zardi P., Wurst K., Licini G., Zonta C.. Concentration-Independent Stereodynamic g-Probe for Chiroptical Enantiomeric Excess Determination. J. Am. Chem. Soc. 2017;139:15616–15619. doi: 10.1021/jacs.7b09469. [DOI] [PubMed] [Google Scholar]
  29. Gholami H., Chakraborty D., Zhang J., Borhan B.. Absolute Stereochemical Determination of Organic Molecules through Induction of Helicity in Host–Guest Complexes. Acc. Chem. Res. 2021;54:654–667. doi: 10.1021/acs.accounts.0c00650. [DOI] [PubMed] [Google Scholar]
  30. Hassan D. S., Kariapper F. S., Lynch C. C., Wolf C.. Accelerated Asymmetric Reaction Screening with Optical Assays. Synthesis. 2022;54:2527–2538. doi: 10.1055/a-1754-2271. [DOI] [Google Scholar]
  31. Formen J. S. S. K., Howard J. R., Anslyn E. V., Wolf C.. Circular Dichroism Sensing: Strategies and Applications. Angew. Chem., Int. Ed. 2024;63:e202400767. doi: 10.1002/anie.202400767. [DOI] [PubMed] [Google Scholar]
  32. Prabodh A., Wang Y., Sinn S., Albertini P., Spies C., Spuling E., Yang L.-P., Jiang W., Brase S., Biedermann F.. Fluorescence Detected Circular Dichroism (FDCD) for Supramolecular Host–guest Complexes. Chem. Sci. 2021;12:9420–9431. doi: 10.1039/D1SC01411K. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ramos De Dios S. M., Tiwari V. K., McCune C. D., Dhokale R. A., Berkowitz D. B.. Biomacromolecule-Assisted Screening for Reaction Discovery and Catalyst Optimization. Chem. Rev. 2022;122:13800–13880. doi: 10.1021/acs.chemrev.2c00213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Penasa R., Licini G., Zonta C.. Advances in Chiral Analysis: From Classical Methods to Emerging Technologies. Chem. Soc. Rev. 2025;54:10940–10955. doi: 10.1039/D4CS01202J. [DOI] [PubMed] [Google Scholar]
  35. Huang X., Rickman B. H., Borhan B., Berova N., Nakanishi K.. Zinc Porphyrin Tweezer in Host-guest Complexation: Determination of Absolute Configurations of Diamines, Amino Acids, and Amino Alcohols by Circular Dichroism. J. Am. Chem. Soc. 1998;120:6185–6186. doi: 10.1021/ja973539e. [DOI] [PubMed] [Google Scholar]
  36. Barcena H. S., Holmes A. E., Zahn S., Canary J. W.. Redox Inversion of Helicity in Propeller-Shaped Molecules Derived from S-Methyl Cysteine and Methioninol. Org. Lett. 2003;5:709–711. doi: 10.1021/ol0275217. [DOI] [PubMed] [Google Scholar]
  37. Kim H., So S. M., Yen C. P., Vinhato E., Lough A. J., Hong J. I., Kim H. J., Chin J.. Highly Stereospecific Generation of Helical Chirality by Imprinting with Amino Acids: A Universal Sensor for Amino Acid Enantiopurity. Angew. Chem., Int. Ed. 2008;47:8657–8660. doi: 10.1002/anie.200803116. [DOI] [PubMed] [Google Scholar]
  38. Joyce L. A., Canary J. W., Anslyn E. V.. Enantio- and Chemoselective Differentiation of Protected α-Amino Acids and β-Homoamino Acids with a Single Copper­(II) Host. Chem.Eur. J. 2012;18:8064–8069. doi: 10.1002/chem.201103592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Scaramuzzo F. A., Licini G., Zonta C.. Determination of Amino Acid Enantiopurity and Absolute Configuration: Synergism between Configurationally Labile Metal-Based Receptors and Dynamic Covalent Interactions. Chem.Eur. J. 2013;19:16809–16813. doi: 10.1002/chem.201302721. [DOI] [PubMed] [Google Scholar]
