Arbeitsgruppe Hartung


E) Structural Chemistry

Aspects of Structural Thiohydroxamate Chemistry – On a Systematic in the 5-(p-Methoxyphenyl)-4-methylthiazole-2(3H)-thione Series

Keywords: Heterocycle; Lithium thiohydroxamate; Pyridinethione; Steric substituent effect; Taft-Dubois parameter; Thiazolethione; Thiohydroxamic acid; X-ray crystallography.


Summary: Bond angles at thiohydroxamate oxygen in crystal structures of 3-alkoxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thiones gradually increases with the size of the 3-alkoxy substituent. This effect is attributed to strain on the basis of (i) a linear free energy relationship (Taft-Dubois correlation) and (ii) a notable barrier for topomerization of the cumyl group by rotation about the nitrogen oxygen bond (DNMR). Changing substitution at thiohydroxamate oxygen from OR (R = prim, sec, and tert-alkyl), OH, to OLi is structurally reflected in a gradual lengthening of the N,O distances and a simulatanous shortening of the thiocarbonyl bond length. This responsivity is significantly more pronounced in the thiazole-2(3H)-thione- than in the pyridine-2(1H)-thione series.


Introduction and outline: Structural thiohydroxamate chemistry so far is dominated by studies on transition metal complexes. Considerably less is known about thiohydroxamic acid solid state chemistry and systematics within series of O-alkyl- (esters) and O-acyl-derivatives (mixed anhydrides). This lack in structural information makes it difficult to convincingly answer long standing questions on experimental difficultities in preparing tertiary O-esters, and understanding changes in alkylation selectivity for 1,3-thiazole- and pyridine-derived thiohydroxamates, although major aspects of this chemistry in the fields of biocides, organic reagents, and radical reactions, have been pursued for decades.

Based on recent progress in the synthesis of primary, secondary, and even tertiary O-esters of the cyclic thiohydroxamic acid 3-hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione (1a), structural thiohydroxamate chemistry began to attract our attention. The compounds (e.g. 1bf) nowadays are standard reagents for generating alkoxyl radicals in chain reactions proceeding under pH neutral non oxidative conditions. Alkali salts (e.g. 2) of acid 1a form non hygoscopic crystalline solids serving as reagents for preparing O-acyl derivatives (e.g. 1g). The latter compounds pose attractive new carbon radical progenitors, to be stored and applied on demand.

The present study dealing with solid state chemistry of N-oxy-substituted thiazole-2(3H)-thiones (12) and their more prominent pyridine-2(1H)-thione congeners (e.g. 34) shows that steric effects exerted by O-alkyl groups widen N–O–R angles. Varying substitution at oxygen along the sequence OR (R = prim, sec, tert-alkyl), OH, and OLi gradually lengthens N,O-bonds, while thiohydromamate C,S distances shorten along the same sequence. The exocyclic C,S-bond is close to the reference value for a double bond in chelated N-(hydroxy)-thiazole-2(3H)-thione-derived lithium salt 2B, but almost a single bond in pyridine-2(1H)-thione analogue 3. Theses systematics are summarized and discussed in the following sections.

Figure 1. Structural formulae and indexing of cyclic thiohydroxamates 14 (An = p-MeOC6H4).


Figure 1. Proton NMR-spectra (stacking plot, deuterochloroform) of 3-cumyloxythiazolethione 1f in the temperature range of –47 to +58 °C showing coalescence of cumyl CH3-signals at 5 °C (left) and shifting of 4-CH3 signal (right).

Figure 2. Ellipsoid graphics (50 % probability level) of 3-(alkoxy)thiazolethiones 1b–f. Hydrogen atoms are drawn as circles of an arbitrary radius.

Figure 3. Ellipsoid graphics (50 % probability level) of lithium 5-(4-methoxyphenyl)-4-methyl-2-thiooxo-2,3-dihydrothiazole-3-olate monohydrate (2) × H2O. Hydrogen atoms are drawn as circles of an arbitrary radius.

Figure 4. Correlation of N3–O1–C14 angles and Taft-Dubois-parameter ES’ [kJ mol–1] (correlation coefficient r = 0.98). a ES’ for the cumyl group was approximated with the value for the tert-butyl substituent.

Figure 5. Correlation of N3–O1 and C2–C2 distances of thiazolethiones 1a [N3–O1 = 1.373(3) Å, C2–S2 = 1.676(3) Å at 299(2) K], 1b1f, and N-benzoyl-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione [1g: N3–O1 = 1.389(2) Å, C2–S2 = 1.662(2) Å at 100(2) K]  (dN3–O1 = –0.66 dC2–S2 + 2.5 Å; r = 0.87).

