Hindered systems

Camphor cannot be protected with this reagent indicating that steric factors will prevent its use in vcr> hindered systems. 

Usually, proton transfer in acid-base equilibria is a fast process, but very hindered systems show slow kinetics. The equilibrium (equation 3) regarding 2,4-dialkylpyridines proceeds through locked-rotor and with intermediates of low entropy44. 

This parameter is widely used to describe the ionic transport by providing information on the effect of pore blockage. A tortuosity factor r = 1, therefore, describes an ideal porous laody with cylindrical and parallel pores, whereas values of r > 1 refer to more hindered systems. Higher tortuosity is good for dendrite resistance but can lead to higher separator resistance. 

Since a direct displacement process characteristic of reactions of square complexes seems unlikely, it would appear that in such sterically-hindered systems the reaction proceeds by a dissociative process similar to that found for six-coordinated... 

Sterically hindered systems - As already pointed out in Sect. 3.2, the sterically hindered ruthenium tetramesitylporphyrins Ru(TMP) or Ru(TMP)L2 (L = MeCN, N2,THF) [204,154] are useful starting materials for the synthesis of or-ganometallic compounds [209, 316]. While the reaction of Ru(N2)2(TMP) with acetylene yielded a divinylidene bridged complex, (TMP)Ru=CH-CH = Ru-(TMP), 1 1 rc-complexes were formed with phenylaacetylene, diphenyl-acetylene, ethylene, or cyclohexene [209]. Ru(CH2 = CH2)(TMP) was deposited solvent-free by evaporation from benezene and precipitated with 2-propanol as a diliganded solvate, Ru(CH2 = CH2)(TMP) i-PrOH i-PrOH. The compounds were characterized by elemental analyses and H and 13C NMR spectra. 

In the less hindered systems, it is not possible to assess the atropiso-mer distribution. 

A more sterically hindered system is exemplified by the tris-pentamethyl-cyclopenta-dienyl samarium complex obtained in the reaction [52]... 

Although species of the general formulation R-P=CR2 wherein trivalent phosphorus is bound to only two (carbon) atoms have been proposed for many years as intermediates in a variety of chemical reactions, it was not until 1978 thatastable compound of this class was isolated. This effort involved the generation of a sterically hindered system with three bulky aromatic rings bound around the P=C site (equation 9) that could reversibly add hydrogen chloride. The P NMR spectrum exhibited a signal at relatively low field in accord with the postulation of such trivalent doubly coordinated phosphorus. Approaches toward this type of species have been reviewed. ... 

Reduction of methylenecyclohexanes. Reduction of 4-t-butylmethylene-cyclohexane (1) with lithium in ethylenediamine is highly stereoselective and independent of the temperature. The result implies that the stereochemistry is controlled by the relative stability of the possible intermediate carbanions. In this case the stable one has an equatorial C—C bond. The stereochemistry of reduction of 4, however, is dependent on the temperature, with the less stable product (6) favored by a rise in temperature. Apparently the rate of protonation of the equatorial carbanion becomes a significant factor at higher temperatures. In even more hindered systems equatorial protonation can be significant, even at 35°. 

Section 2.1.1.10.2). For coupling of extremely hindered systems, such as N-protected Aib or (Me)Aib to amine-free (Me)Aib derivatives, arylsulfonic-protected amino acid chlorides proved to be the method of choice, while the corresponding acid fluorides do not react at... 

Very difficult peptide syntheses are those which contain sterically hindered C -dialkylannino adds such as Aib residues, especially if these residues are found next to each other. Due to their influence on the stabilization of helical stmcturest l in small peptides, the introduction of such amino acids is of interest. Various protocols for the coupling of hindered systems using UNCAs,t l symmetric anhydrides,t HATU,b CIP/HOAt, and PyBroPl l activation have been reported. In a comparative analysis of activation methods for the synthesis of H-Aib-Aib-Aib-Aib-OH as a model peptide which included the symmetric anhydride, PyBroP, acid fluoride, and UNCA methods, the acid fluoride technique was shown to be exceptionally well suited.t 1... 

Although alkali metal-NHs reductions are usually preferable to Na-alcohol reductions in terms of yield and convenience, the stereochemical consequences of both systems are similar, at least for all sterically hindered systems studied thus far. Illustrative examples are the reductions of bicyclo[3.3.1 ]nonan-ones (35 equation 14) and (36 equation 15). ° In both cases the equatorial alcohols (37) and (38) were obtained in excellent yield and with complete stereoselectivity. LAH reduction of ketone (35) gave only the epimeric axial alcohol, while (36) gave a mixture of (38) and its epimer. ... 

The reaction of conjugated enones and dienones with trimethyl- and triethyl-silane in the presence of TiCU, followed by aqueous work-up produces the corresponding saturated ketones. This Lewis acid catalysis is particularly useful for conjugated reduction of sterically hindered systems (Scheme 46). " a,p-Unsaturated esters are not reduced under these conditions. 

Although carboxylic acids and their derivatives are somewhat weaker carbon acids than aldehydes and ketones, it is generally possible to quantitatively convert them to the corresponding metal enolates with dialkylamide bases, the most popular of which is LDA. - - Thus, monoanions of saturated esters, lactones, nitriles, /VA -dialkylamides and V-alkyllactams and dianions of carboxylic acids and V-unsub-stituted amides and lactams are easily prepared in aprotic solvents such as THF and C-alkylated with a variety of simple and functionalized SN2-reactive alkylating agents at room temperature or below. When more-hindered systems are involved, the basicity of the metal dialkylamide and the reactivity of the metal enolate can be enhanced by the addition of HMPA. Of course, many of the indirect methods used for the generation of aldehyde and ketone enolates are also applicable to the preparation of enolates of carboxylic acid derivatives (Section 1.1.2.1). O-Alkylations or dialkylations at carbon generally are of minimal importance with metal enolates of carboxylic acid derivatives. 

Introducing the Triazole Rina. The final step of the synthesis was displacement of the carbon-bound chlorine with triazole salts. Once again, silicon made life easy for us, since it activates such hindered systems toward displacement. The corresponding all-carbon compounds react very sluggishly with triazole salts. Luckily, silicon-carbon bond cleavage is not observed, provided water or other oxygen nucleophiles are excluded. The displacement reaction is illustrated in Equation 5 for DPX-H6573. 

Methoxyethyl ether (diglyme) is the solvent of choice for more hindered systems or for the preparation of unconjugated dienes. For tertiary alcohols, heating is also required. t-BuOK has also been used successfully as the base. ... 

The kinetics of the rotation about the C—N bond in hindered systems have been studied by Mannschreck and Klle. AG values evaluated from the H-NMR methyl signals (see Table 8) indicate that the rate of rotation in enamines 31-35 depends upon the electron-attracting properties of the substituents. In 36 and 37 the benzo ring reduces the rotational barriers by 9.7-12.5 kj mol as compared to 38 and 39. A formyl group raises the free energies of activation by 13.3-17.9 kJ mol , as can be seen in the table by comparing 36 to 37,38 to 39 and 39 to 40. If one of the N-methyl groups is replaced by another substituent, rotational isomers are possible. It will be difficult to separate such isomers in systems like 40 or 41, since the AG values for the isomerization are expected to be only 84.4 or 89.9 kJ mol ... 

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