  40. Bentley K. W., Nam Y. G., Murphy J. M., Wolf C.. Chirality Sensing of Amines, Diamines, Amino Acids, Amino Alcohols, and α-Hydroxy Acids with a Single Probe. J. Am. Chem. Soc. 2013;135:18052–18055. doi: 10.1021/ja410428b. [DOI] [PubMed] [Google Scholar]
  41. Biedermann F., Nau W. M.. Noncovalent Chirality Sensing Ensembles for the Detection and Reaction Monitoring of Amino Acids, Peptides, Proteins, and Aromatic Drugs. Angew. Chem., Int. Ed. 2014;53:5694–5699. doi: 10.1002/anie.201400718. [DOI] [PubMed] [Google Scholar]
  42. Badetti E., Wurst K., Licini G., Zonta C.. Multimetallic Architectures from the Self-assembly of Amino Acids and Tris­(2-pyridylmethyl)­amine Zinc­(II) Complexes: Circular Dichroism Enhancement by Chromophores Organization. Chem.Eur. J. 2016;22:6515–6518. doi: 10.1002/chem.201600480. [DOI] [PubMed] [Google Scholar]
  43. De los Santos Z. A., Wolf C.. Chiroptical Asymmetric Reaction Screening via Multicomponent Self-Assembly. J. Am. Chem. Soc. 2016;138:13517–13520. doi: 10.1021/jacs.6b08892. [DOI] [PubMed] [Google Scholar]
  44. Thanzeel F. Y., Wolf C.. Substrate-Specific Amino Acid Sensing Using a Molecular D/L-Cysteine Probe for Comprehensive Stereochemical Analysis in Aqueous Solution. Angew. Chem., Int. Ed. 2017;56:7276–7281. doi: 10.1002/anie.201701188. [DOI] [PubMed] [Google Scholar]
  45. Thanzeel F. Y., Sripada A., Wolf C.. Quantitative Chiroptical Sensing of Free Amino acids, Biothiols, Amines and Amino Alcohols with an Aryl Fluoride Probe. J. Am. Chem. Soc. 2019;141:16382–16387. doi: 10.1021/jacs.9b07588. [DOI] [PubMed] [Google Scholar]
  46. Nelson E., Formen J. S. S. K., Wolf C.. Rapid Organocatalytic Chirality Analysis of Amines, Amino Acids, Alcohols, Amino Alcohols and Diols with Achiral Iso­(thio)­cyanate Probes. Chem. Sci. 2021;12:8784–8790. doi: 10.1039/D1SC02061G. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Li B., Zhang J., Li L., Chen G.. A Rapid and Sensitive Method for Chiroptical Sensing of α-Amino Acids via Click-like Labeling with o-Phthalaldehyde and p-Toluenethiol. Chem. Sci. 2021;12:2504–2508. doi: 10.1039/D0SC05749E. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Hassan D. S., De los Santos Z. A., Brady K. G., Murkli S., Isaacs L., Wolf C.. Chiroptical Sensing of Amino Acids, Amines, Amino Alcohols, Alcohols and Terpenes with π-Extended Acyclic Cucurbiturils. Org. Biomol. Chem. 2021;19:4248–4253. doi: 10.1039/D1OB00345C. [DOI] [PubMed] [Google Scholar]
  49. Formen J. S. S. K., Wolf C.. Chiroptical Switching and Quantitative Chirality Sensing with (Pseudo)­halogenated Quinones. Angew. Chem., Int. Ed. 2021;60:27031–27038. doi: 10.1002/anie.202111542. [DOI] [PubMed] [Google Scholar]
  50. Sripada A., Thanzeel F. Y., Wolf C.. Unified Sensing of the Concentration and Enantiomeric Composition of Chiral Compounds with an Achiral Probe. Chem. 2022;8:1734–1749. doi: 10.1016/j.chempr.2022.03.008. [DOI] [Google Scholar]