Figure 6. Ellipsoid graphics (50 % probability level) of lithium 2-thiooxo-1,2-dihydropyridine-1-olate monohydrate (3) [100(2) K, symmetry code for O2*: x, -y+1/2, z]. Hydrogen atoms are drawn as circles of an arbitrary radius. Selected bond lengths [Å]: C2–S1 = 1.723(3), N1–O1 = 1.360(3), N1–C2 = 1.371(4), C2–C3 = 1.416(4), C3–C4 = 1.376(4), C4–C5 = 1.399(4), C5–C6 = 1.367(4), C6–N1 = 1.365(4). Selected angles [°]: N1–O1–Li1 = 121.2(2), C2–N1–O1 = 120.3(2), C6–N1–O1 = 117.1(2), S1–C2–N1 = 120.1(2), S1–C2–C3 = 123.4(2), N1–C2–C3 = 116.6(3), C2–C3–C4 = 121.4(3), C3–C4–C5 = 119.6(3), C4–C5–C6 = 119.1(3), C5–C6–N1 = 120.8(3), C6–N1–C2 = 122.6(3), C2–N1–O1–Li1 = 0.0(2).

Figure 7. Correlation of N1–O1 and C2–S1 distances of lithium 2-thiooxo-1,2-dihydropyridine-1-olate monohydrate (3) (Figure 4), 1-hydroxypyridinethione 4 [N1–O1 = 1.377(3) Å, C2–S1 = 1.684(2) Å at 297(2) K], N-[4-trans-(tert-butylcyclohexyl-1-oxy)]pyridine-2(1H)-thione (5) [N1–O1 = 1.384(4) Å, C2–S1 = 1.666(4) Å at 297(2) K], and N-[4-trans-(tert-butylcyclohexyl-1-carbonyloxy)]pyridine-2(1H)-thione (6) [N1–O1 = 1.392(5) Å, C2–S1 = 1.662(6) Å at 300(2) K] (dN1–O1 = –0.48 dC2–S1 + 2.2 Å; r = 0.98).


Concluding remarks: The pursuit of structural chemistry in the series of 3-alkoxy-5-(p-methoxyphenyl)-4-methylthiazolethiones 1bf, acid 1a, lithium salt 2 and N-hydroxypyridinethione lithium sald 3 provides three distinctive results.

(i) Bond angles at thiohydroxamate oxygen gradually increases along the series of substituents CH3 (1b) via primary alkyl (e.g. 1cd), secondary alkyl (1e) to tertiary alkyl (1f). The magnitude of angle widening correlates with Taft-Dubois parameter of associated ester substituents thus pointing to strain as major inductor for the observed effects.

(ii) In a set of 3-hydroxy-, 3-alkoxy- and 3-benzoyloxy-substituted compounds 1ag and lithium salt 2, N,O- and C,S-bond lengths are inversely correlated. The stronger gradient of the N,O/C,S-relationships upon substitution at exocyclic oxygen points to stronger structural responsivity of N-oxy-substituted thiazole-2(3H)-thiones upon substitution at oxygen than in the pyridine-2(1H)-thione series. This aspect is possibly is the key to facilitate O-alkylation with sterically demanding, e.g., tertiary substitutents in thiazole-2(3H)-derived thiohydroxamates.

(iii) Exocyclic C,S-bonds are in line with a double bond for the lithium salt of a 3-hydroxythiazole-2(3H)-thione (compound 2) and for a single bond in the lithium salt of 1-hydroxypyridine-2(1H)-thione (compound 3). If interpreted in terms of charge distribution, this picture correlated with the selectivity for alkylation at oxygen in thiazolethione-derived thiohydroxamate salts, whereas alkylation of pyridinethione congeners occur to significant extend also at sulfur.



Prof. Dr. Hartmut Fuess, TU Darmstadt.


Leading Reference:

Aspects of Structural Thiohydroxamate Chemistry – On a Systematic in the 5-(p-Methoxyphenyl)-4-methylthiazole-2(3H)-thione Series. J. Hartung, U. Bergsträsser, K. Daniel, N. Schneiders, I. Svoboda, H. Fuess, Tetrahedron 2009, 65, 2567–2573.



Deutsche Forschungsgemeinschaft.

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