Basicity of Amines

• A review of basic acid base concepts should be helpful to the following discussion. 
• Like ammonia, most amines are Brønsted and Lewis bases, but their base strength can be changed enormously by substituents.
•  It is common to compare basicity's quantitatively by using the pkas of their conjugate bases rather than their pK_b's. Since pK_a + pK_b = 14, the higher the pK_a the stronger the base, in contrast to the usual inverse relationship of pK_a with acidity. 
• Most simple alkyl amines have pK_a's in the range 9.5 to 11.0, and their water solutions are basic (have a pH of 11 to 12, depending on concentration).
•  The first four compounds in the following table, including ammonia, fall into that category.
• The last five compounds (colored cells) are significantly weaker bases as a consequence of three factors.
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• The first of these is the hybridization of the nitrogen. 
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• In pyridine the nitrogen is sp² hybridized, and in nitriles (last entry) an sp hybrid nitrogen is part of the triple bond. 
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• In each of these compounds (shaded red) the non-bonding electron pair is localized on the nitrogen atom, but increasing s-character brings it closer to the nitrogen nucleus, reducing its tendency to bond to a proton.
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• to bond to a proton.
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• Secondly, aniline and p-nitroaniline (first two green shaded structures) are weaker bases due to delocalization of the nitrogen non-bonding elect
• Secondly, aniline and p-nitroaniline (first two green shaded structures) are weaker bases due to delocalization of the nitrogen non-bonding electron pair into the aromatic ring (and the nitro substituent). 
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•  The  electron pair delocalization is accompanied by a degree of rehybridization of the amino nitrogen atom, but the electron pair delocalization is probably the major factor in the reduced basicity of these compounds.
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•  A similar electron pair delocalization is responsible for the very low basicity (and nucleophilic reactivity) of amide nitrogen atoms (last green shaded structure). 
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•  Although 4-dimethylaminopyridine (DMAP) might appear to be a base similar in strength to pyridine or N,N-dimethylaniline, it is actually more than ten thousand times stronger, thanks to charge delocalization in its conjugate acid.
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•  The structure in the gray box shows the locations over which positive charge (colored red) is delocalized in the conjugate acid. This compound is often used as a catalyst for acyl transfer reactions.
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• Finally, the very low basicity of pyrrole (shaded blue) reflects the exceptional delocalization of the nitrogen electron pair associated with its incorporation in an aromayic ring . 
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• Indole (pK_a = -2) and imidazole (pK_a = 7.0), see above , also have similar heterocyclic aromatic rings.
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•  Imidazole is over a million times more basic than pyrrole because the sp² nitrogen that is part of one double bond is structurally similar to pyridine, and has a comparable basicity.
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• Although resonance delocalization generally reduces the basicity of amines, a dramatic example of the reverse effect is found in the compound guanidine (pK_a = 13.6).
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•  Here, as shown below, resonance stabilization of the base is small, due to charge separation, while the conjugate acid is stabilized strongly by charge delocalization.
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• guanidine is exceptionally 
• Guanidine is protonated in physiological conditions. This conjugate acid is called the guanidinium cation, [CH₆N₃]⁺. The guanidinium cation has a charge of +1. It is a highly stable cation in aqueous solution due to the efficient resonance stabilization of the charge and efficient solvation by water molecules. As a result, itspK_a is 13.6^[7] meaning that guanidine is a very strong base in water.
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•  Consequently, aqueous solutions of guanidine are nearly as basic as are solutions of sodium hydroxide.

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Strong bases have weak conjugate acids, and weak bases have strong conjugate acids.