  51. Kariapper F. S., Wolf A. U., Wolf C.. Repurposing the Sanger Reagent for Optical Sensing of the Concentration and Enantiomeric Ratio of Chiral Amines, Amino Alcohols and Amino Acids. Chirality. 2025;37:e70062. doi: 10.1002/chir.70062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Wu X., Chen X.-X., Song B.-N., Huang Y.-J., Li Z., Chen Z., James T. D., Jiang Y.-B.. Induced Helical Chirality of Perylenebisimide Aggregates Allows for Enantiopurity Determination and Differentiation of α-Hydroxy Carboxylates by Using Circular Dichroism. Chem.Eur. J. 2014;20:11793–11799. doi: 10.1002/chem.201402627. [DOI] [PubMed] [Google Scholar]
  53. Peng R., Lin L., Cao W., Guo J., Liu X., Feng X. A.. Racemic N,N ’-Dioxide-iron­(III) Complex Chemosensor for Determination of Enantiomeric Excess, Concentration and Identity of Hydroxy Carboxylic Acids with Circular Dichroism and Fluorescence Responses. Tetrahedron Lett. 2015;56:3882–3885. doi: 10.1016/j.tetlet.2015.04.101. [DOI] [Google Scholar]
  54. Bentley K. W., Zhang P., Wolf C.. Miniature High-Throughput Chemosensing of Yield, Ee and Absolute Configuration from Crude Reaction Mixtures. Sci. Adv. 2016;2:e1501162. doi: 10.1126/sciadv.1501162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. De los Santos Z. A., Lynch C. C., Wolf C.. Optical Chirality Sensing with an Auxiliary-Free Earth-Abundant Cobalt Probe. Angew. Chem., Int. Ed. 2019;58:1198–1202. doi: 10.1002/anie.201811761. [DOI] [PubMed] [Google Scholar]
  56. De los Santos Z. A., Joyce L. A., Sherer E. C., Welch C. J., Wolf C.. Optical Chirality Sensing with a Stereodynamic Aluminum Biphenolate Probe. J. Org. Chem. 2019;84:4639–4645. doi: 10.1021/acs.joc.8b01301. [DOI] [PubMed] [Google Scholar]
  57. Lynch C. C., De los Santos Z. A., Wolf C.. Chiroptical Sensing of Unprotected Amino Acids, Hydroxy acids, Amino Alcohols, Amines and Carboxylic Acids with Metal Salts. Chem. Commun. 2019;55:6297–6300. doi: 10.1039/C9CC02525A. [DOI] [PubMed] [Google Scholar]
  58. Thanzeel F. Y., Balaraman K., Wolf C.. Quantitative Chirality and Concentration Sensing of Alcohols, Diols, Hydroxy Acids, Amines and Amino Alcohols using Chlorophosphite Sensors in a Relay Assay. Angew. Chem., Int. Ed. 2020;59:21382–21386. doi: 10.1002/anie.202005324. [DOI] [PubMed] [Google Scholar]
  59. Begato F., Penasa R., Licini G., Zonta C.. Chiroptical Enhancement of Chiral Dicarboxylic Acids from Confinement in a Stereodynamic Supramolecular Cage. ACS Sens. 2022;7:1390–1394. doi: 10.1021/acssensors.2c00038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Moor S. R., Howard J. R., Herrera B. T., McVeigh M. S., Marini F., Keatinge-Clay A. T., Anslyn E. V.. Determination of Enantiomeric Excess and Diastereomeric Excess via Optical Methods. Application to α-Methyl-α-hydroxy-carboxylic Acids. Org. Chem. Front. 2023;10:1386–1392. doi: 10.1039/d2qo01444k. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Yang Q., Olmsted C., Borhan B.. Absolute Stereochemical Determination of Chiral Carboxylic Acids. Org. Lett. 2002;4:3423–3426. doi: 10.1021/ol026527t. [DOI] [PubMed] [Google Scholar]
  62. Tanasova M., Anyika M., Borhan B.. Sensing Remote Chirality: Stereochemical Determination of β-, γ-, and δ-Chiral Carboxylic Acids. Angew. Chem., Int. Ed. 2015;54:4274–4278. doi: 10.1002/anie.201410371. [DOI] [PubMed] [Google Scholar]
