MED-108 Organic Chemistry Nitrogen Compounds 2024 PDF

MED-108 Organic Chemistry Nitrogen Compounds LOBs covered Describe the physical properties of amines Discuss the effect of chemical structure on the degree of basicity of amines Explain why amides are not basic Identify reagents and products in reactions of amines Structure of Amines Trivalent sp3 n...

MED-108 Organic Chemistry Nitrogen Compounds LOBs covered Describe the physical properties of amines Discuss the effect of chemical structure on the degree of basicity of amines Explain why amides are not basic Identify reagents and products in reactions of amines Structure of Amines Trivalent sp3 nitrogen with a lone pair on it Trigonal pyramidal geometry N is electron-rich: Good nucleophile (Lewis base) Classification of Amines Primary, secondary, and tertiary Recall that alkyl groups (R) donate electron density Electron-donation makes the Nitrogen atom more nucleophilic Quaternary Ammonium Salts Four single bonds – no lone pair – positive N Amine Odours Small amines smell fishy! Diamines smell rotten! cadaverine Solubility of Amines Due to the N: feature, amines and water form strong hydrogen bonds Amines with fewer than 5 carbons are water-soluble Alkalinity of Amines Nucleophiles – weak bases The nitrogen lone pair governs the chemical reactivity of amines RNH2 + H2O  RNH3+ + OH[RNH 3+ ][OH - ] Kb = [RNH 2 ] pKb = -log Kb High pKb means weak base Low pKb means strong base pKb and Base Strength High pKb means weak base Low pKb means strong base Consider effectiveness of hydration Further Explanations for Revision As the pKb value decreases, the base becomes stronger. Recall that methyl groups (-CH3) are electron-donating. Donating electron density to the N atom makes it more electron-rich, and the base becomes stronger. Therefore, we see an expected increase in the strength of the base as we go from NH3, to a primary amine, to a secondary amine (4.76 to 3.36 to 3.23). We would expect this trend to continue for the tertiary system, but instead we see a pKb value of 4.20, which means the tertiary amine is a weaker base! The explanation for this has to do with the hydration of the amine in water. Recall that in order for the amine to produce OH- ions, it has to react with water. As the number of methyl groups increase, the amine becomes less soluble in water, and therefore the reaction between the amine and water becomes less complete. Thus, we see that primary and secondary amines have approximately equal strength, and the tertiary system is much weaker because with three methyl groups, water molecules do not hydrate it efficiently. Another way to measure basicity pKa of ammonium cation (conjugate acid) pKa + pKb = pKw = 14 Recall: low pKb means strong base Low pKa means weak base High pKa means strong base pKa of Conjugate Acid and Basicity In the middle compound, the F atom draws electron density away from the N atom, making it less electron-rich, and a weaker base (lower pKa). In the rightmost compound, as we move the F atom closer to the N atom, the electron-withdrawing effect is stronger, and the base becomes even weaker. Are Amides Basic? Structure: Lone pair may imply basicity The positive charge on the N atom in the rightmost resonance form makes the nitrogen less electron-rich, and it does not act as a base 5-Minute Break Synthesis of Amines Reduction of amides Reduction of nitriles Reduction of nitro-compounds Reduction of Amides Conversion of C=O to CH2 Recall the Wolff-Kishner reaction (NH2NH2/KOH) Reduction of Nitriles Conversion of CN to CH2NH2 Reduction of Nitro Compounds Conversion of NO2 to NH2 Reduction can take place using a variety of other reducing agents such as H2 gas, NaBH4, or LiAlH4 Hofmann Rearrangement Complete elimination of C=O group This is called a rearrangement reaction even though a C=O group is completely eliminated Reactions of Amines Hofmann Elimination – anti-Zaitsev This is called an elimination reaction because it forms alkenes (recall dehydration of alcohols forming alkenes – elimination of H2O) Zaitsev’s Rule In the elimination of HX (or HOH) from an alkyl halide (or alcohol), the more highly substituted alkene dominates the product mixture Reactions of Amines Hofmann Elimination – anti-Zaitsev Hofmann Confusion! It is easy to confuse and mix-up Hofmann rearrangement and Hofmann elimination Summary for Revision Amines have a trivalent N atom with a lone pair on it and trigonal pyramidal geometry. This makes them polar but also good Lewis bases (electron-pair donors). Low molecular weight amines smell fishy. Larger diamines smell rotten. Amines with less than 5 C atoms are fully soluble in water due to hydrogen bond formation. Amines with 5 or more C atoms have a larger hydrophobic part and do not dissolve well in water. Amines with lower pKb values are stronger bases. Amines with higher conjugate acid pKa values are stronger bases. In general, as the number of alkyl groups connected to the N atom increases, so should the strength of the base. However, one must also consider the hydration effect. This makes tertiary amines weaker bases than primary or secondary amines. Amides are not good bases despite the lone pair of electrons on the N atom. This is due to a second resonance form that involves a positive charge on the N atom, making it a poor base. Amines can be prepared by: reduction of amides (Wolff-Kishner), reduction of nitriles, reduction of nitro groups, as well as reductive amination of aldehydes and ketones. Hofmann rearrangement deletes completely the C=O group from an amide, forming an amine. Hofmann elimination produces the anti-Zaitsev alkene as the major product.