Hydrolysis chemistry of the metallocene dichlorides M(η5-C5H5)2Cl2, M = Ti, V, Zr. Aqueous kinetics, equilibria, and mechanistic implications for a new class of antitumor agents

Jeffrey H. Toney, Tobin J Marks

Research output: Contribution to journalArticle

280 Citations (Scopus)

Abstract

This paper reports an integrated chemical/physicochemical investigation of the aqueous chemistry of Cp2TiCl2, Cp2VCl2, and Cp2ZrCl2, employing high-field FT NMR, chloride potentiometry, pH titrimetry, and electrical conductivity. Experimental conditions include those employed previously to study the hydrolysis of cis-dichlorodiammineplatinum(II) ("cisplatin") and those approximating physiological. In unbuffered aqueous 0.32 M KNO3 solution at 37°C, the order of decreasing hydrolytic stability of the M-(η5-C5H5) bond in the Cp2MCl2 complexes (monitored by high-field FT NMR) was found to be V (kinitial ≤ 3.0 × 10-3 h-1) > Ti (Jinitial = 6.4 (1) × 10-3h-1) ≫ Zr (kinitial = 3.8 (1) × 10-2 h-1). Of the three complexes studied, only Cp2VCl2 was found to possess a stable M-(η5-C5H5) bond at physiological pH. Addition of any of the Cp2MCl2 complexes to water (pure or 0.32 M KNO3) results in rapid chloride ion dissociation with approximate half-lives for the loss of the second chloride (the first is too rapid to measure) of 50 min (M = Ti), 30 min (M = Zr), and 24 min (M = V) in contrast to the relatively slow chloride hydrolysis observed with cisplatin. Chloride dissociation is also more extensive than that in cisplatin. Equilibrium chloride ion concentration measurements indicate that the equilibrium constant (K1) for the first Cp2MCl2 chloride dissociation is too large to measure, whileK2 = 4.2 (2.7) × 10-2M (M = Ti) and 2.7 (1.2) X 10-3 M (M = V). Titrimetric studies indicate that the acidity of the Cp2M2+-bound water molecules is uniformly more acidic than the metal-bound water molecules of cis-[Pt(NH3)2(H2O)2]2+ (Ti, pKa = 3.5 (5) and 4.35 (9); V, pKa = 4.73 (3) and 5.15 (13)). Implications of these results for the observed biological activity of the Cp2MCl2 complexes are briefly discussed.

Original languageEnglish
Pages (from-to)947-953
Number of pages7
JournalJournal of the American Chemical Society
Volume107
Issue number4
Publication statusPublished - 1985

Fingerprint

Antineoplastic Agents
Chlorides
Hydrolysis
Kinetics
Cisplatin
Nuclear magnetic resonance
Water
Molecules
Equilibrium constants
Ions
Bioactivity
Acidity
Titrimetry
Potentiometry
Electric Conductivity
Metals
metallocene

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

@article{d9232336987146fd93d27847ab26a508,
title = "Hydrolysis chemistry of the metallocene dichlorides M(η5-C5H5)2Cl2, M = Ti, V, Zr. Aqueous kinetics, equilibria, and mechanistic implications for a new class of antitumor agents",
abstract = "This paper reports an integrated chemical/physicochemical investigation of the aqueous chemistry of Cp2TiCl2, Cp2VCl2, and Cp2ZrCl2, employing high-field FT NMR, chloride potentiometry, pH titrimetry, and electrical conductivity. Experimental conditions include those employed previously to study the hydrolysis of cis-dichlorodiammineplatinum(II) ({"}cisplatin{"}) and those approximating physiological. In unbuffered aqueous 0.32 M KNO3 solution at 37°C, the order of decreasing hydrolytic stability of the M-(η5-C5H5) bond in the Cp2MCl2 complexes (monitored by high-field FT NMR) was found to be V (kinitial ≤ 3.0 × 10-3 h-1) > Ti (Jinitial = 6.4 (1) × 10-3h-1) ≫ Zr (kinitial = 3.8 (1) × 10-2 h-1). Of the three complexes studied, only Cp2VCl2 was found to possess a stable M-(η5-C5H5) bond at physiological pH. Addition of any of the Cp2MCl2 complexes to water (pure or 0.32 M KNO3) results in rapid chloride ion dissociation with approximate half-lives for the loss of the second chloride (the first is too rapid to measure) of 50 min (M = Ti), 30 min (M = Zr), and 24 min (M = V) in contrast to the relatively slow chloride hydrolysis observed with cisplatin. Chloride dissociation is also more extensive than that in cisplatin. Equilibrium chloride ion concentration measurements indicate that the equilibrium constant (K1) for the first Cp2MCl2 chloride dissociation is too large to measure, whileK2 = 4.2 (2.7) × 10-2M (M = Ti) and 2.7 (1.2) X 10-3 M (M = V). Titrimetric studies indicate that the acidity of the Cp2M2+-bound water molecules is uniformly more acidic than the metal-bound water molecules of cis-[Pt(NH3)2(H2O)2]2+ (Ti, pKa = 3.5 (5) and 4.35 (9); V, pKa = 4.73 (3) and 5.15 (13)). Implications of these results for the observed biological activity of the Cp2MCl2 complexes are briefly discussed.",
author = "Toney, {Jeffrey H.} and Marks, {Tobin J}",
year = "1985",
language = "English",
volume = "107",
pages = "947--953",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "4",

}

TY - JOUR

T1 - Hydrolysis chemistry of the metallocene dichlorides M(η5-C5H5)2Cl2, M = Ti, V, Zr. Aqueous kinetics, equilibria, and mechanistic implications for a new class of antitumor agents

AU - Toney, Jeffrey H.

