Tetrazoles ionization

Unsubstituted tetrazole behaves as an organic acid with acidity close to that of acetic acid. In general, depending on the substituent in position 5, tetrazole ionization occurs in the range from —0.8 unit of the Hq scale to 7 unit of the pH scale. Proton elimination from 1H- and 277-tetrazoles 24 and 106 results in formation of the tetrazolate anion (tetrazolide) 7 (Scheme 5) characterized by high aromaticity and good Jt-electron delocalization. 

It has been suggested that imidazole, 1,3,4-triazole, and tetrazole are ionized in the solid state (cf. 13). However, a careful assessment of X-ray, dipole moment, and ultraviolet spectral evidence by Zimmerman led to the conclusion that imidazoles are associated but not ionized. The same author has also interpreted the infrared spectra of... 

Substituted tetrazoles reacting in the mass spectrometer with acyl ions afforded 2,5-disubstituted 1,3,4-oxadiazoles with nitrogen loss. Tandem mass spectrometry allowed for the collision-induced dissociation of the products. Chemical ionization was the better method to make the transformation. A scheme for the transformation of 5-substituted tetrazoles into 2,5-disubstituted 1,3,4-oxadiazoles was proposed (Scheme 1) <2001JMP1069>. The fragmentation patterns of monocyclic l,3,4-oxadiazolium-2-thiolates have been proposed by Ollis and Ramsden <1974J(P1)645>. 

Soreq [41] has developed a nitrogen-rich (31% by weight) N-based ionization detector liquid scintillator based on di-methyl-tetrazole that is resonance sensitive (24% efficient for resonant photons) and is well suited for the explosive detection application. 

Acid-like includes carboxylic acid, tetrazole, sulphonamide (ionizable NH) etc. Amide like includes (substituted) amide. Tetrazole, sulfonamide, etc. Ester-like includes tertiary amide (substituted, no NH) ureas, urethane, sulfonamide, etc. 

Besides pyrazoles and imidazoles, we have extended these studies to other azoles, for instance to C-halogeno 1/7-1, , 4-triazoles 60 (X = Cl, Br) [73] (for DFT studies of other C-substituted 1,2,4-triazoles, see [74]) and to 5-substituted tetrazoles 61 (X = H, CH3, t-Bu, C6H5, Cl, CF3, N02) [75], The 1,2,4-triazole series 60 was examined regarding tautomerism in solution and in the solid state (the most stable is 60a and the least stable 60c). The paper on 5-substituted tetrazoles 61 concerns, besides tautomerism, their ionization (proton loss) to tetrazolate anion 62. 

Reference data on total energies of forms 19-23 optimized by means of different theoretical methods in the gas phase are given in Table 2. Various energetic characteristics of tetrazoles can be successfully estimated. The vertical adiabatic ionization potentials of both neutral tautomers 20 and 21 were calculated for a- and Tt-radical cations <2000CPL(330)212>. The standard molar thermodynamic functions (enthalpies, heat capacities, and entropies) of... 

Acylation with the acylium ion in the gas phase. An unusual experiment was performed by Seldes et aL <20010MS1069>. The N2-tautomeric form of a 5-substituted tetrazole was reacted in the gas phase with an acyl ion generated as the secondary reactive chemical by ionization plasma in a mass spectrometer. It was suggested that the mechanism of this process involved the formation of an acylated tetrazole intermediate, which could not be isolated in a condensed phase, and by rearrangement with nitrogen loss afforded an oxadiazole <20010MS1069> (cf. Section 6.07.5.2.2, Equation 16). This experiment has no preparative value but provides important information on the interaction mechanism between the neutral N-unsubstituted tetrazoles and electrophilic agents in the gas phase. 

N5 has a vertical ionization potential of 5.6 eV [5,11]. Nj dissociates into N3 and N2 with a barrier of 27 kcal/mol [5,7]. Tetrazolate anion, the CH derivative, is experimentally well known and has a lower vertical ionization potential (4.5 eV [11]). However, since the previous chapters have shown that substitution by less electronegative elements can increase the electron affinity, we will consider P and CO derivatives. Substitution of O for N results in cyclic N40. N40, N4P, and two possible CN30 isomers are not yet known and we will investigate if they have better properties. 

I.P. stands for ionization potential italic characters denote dipole moments measured in gas phase (imidazole, 1,2,4-triazole and tetrazole) and for the two last compounds (value below the first one) also in 1,4-dioxane solution electron densities are from (03MI)... 

Acidic ionizable center (negatively charged at physiological pH of about 7) (e.g., carboxylic acid, unsubstituted tetrazole, acyl sulfonamide)... 

The substitution of the Mi l side chain and the presence of the 2-methyl-l,3,4-thiodiazole-5-thiole (MTD) side ring in position 3 of the cephem nucleus of cefotiam, cefonicid and cefazolin (Figure 3) induces weaker but similar effects to those caused by the M i l side ring. It appears that the ionization of the N-dim-ethylaminoethyl group attached to the N-methyl-tetrazole-thiol (NMTT) side chain of cefotiam enhances its secretory transport in kidney epitheUal cells [64]. 

Double trapping. Normally, adducts obtained from trapping of ionized acetonides with MesSiCN have little synthetic value. However, the observation that further reaction of the cyano group with an internal azide to form a tetrazole unit is worth attention. 

A particularly novel isosteric replacement for the carboxyl group is the tetrazole ring, whose acidity is only somewhat less than most carboxylic acids (pKa 4.9 vs. 4.0-4.4). The ionization and resonance forms of both functional groups are depicted below. 

Photoelectron spectroscopy was applied to study the azide-tetrazole equilibrium of (1). The observed bands were correlated with calculated (MNDO) ionization potentials <81MI 815-01, 82MI 815-01,90ZN(B)59>. Measurements carried out at different temperatures revealed that the equilibrium is clearly shifted to the azide with higher temperatures. 

Substitution of tetrazol-5-one for the thiophene ring in sufentanil results in a decrease in potency ( 25 times that of morphine) and a decrease in the pKa of the resultant compound, alfentanil (Table 24.4). The lower pKa of alfentanil results in a lower percentage of the drug existing in the ionized form at physiological pH. Being more un-ionized, alfentanil penetrates the blood-brain barrier faster than other fentanyl derivatives and has a faster onset and shorter duration of action. Alfentanil is 99% metabolized in the liver and has a half-life of only 1.3 hours. Alfentanil is available as an intravenous dosage form for use in ultrashort anesthetic procedures. 

---