Bases sterically hindered

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

LDA (Section 21.10) Abbreviation for lithium diisopropyl-amide LiN[CH(CH3)2]. LDA is a strong, sterically hindered base, used to convert esters to their enolates. 

Sterically hindered bases may greatly favor one enolate over the other. See, for example, Prieto, J.A. Suarez, J. Larson, G.L. Synth. Commun., 1988, 18, 253 Gaudemar, M. Bellassoued, M. Tetrahedron Lett., 1989, 30, 2779. 

Consider the elimination reaction below, which uses a strong, sterically hindered base (LDA). The product will be a double bond. This reaction will produce the Hoffmann product. Draw this product. 

In this case, the Hofmann product is the major product, because a sterically hindered base was used. This case illustrates an important concept The regiochemical outcome of an E2 reaction can often be controlled by carefully choosing the base. Below are two examples of sterically hindered bases that will be encountered frequently throughout your organic chemistry course ... 

ANSWER Let s first consider the expected regiochetnical outcome of the reaction. The reaction does not employ a sterically hindered base, so we expect formation of the more substituted alkene (the Zaitsev product) ... 

The Zaitsev product is generally favored over the Hofmann product, unless a sterically hindered base is used, in which case the Hofmann product will be favored. 

For the regiochemical outcome, we expect the Zaitsev product to be the major product, because the reaction does not utilize a sterically hindered base ... 

We can control which product we get by carefully choosing our base. If we use a strong base (like methoxide or ethoxide), then we will get the more substituted alkene. However, if we use a strong, sterically hindered base, such as tert-butoxide, then we will get the less substituted alkene. 

After we have converted the OH into a tosylate, then we can do our technique (using a strong, sterically hindered base to eliminate, followed by anti-Markovnikov addition of H and OH) ... 

We have also shown ( 8) that other bases stronger than CH-CX) (pK. 4.75) catalyse the decomposition of N -nitroso-2-pyrrolidone at o C. With the exception of imidazole, these reactions follow uncomplicated second order kinetics (Rate = kp[Substrate][Base]) and only products of deamination (hydrolysisT are obtained. Generally, values increase with the base strength of the catalyst and fit tne Br/e(nsted relationship withes 0.66. However, the absence of significant catalysis by sterically hindered bases 2,6-lutidine), the strong catalysis by imidazole relative to HPOi (k2(Imidazole)/k2(HP0J ) = 83) and by hydroxide ion relative to... 

Iron The air-stable [t-oxo dimer (54) was prepared by reacting 50 with anhydrous Fe(OAc)2 in sterically hindered base, 2,4,6-trimethylpyridine (113). The dimeric form of the pz was confirmed by IR. An intense band at 803.5 cm4, which is diagnostic for the Fe-O-Fe stretch, was observed (15). A broad UV-vis spectrum, which indicates ji-ji stacking (further evidence of the J.-oxo dimer) was also observed (80). Addition of HC1 converted the dimer to the monomer, FclnCI pz(.V-Et)8 (55) which was structurally characterized and found to have analogous parameters to Mnm[pz(A4)] A = dkS -ethyl (52). 

In the case of protonated pyrroles, the p Ta value lies in the range between 4 and —4, whereas the pATa value of acetonitrile is about —10. Therefore, the oligomerization of pyrrole in pure acetonitrile may already stop at the level of a-intermediates of hi- or more likely of tetrapyrrole. Acetonitrile is a weaker base than the a-intermediates. Consequently, a stronger base must be used to initiate the elimination of protons. Water fulfills this condition. Pyrrole can be polymerized in acetonitrile in the presence of 1% water [6, 37]. A similar effect results from the application of a sterically hindered base such as 2,6-di-tert-butylpyridine [38]. However, the concentration should be kept low because, at high concentrations proton, abstraction from the monomeric radical cation may occur, thus forming a neutral radical [28d]. The base effect can be also observed in the case of thiophenes. 

The sterically hindered base 2,6-bis(tert-butyl)pyridine does not inhibit cyclization triaryl-amine retards this reaction photosensibilized one-electron oxidation of a diene leads to the same products, which are formed in the presence of ammoniumyl salt. As shown, in majority of cases, only the cation-radical chain mechanism of the diene-diene cyclization is feasible (Bauld et al. 1987). Meanwhile, cyclodimerizations of 2,4-dimethylpenta-l,3-diene (Gassman and Singleton 1984) and l,4-dimethylcyclohexa-l,3- or -1,4-diene (Davies et al. 1985) proceed through both mechanisms. 

With heterocycles containing an sp--nitrogen atom, a totally different problem can occur, namely nucleophilic addition of the base to the azo-methine (C=N) bond. The use of very sterically hindered bases such as lithium tetramethylpiperidide (LiTMP) can prevent this type of addition in certain cases, but bases of this sort tend to be expensive and not suitable for general use. However, two different approaches to overcoming the problem of azomethine addition have been developed over the years, both relying on the fact that the addition is temperature dependent, and that by enabling metalation reactions to be performed at low temperatures, the desired carbanion formation can often be achieved. 