AU - Marks, Tobin J

PY - 1985

Y1 - 1985

N2 - This paper reports an integrated chemical/physicochemical investigation of the aqueous chemistry of Cp2TiCl2, Cp2VCl2, and Cp2ZrCl2, employing high-field FT NMR, chloride potentiometry, pH titrimetry, and electrical conductivity. Experimental conditions include those employed previously to study the hydrolysis of cis-dichlorodiammineplatinum(II) ("cisplatin") and those approximating physiological. In unbuffered aqueous 0.32 M KNO3 solution at 37°C, the order of decreasing hydrolytic stability of the M-(η5-C5H5) bond in the Cp2MCl2 complexes (monitored by high-field FT NMR) was found to be V (kinitial ≤ 3.0 × 10-3 h-1) > Ti (Jinitial = 6.4 (1) × 10-3h-1) ≫ Zr (kinitial = 3.8 (1) × 10-2 h-1). Of the three complexes studied, only Cp2VCl2 was found to possess a stable M-(η5-C5H5) bond at physiological pH. Addition of any of the Cp2MCl2 complexes to water (pure or 0.32 M KNO3) results in rapid chloride ion dissociation with approximate half-lives for the loss of the second chloride (the first is too rapid to measure) of 50 min (M = Ti), 30 min (M = Zr), and 24 min (M = V) in contrast to the relatively slow chloride hydrolysis observed with cisplatin. Chloride dissociation is also more extensive than that in cisplatin. Equilibrium chloride ion concentration measurements indicate that the equilibrium constant (K1) for the first Cp2MCl2 chloride dissociation is too large to measure, whileK2 = 4.2 (2.7) × 10-2M (M = Ti) and 2.7 (1.2) X 10-3 M (M = V). Titrimetric studies indicate that the acidity of the Cp2M2+-bound water molecules is uniformly more acidic than the metal-bound water molecules of cis-[Pt(NH3)2(H2O)2]2+ (Ti, pKa = 3.5 (5) and 4.35 (9); V, pKa = 4.73 (3) and 5.15 (13)). Implications of these results for the observed biological activity of the Cp2MCl2 complexes are briefly discussed.

AB - This paper reports an integrated chemical/physicochemical investigation of the aqueous chemistry of Cp2TiCl2, Cp2VCl2, and Cp2ZrCl2, employing high-field FT NMR, chloride potentiometry, pH titrimetry, and electrical conductivity. Experimental conditions include those employed previously to study the hydrolysis of cis-dichlorodiammineplatinum(II) ("cisplatin") and those approximating physiological. In unbuffered aqueous 0.32 M KNO3 solution at 37°C, the order of decreasing hydrolytic stability of the M-(η5-C5H5) bond in the Cp2MCl2 complexes (monitored by high-field FT NMR) was found to be V (kinitial ≤ 3.0 × 10-3 h-1) > Ti (Jinitial = 6.4 (1) × 10-3h-1) ≫ Zr (kinitial = 3.8 (1) × 10-2 h-1). Of the three complexes studied, only Cp2VCl2 was found to possess a stable M-(η5-C5H5) bond at physiological pH. Addition of any of the Cp2MCl2 complexes to water (pure or 0.32 M KNO3) results in rapid chloride ion dissociation with approximate half-lives for the loss of the second chloride (the first is too rapid to measure) of 50 min (M = Ti), 30 min (M = Zr), and 24 min (M = V) in contrast to the relatively slow chloride hydrolysis observed with cisplatin. Chloride dissociation is also more extensive than that in cisplatin. Equilibrium chloride ion concentration measurements indicate that the equilibrium constant (K1) for the first Cp2MCl2 chloride dissociation is too large to measure, whileK2 = 4.2 (2.7) × 10-2M (M = Ti) and 2.7 (1.2) X 10-3 M (M = V). Titrimetric studies indicate that the acidity of the Cp2M2+-bound water molecules is uniformly more acidic than the metal-bound water molecules of cis-[Pt(NH3)2(H2O)2]2+ (Ti, pKa = 3.5 (5) and 4.35 (9); V, pKa = 4.73 (3) and 5.15 (13)). Implications of these results for the observed biological activity of the Cp2MCl2 complexes are briefly discussed.

UR - http://www.scopus.com/inward/record.url?scp=0021912585&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0021912585&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:0021912585

VL - 107

SP - 947

EP - 953

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 4

ER -