Reaction Kinetics of Aliphatic Tertiary β-Chloroethylamines in Dilute Aqueous Solution. I. The Cyclization Process<sup>1</sup>

Cohen, Barnett; Artsdalen, E. R. Van; Harris, Joseph

doi:10.1021/ja01181a086

Cited by 50 publications

(14 citation statements)

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“…RzNCHzCH2C1 Ft Rz&' I C1--j products C Hz XCIII \ Consideration of the cyclization process as an intramolecular direct displacement reaction is consistent with the observed increase in rate with an increase in the basicity of the amino group (53,150,547).…”

Section: Ch2supporting

confidence: 61%

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Solvolytic Displacement Reactions At Saturated Carbon Atoms

1956

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Section: Ch2supporting

confidence: 61%

“…Aqueous solvolysis of these compounds has been abundantly shown to involve a reactive though isolable ethylenimonium ion intermediate, XCIII (44,52,53,150,271,283,284,306,323,572,573,574,625).…”

Section: Solvolyeie(b)mentioning

confidence: 99%

Solvolytic Displacement Reactions At Saturated Carbon Atoms

1956

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“…Hence, if the C-C cross-link occurs through N3 of cytosine, then its formation should be blocked by protonation of N3 at low pH. However, for mechlorethamine, this is complicated by protonation of the mustard itself [mechlorethamine has a pK a of 6.45 (42)], which would be expected to reduce the reactivity of the cross-linking agent. Because of this, we also carried out the pH-dependent cross- linking experiments using chlorambucil (Figure 1a), which, due to the aromatic ring, has an amine with a much lower pK a of 2.49 (43), and is essentially unprotonated at the pH corresponding to the pK a of the C-C mismatch.…”

Section: Resultsmentioning

confidence: 99%

Anomalous Cross-Linking by Mechlorethamine of DNA Duplexes Containing C−C Mismatch Pairs

1999

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Nitrogen mustards such as mechlorethamine have previously been shown to covalently cross-link DNA through the N7 position of the two guanine bases of a d[GXC].d[GYC] duplex sequence, a so-called 1,3 G-G-cross-link, when X-Y = C-G or T-A. Here, we report the formation of a new mechlorethamine cross-link with the d[GXC].d[GYC] fragment when X-Y is a C-C mismatch pair. Mechlorethamine cross-links this fragment preferentially between the two mismatched cytosine bases, rather than between the guanine bases. The cross-link also forms when one or both of the guanine bases of the d[GCC].d[GCC] fragment are replaced by N7-deazaguanine, and, more generally, forms with any C-C mismatch, regardless of the flanking base pairs. Piperidine cleavage of the cross-link species containing the d[GCC].d[GCC] sequence gives DNA fragments consistent with alkylation at the mismatched cytosine bases. We also provide evidence that the cross-link reaction occurs between the N3 atoms of the two cytosine bases by showing that the formation of the C-C cross-link is pH dependent for both mechlorethamine and chlorambucil. Dimethyl sulfate (DMS) probing of the cross-linked d[GCC].d[GCC] fragment showed that the major groove of the guanine adjacent to the C-C mismatch is still accessible to DMS. In contrast, the known minor groove binder Hoechst 33258 inhibits the cross-link formation with a C-C mismatch pair flanked by A-T base pairs. These results suggest that the C-C mismatch is cross-linked by mechlorethamine in the minor groove. Since C-C pairs may be involved in unusual secondary structures formed by the trinucleotide repeat sequence d[CCG]n, and associated with triplet repeat expansion diseases, mechlorethamine may serve as a useful probe for these structures.

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“…Before discussing alternative analytical methods, it is necessary to review the chemistry of tertiary b-chloroethylamines, a subject that has been extensively studied because these compounds are closely related to the nitrogen mustards, RN(C 2 H 4 Cl) 2 . 2,3 The hydrochloride salts are almost unreactive as alkylating agents, and they are stable at room temperature in aqueous solutions of sufficiently low pH. Cyclisation to the corresponding aziridinium ions occurs in solution, as shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

“…2 for DMC, at rates that are proportional to the nonprotonated fraction. 3 The dimethylaziridinium ion (DMA) that is formed from DMC reacts only slowly with water, but such ions react relatively rapidly with other nucleophiles, including any buffer or salt anions that may be present. 4 Since reaction with chloride ion restores the original open-chain compound, the reaction is reversible when chloride is the dominant anion.…”

Section: Introductionmentioning

confidence: 99%

Determination of N,N-dimethylaminoethyl chloride and the dimethylaziridinium ion at sub-ppm levels in diltiazem hydrochloride by LC-MS with electrospray ionisation

Lee

Hubert

Dau

et al. 2000

Analyst

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An LC-MS method is described for the determination of the synthetic reagent N,N-dimethylaminoethyl chloride (DMC) in the drug substance diltiazem hydrochloride, for which the permissible limit is not more than 1 ppm (microgram g-1). The N,N-dimethylaziridinium ion (DMA), the reactive intermediate formed by cyclisation of DMC, is also detected. A column switching arrangement is used: diltiazem hydrochloride is trapped on a reversed-phase HPLC column, and the polar analytes are separated by ion exchange chromatography. Ionisation is effected by positive-ion electrospray, and the quadrupole filter mass spectrometer is operated in the selected ion recording mode. The detection limit (peak height-to-baseline noise ratio = 3) for DMC varies from day to day in the range < 0.05 to 0.1 ppm. The response for DMC is linear (r > 0.999) over the concentration range 0.2-10 ppm, and the repeatability is better than 7% (relative standard deviation) at 1.0 ppm. Concentrations of DMC in diltiazem hydrochloride from the manufacturing facility under study ranged from undetectable to about 0.07 ppm. An indirect TLC method has been published for the determination of DMC in mepyramine maleate, but it lacks the necessary sensitivity and specificity. The LC-MS method presented is direct, straightforward and suitable for routine use.

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Reaction Kinetics of Aliphatic Tertiary β-Chloroethylamines in Dilute Aqueous Solution. I. The Cyclization Process¹

Cited by 50 publications

References 0 publications

Solvolytic Displacement Reactions At Saturated Carbon Atoms

Solvolytic Displacement Reactions At Saturated Carbon Atoms

Anomalous Cross-Linking by Mechlorethamine of DNA Duplexes Containing C−C Mismatch Pairs

Determination of N,N-dimethylaminoethyl chloride and the dimethylaziridinium ion at sub-ppm levels in diltiazem hydrochloride by LC-MS with electrospray ionisation

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Reaction Kinetics of Aliphatic Tertiary β-Chloroethylamines in Dilute Aqueous Solution. I. The Cyclization Process1

Cited by 50 publications

References 0 publications

Solvolytic Displacement Reactions At Saturated Carbon Atoms

Solvolytic Displacement Reactions At Saturated Carbon Atoms

Anomalous Cross-Linking by Mechlorethamine of DNA Duplexes Containing C−C Mismatch Pairs

Determination of N,N-dimethylaminoethyl chloride and the dimethylaziridinium ion at sub-ppm levels in diltiazem hydrochloride by LC-MS with electrospray ionisation

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Reaction Kinetics of Aliphatic Tertiary β-Chloroethylamines in Dilute Aqueous Solution. I. The Cyclization Process¹