Hofmann rule

The least sterically hindered p hydrogen is removed by the base m Hofmann elim matron reactions Methyl groups are deprotonated m preference to methylene groups and methylene groups are deprotonated m preference to methmes The regioselectivity of Hofmann elimination is opposite to that predicted by the Zaitsev rule (Section 5 10) Elimination reactions of alkyltrimethylammonmm hydroxides are said to obey the Hofmann rule, they yield the less substituted alkene... 

The amino functional group is not commonly encountered in steroid synthesis except perhaps in steroidal alkaloids. However, certain elimination reactions have been shown to have theoretical and limited preparative importance, largely due to the efforts of McKenna and co-workers. The Hofmann rule for 2 elimination predicts that alkaline elimination of quaternary ammonium salts will occur towards the carbon carrying the most hydrogen atoms cf. the converse Saytzeff orientation, above). In cyclohexyl systems, the requirement for diaxial elimination appears to be important, as in other 2 eliminations, and the Hofmann rule frequently is not obeyed [e.g., (116) (117)]. 

According to the Woodw ard-Hofmann rules the concerted thermal [2n + 2n] cycloaddition reaction of alkenes 1 in a suprafacial manner is symmetry-forbidden, and is observed in special cases only. In contrast the photochemical [2n + 2n cycloaddition is symmetry-allowed, and is a useful method for the synthesis of cyclobutane derivatives 2. 

An explanation for the finding that concerted [4 -I- 2] cycloadditions take place thermally, while concerted [2 + 2] cycloadditions occur under photochemical conditions, is given through the principle of conservation of orbital symmetry. According to the Woodw ard-Hofmann rules derived thereof, a concerted, pericyclic [4 -I- 2] cycloaddition reaction from the ground state is symmetry-allowed. 

For the formation of the new double bond, the general rules for eliminations do apply. Following Bredt s rule, no double bond to a bridgehead carbon atom will be formed. If the elimination can lead to a conjugated system of unsaturated groups, this pathway will be favored. Otherwise the Hofmann rule will be followed, which favors an elimination towards the less substituted carbon center. 

With substrates, where a /3-hydrogen as well as a /3 -hydrogen is available for elimination, product formation follows the so-called Hofmann rule, which states... 

The photochemical cycloaddition of a carbonyl compound 1 to an alkene 2 to yield an oxetane 3, is called the Patemo-Buchi reaction - This reaction belongs to the more general class of photochemical [2 + 2]-cycloadditions, and is just as these, according to the Woodward-Hofmann rules, photochemically a symmetry-allowed process, and thermally a symmetry-forbidden process. 

If more than one /3-hydrogen in the quaternary ion is present, the Hofmann rule states that in the /3-elimination predominance is given to the least substituted ethylene. 

In cyclic systems, the usual simple requirements of Saytzev or Hofmann rules may be overridden by other special requirements of the system, e.g. the preference for elimination from the truns-diaxial conformation in cyclohexane derivatives (cf. p. 255). Another such limitation is that it is not normally possible to effect an elimination so as to introduce a double bond on a bridgehead carbon atom in a fused ring system (Bredt s rule), e.g. (47) (48) ... 

The problem of competition of the molecular reaction (direct route) and chain reaction (complicated, multistage route) was firstly considered in the monograph by Semenov [1], The new aspect of this problem appeared recently because the quantum chemistry formulated the rule of conservation of orbital symmetry in chemical and photochemical reactions (Woodward-Hofmann rule [4]). Very often the structure of initial reactants suggests their direct interaction to form the same final products, which are also obtained in the chain reaction, and the thermodynamics does not forbid the reaction with AG < 0. However, the experiment often shows that many reactions of this type occur in a complicated manner through several intermediate stages. For example, the reaction... 

Hofmann Rule Form the least-substituted alkene... 

The primary products obtained from 2-butanol are of mechanistic. significance and may be compared with other eliminations in the sec-butyl system 87). The direction of elimination does not follow the Hofmann rule 88) nor is it governed by statistical factors. The latter would predict 60% 1-butene and 40% 2-butene. The greater amount of 2-alkene and especially the unusual predominance of the cis-olefin over the trans isomer rules out a concerted cis elimination, in which steric factors invariably hinder the formation of cis-olefin. For example, the following ratios oicisjtrans 2-butene are obtained on pyrolysis of 2-butyl compounds acetate, 0.53 89, 90) xanthate, 0.45 (S7) and amine oxide, 0.57 86) whereas dehydration of 2-butanol over the alkali-free alumina (P) gave a cisjtrans ratio of 4.3 (Fig. 3). 

HISTIDINOL-PHOSPHATE PHOSPHATASE HISTIDYL-tRNA SYNTHETASE HISTONE KINASE Hofmann rule,... 

The olefins formed under these conditions using other tertiary alcohols tend to follow the Hofmann rule [6a]. However, tertiary alcohols and phenols [6b] can be made to react with isocyanates to give urethanes when they are catalyzed by acids or bases such as pyridine [6b], triethylamine, sodium acetate, boron trifluoride etherate, hydrogen chloride, or aluminum chloride [7]. Table I indicates the results of preparing phenylurethanes of tertiary alcohols... 

Hofmann Rule Elimination from quaternary ammonium and tertiary sulfonium salts generally provides the lesser-substituted alkene as major product. 

With tertiary halides, bimolecular elimination usually occurs if isomeric alkenes can result, the proportions formed depend on the steric requirements of the pyridine because formation of the more substituted alkene (Saytsev Rule) is more sensitive to steric hindrance than formation of the less substituted alkene (Hofmann Rule). Pyridine and r-amyl bromide give 25% of 2-methylbut-l-ene (less... 

HOFMANN RULE. When a quaternary ammonium hydroxide containing different primary alkyl radicals is decomposed, the leasl-substituted olelin is formed preferentially. 

The reaction has been extensively used for the determination of the structure of naturally occurring bases (e.g. the alkaloids). However it has rather limited preparative value, even though the elimination reaction occurs without any rearrangement of the carbon skeleton, and the regioisomer which predominates in the product is the less highly substituted alkene (Hofmann rule contrast the Saytzeff rule). Such alkenes are now more usually prepared by other procedures noted below. 

Sometimes referred to as the Hofmann Degradation. This elimination reaction of alkyl trimethyl amines proceeds with anti-stereochemistry, and is generally suitable for producing alkenes with one or two substituents. The reaction follows the Hofmann Rule. 

Ester Pyrolysis also obeys this preference, and the Hofmann Rule is generally followed whenever a reaction passes through a cyclic transition state. 

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