In order to sever the nitrogen function from the molecule, a second Hofmann elimination must be carried out. Example #1 is interesting in two respects. Legal. a Key: (a, b) ring-opening Hofmann β-elimination and (c, d) ring-opening substitution. It seems that a combination of these factors acts to favor base attack at the least substituted (least hindered and most acidic) set of beta-hydrogens. At the other extreme, if the acidity of the beta-hydrogens is enhanced, then substantial breaking of C–H may occur before the other bonds begin to be affected. Thus, if 2-amino-1-phenylpropane is treated in the manner of example #3, the product consists largely of 1-phenylpropene (E & Z-isomers). 17. A concentrated aqueous solution of the halide salt is simply dropped into a refluxing sodium hydroxide solution, and the volatile hydrocarbon product is isolated by distillation. First, it generates a 4º-ammonium halide salt in a manner different from exhaustive methylation. In this context, the anion-exchange membrane fuel cell (AEMFC) has emerged as a viable alternative to the proton-exchange membrane fuel cell (PEMFC), which has been extensively developed over the last decade. Three additional examples of the Hofmann elimination are shown in the following diagram. In cases where other activating groups, such as phenyl or carbonyl, are present, the Hofmann Rule may not apply. In example #2 above, two of the alkyl substituents on nitrogen have beta-hydrogens, all of which are on methyl groups (colored orange & magenta). In cases where other activating groups, such as phenyl or carbonyl, are present, the Hofmann Rule may not apply. Several puckered conformations that avoid angle strain are possible, and one of the most stable of these is shown on the right. More bonds are being broken and formed, with the possibility of a continuum of states in which the extent of C–H and C–X bond-breaking and C=C bond-making varies. 20.8: The Hofmann Elimination: Amines as Leaving Groups, 20.9: Oxidation of Amines - The Cope Elimination. When the leaving group X carries a positive charge, as do the 4º-ammonium compounds discussed here, the inductive influence of this charge will increase the acidity of both the alpha and the beta-hydrogens. Example #3 is noteworthy because the less stable trans-cyclooctene is the chief product, accompanied by the cis-isomer. Hofmann elimination is an elimination reaction of an amine where the least stable (least substituted) alkene, the Hofmann product, is formed. The cis-cyclooctene produced in this reaction could also be formed by a syn-elimination. Mechanism: Stage 1: Stage 2: Stage 3: Stage 3 is a 1,2-elimination via E1cB mechanism. It seems that a combination of these factors acts to favor base attack at the least substituted (least hindered and most acidic) set of beta-hydrogens. Cyclooctane is a conformationally complex structure. eg: Watch the recordings here on Youtube! Hofmann Elimination. The resulting hydroxide salt must then be heated (100 - 200 ºC) to effect the E2-like elimination of a 3º-amine. Second, this salt is not converted to its hydroxide analog prior to elimination. Missed the LibreFest? The cis-cyclooctene produced in this reaction could also be formed by a syn-elimination. 1-methylmorpholinium via ring opening by both Hofmann elimination and substitution reactions, while no degradation was detected by1H NMR spectroscopy of other cations after 16 days in 1 M NaOH at 90 C. The hydroxide ion conductivity of the AEMs in the study reached values between 64 and Missed the LibreFest? When a given alkyl group has two different sets of beta-hydrogens available to the elimination process (colored orange & magenta here), the major product is often the alkene isomer having the less substituted double bond. Hofmann elimination is regioselective. Draw the product for a Hoffman elimination for each of the following molecules. This tendency, known as the Hofmann alkene synthesis rule, is in contrast to usual elimination reactions, where Zaitsev's rule predicts the formation of the most stable alkene. Since the 1,2-elimination in Stage 3 occurs via E1cB mechanism, Hofmann rule is used to predict the major product. Have questions or comments? Simple amines are easily converted to the necessary 4º-ammonium salts by exhaustive alkylation, usually with methyl iodide (methyl has no beta-hydrogens and cannot compete in the elimination reaction). Cyclooctane is a conformationally complex structure. The favored anti orientation of the leaving group and beta-hydrogen, noted for dehydrohalogenation, is found for many Hofmann eliminations; but syn-elimination is also common, possibly because the attraction of opposite charges orients the hydroxide base near the 4º-ammonium leaving group. To understand why the base-induced elimination of 4º-ammonium salts behaves differently from that of alkyl halides it is necessary to reexamine the nature of the E2 transition state, first described for dehydrohalogenation. Furthermore, the 4º-ammonium substituent is much larger than a halide or hydroxyl group and may perturb the conformations available to substituted beta-carbons. Since the trimethylammonium substituent is large (about the size of tert-butyl) it will probably assume an equatorial-like orientation to avoid steric crowding. We also acknowledge previous National Science Foundation support under grant numbers 1246120, 1525057, and 1413739. The resulting hydroxide salt must then be heated (100 - 200 ºC) to effect the E2-like elimination of a 3º-amine.