Example #2 illustrates an important aspect of the Hofmann elimination. If the nitrogen atom is part of a ring, then a single application of this elimination procedure does not remove the nitrogen as a separate 3º-amine product. In order to sever the nitrogen function from the molecule, a second Hofmann elimination must be carried out. Indeed, if the nitrogen atom was a member of two rings (fused or spiro), then three repetitions of the Hofmann elimination would be required to sever the nitrogen from the remaining molecular framework.
Example #3 is noteworthy because the less stable trans-cyclooctene is the chief product, accompanied by the cis-isomer. An anti-E2-transition state would necessarily give the cis-cycloalkene, so the trans-isomer must be generated by a syn-elimination. The cis-cyclooctene produced in this reaction could also be formed by a syn-elimination. Cyclooctane is a conformationally complex structure. Several puckered conformations that avoid angle strain are possible, and one of the most stable of these is shown on the right. Some eclipsed bonds occur in all these conformers, and transannular hydrogen crowding is unavoidable. Since the trimethylammonium substituent is large (about the size of tert-butyl) it will probably assume an equatorial-like orientation to avoid steric crowding. An anti-E2 transition state is likely to require an axial-like orientation of this bulky group, making this an unfavorable path.
In comparing the chemistry of the amines with alcohols and ethers, we discover many classes of related compounds in which nitrogen assumes higher oxidation states, in contrast to limited oxidation states of oxygen. In this context, keep in mind that the oxidation state of elemental oxygen (O2) and nitrogen (N2) is defined as zero.
The most prevalent state of covalently bonded oxygen is -2. This is the case for water, alcohols, ethers and carbonyl compounds. The only common higher oxidation state (-1) is found in the peroxides, R–O–O–R, where R=hydrogen, alkyl, aryl or acyl. Because of the low covalent bond energy of the peroxide bond (ca.35 kcal/mole), these compounds are widely used as free radical initiators, and are sometimes dangerously explosive in their reactivity (e.g. triacetone triperoxide used by terrorist bombers).
Nitrogen compounds, on the other hand, encompass oxidation states of nitrogen ranging from -3, as in ammonia and amines, to +5, as in nitric acid. The following table lists some of the known organic compounds of nitrogen, having different oxidation states of that element. Some of these classes of compounds have been described; others will be discussed later.
|RN=NR (azo cpd.)|
R2NOH (hydroxyl amine)
R3NO (amine oxide)
|R–N=O (nitroso)||R-NO2 (nitro)|
RO–N=O (nitrite ester)
Amine oxides are prepared by oxidizing 3º-amines or pyridines with hydrogen peroxide or peracids (e.g. ZOOH, where Z=H or acyl).
R3N: + ZOOH
R3N(+)–O(–) + ZOH
An elimination reaction, complementary to the Hofmann elimination, occurs when 3º-amine oxides are heated at temperatures of 150 to 200 ºC. This reaction is known as the Cope Elimination. It is commonly carried out by dropwise addition of an amine oxide solution to a heated tube packed with small glass beads. A stream of nitrogen gas flowing through the column carries the volatile alkene products to a chilled receiver. The nitrogen-containing product is a hydroxyl amine. Unlike the Hofmann elimination, this reaction takes place by a concerted cyclic reorganization, as shown in the following diagram. For such a mechanism, the beta-hydrogen and amine oxide moieties necessarily have a syn-relationship.
Cope elimination of diastereomeric amine oxides, such as those shown in examples #2 & 3 above, provide proof of the syn-relationship of the beta-hydrogen and amine oxide groups. These examples also demonstrate a strong regioselectivity favoring the more stable double bond.
2º-Amines lacking α-hydrogens are oxidized by peroxides (ZOOH) to nitroxide radicals of surprising stability. In the example shown at the top of the following diagram it should be noted that resonance delocalization of the unpaired electron contributes to a polar N–O bond. The R=H compound, known by the acronym TEMPO, is a relatively stable red solid. Many other nitroxides have been prepared, three of which are drawn at the lower right. If one or more hydrogens are present on an adjacent carbon, the nitroxide decomposes to mixtures including amine oxides and nitrones, as shown at the lower left. Nitroxides are oxidized to unstable oxammonium cations by halogens.
The following problems review several aspects of amine chemistry. The first demonstrates the use of chemical tests, such as the Hinsberg test, for distinguishing 1º, 2º & 3º-amines. The second asks you to draw the product of a reaction selected from 54 possible combinations of amines and reagents. The third explores the consequences of repetitive Hofmann eliminations, and the last problem demonstrates the importance of aryl amine reactions in synthesis.
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