  63. Akdeniz A., Mosca L., Minami T., Anzenbacher P. Jr.. Sensing of Enantiomeric Excess in Chiral Carboxylic Acids. Chem. Commun. 2015;51:5770–5773. doi: 10.1039/c5cc00376h. [DOI] [PubMed] [Google Scholar]
  64. Proni G., Pescitelli G., Huang X., Quaraishi N. Q., Nakanishi K., Berova N.. Configurational Assignment of α-Chiral Carboxylic Acids by Complexation to Dimeric Zn-Porphyrin: Host-Guest Structure, Chiral Recognition and Circular Dichroism. Chem. Commun. 2002;38:1590–1591. doi: 10.1039/b204554k. [DOI] [PubMed] [Google Scholar]
  65. Wezenberg S. J., Salassa G., Escudero-Adan E. C., Benet-Buchholz J., Kleij A. W.. Effective Chirogenesis in a Bis­(metallosalphen) Complex Through Host–Guest Binding with Carboxylic Acids. Angew. Chem., Int. Ed. 2011;50:713–716. doi: 10.1002/anie.201004957. [DOI] [PubMed] [Google Scholar]
  66. Joyce L. A., Maynor M. S., Dragna J. M., da Cruz G. M., Lynch V. M., Canary J. W., Anslyn E. V.. A Simple Method for the Determination of Enantiomeric Excess and Identity of Chiral Carboxylic Acids. J. Am. Chem. Soc. 2011;133:13746–13752. doi: 10.1021/ja205775g. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Formen J. S. S. K., Nelson E., Wolf C.. Molecular Sensing of Chiral Carboxylic Acid Enantiomers Using CD Inductions in the Visible Light Region. J. Org. Chem. 2025;90:994–1000. doi: 10.1021/acs.joc.4c02055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. De los Santos Z. A., Yusin G., Wolf C.. Enantioselective Sensing of Carboxylic Acids with a Bis­(urea)­oligo­(phenylene)­ethynylene Foldamer. Tetrahedron. 2019;75:1504–1509. doi: 10.1016/j.tet.2019.01.070. [DOI] [Google Scholar]
  69. Osawa K., Tagaya H., Kondo S. I.. Induced Circular Dichroism of Achiral Cyclic Bisurea via Hydrogen Bonds with Chiral Carboxylates. J. Org. Chem. 2019;84:6623–6630. doi: 10.1021/acs.joc.9b00073. [DOI] [PubMed] [Google Scholar]
  70. Bentley K. W., Proano D., Wolf C.. Chirality Imprinting and Direct Asymmetric Reaction Screening Using a Stereodynamic Brønsted/Lewis Acid Receptor. Nat. Commun. 2016;7:12539. doi: 10.1038/ncomms12539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Huang X., Wang X., Quan M., Yao H., Ke H., Jiang W.. Biomimetic Recognition and Optical Sensing of Carboxylic Acids in Water by Using a Buried Salt Bridge and the Hydrophobic Effect. Angew. Chem., Int. Ed. 2021;60:1929–1935. doi: 10.1002/anie.202012467. [DOI] [PubMed] [Google Scholar]
  72. Jawiczuk M., Górecki M., Suszczyńska A., Karchier M., Jaźwiński J., Frelek J.. Dimolybdenum Tetracarboxylates as Auxiliary Chromophores in Chiroptical Studies of vic-Diols. Inorg. Chem. 2013;52:8250–8263. doi: 10.1021/ic401170m. [DOI] [PubMed] [Google Scholar]
  73. Guk D. A., Gibadullina K. R., Burlutskiy R. O., Pavlov K. G., Moiseeva A. A., Tafeenko V. A., Lyssenko K. A., Gandalipov E. R., Shtil A. A., Beloglazkina E. K.. New Titanocene (IV) Dicarboxylates with Potential Cytotoxicity: Synthesis, Structure, Stability and Electrochemistry. Int. J. Mol. Sci. 2023;24:3340. doi: 10.3390/ijms24043340. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

jo6c01097_si_001.pdf (2.8MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Articles from The Journal of Organic Chemistry are provided here courtesy of American Chemical Society

RESOURCES