Kinetic control can be achieved by slow addition of the ketone to an excess of strong base in an aprotic solvent. Kinetic control requires a rapid, quantitative and irreversible deprotonation reaction 2-6. The use of a very strong, sterically hindered base, such as lithium diisopropylamide or triphenylmethyllithium (trityllithium), at low temperature (— 78 °C) in an aprotic solvent in the absence of excess ketone has become a general tool for kinetic control in selective enolate formation. It is important to note that the nature of the counterion is sometimes important for the regioselectivity. Thus, lithium is usually better than sodium and potassium for the selective generation of enolates by kinetic control. 

Trifluoroacetyl triflate is probably the most powerful trifluoro-acetylating agent known, as evidenced by its reactivity toward several types of nucleophiles under mild conditions. A sterically hindered base, 2,6-di-... 

Notes Strong, sterically-hindered base, soluble in THF, ether, and toluene. The Li and K analogs are also available. The reagent also can act as a nucleophile under certain conditions. 

Two different methods were used to selectively reduce the surface activity of Y zeolites i) the action of a steric hindered base such as phenan-thridine and ii) the chemical vapour deposition of alkoxysilane (ref. 20). 

Deoxygenation ofketones. Enol triflates, readily available by reaction of ketones and triflic anhydride catalyzed by this sterically hindered base, undergo rapid hydrogenolysis to the saturated hydrocarbon. Overall yields are 65-90%. ... 

A regioselective and highly syn-stereoselective catalyst-free intermolecular alkylation of aryl borates with aryl epoxides under mild, neutral conditions has been reported.27 The reaction of /ra .s-stilbene oxide with tri(3,5-dimethylphenyl)borate gave a 38% yield (>95% syn) of the C-alkylated product (13), easily separated from (g) the O-alkylated product(s). Triflic anhydride has been used to activate enones to nucleophilic attack by electron-rich arenes in the presence of a sterically hindered base.28 Resorcinol dimethyl ether, for example, reacted with cyclohex-2-en-l-one to... 

So, if we look back at the reaction above, we find that the two possible products are monosubstituted and disubstituted double bonds. Whenever you have an elimination reaction where more them one possible double bond can be formed, we have names for the different products based on which one is more substituted and w hich one is less substituted. The more substituted product is called the Zaitsev product, and the less substituted product is called the Hoffmann product. Usually you get the Zaitsev product, but under special circumstances you can get the Hoffman product. If you use a strong, sterically hindered base, you can form the Hoffman product. 

PROBLEM 10.28 Search through your textbook, find the section that covers formation of Hoffmann products, and then draw the structures of the sterically hindered bases that your textbook show s you. 

Stereochemistry = if there are cis/trans isomers, you will get the one determined by the H and LG being antiperiplanar (draw Newman projections) Regiochemistry = form the more substituted double bond (Zaitsev product). If you are using a strong, sterically hindered base, then form the less substituted double bond (Hoffmann product)... 

The absence of scatter in a Bronsted plot for a general base-catalysed reaction can imply that the reaction mechanism involves a rate-limiting proton transfer step. This is because proton transfer to the base in the reaction is closely similar to the equilibrium proton transfer to the base in the reaction which defines the p Ka of the conjugate acid of that base. The observation of scatter, especially for sterically hindered bases (such as 2,6-dimethylpyridine), is evidence that nucleophilic catalysis is operating as opposed to general base catalysis. 

The use of sterically hindered bases raises the activation energy barrier for the pathway to the product predicted by Saytzeffs Rule. Thus, a sterically hindered base will preferentially react with the least hindered protons, and the product distribution will be controlled by kinetics. 

An attempt to generate an amino-aryl carbene 154 from the alkylated phenanthridinium salt 153 (Equation 78) <2006TL531> was unsuccessful due to steric interactions. The actual reaction with a variety of strong, sterically hindered bases/nucleophiles is shown (Equations 79-81). The mesityllithium products proved that a carbene intermediate is not possible. Unlike /-butyl alcohol and hexamethyldisilazane, trimethylbenzene, the conjugate acid of mesityllithium, is not prone to carbene insertion reactions. Electronically this is explained by the planar nature of 153 which serves to lower the lowest unoccupied molecular orbital (LUMO) energy of the iminium moiety. 

The sterically hindered base ferf-BuO reacts with tert-amyl bromide in a different manner than EtO and in such a way that steric interactions are minimized (Figure 4.21). This makes the substructure C. —H a more suitable point of reaction than the substructure C —... 

Fig. 4. 22. Saytzeff product is produced preferentially although not exclusively. The reaction of the sterically hindered base tBuO is directed preferentially toward the more readily accessible H atoms at the primary C atom. Therefore, it mainly provides the Hofmann product.

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