General structure of an amide (specifically, a carboxamide)Formamide, the simplest amideAsparagine (zwitterionic form), anamino acid with a side chain (highlighted) containing an amide group
The core−C(=O)−(N) of amides is called theamide group (specifically,carboxamide group).
In the usual nomenclature, one adds the term "amide" to the stem of the parent acid's name. For instance, the amide derived fromacetic acid is namedacetamide (CH3CONH2). IUPAC recommendsethanamide, but this and related formal names are rarely encountered. When the amide is derived from a primary or secondary amine, the substituents on nitrogen are indicated first in the name. Thus, the amide formed fromdimethylamine andacetic acid isN,N-dimethylacetamide (CH3CONMe2, where Me = CH3). Usually even this name is simplified todimethylacetamide. Cyclic amides are calledlactams; they are necessarily secondary or tertiary amides.[5][7]
Amides are pervasive in nature and technology.Proteins and importantplastics likenylons,aramids,Twaron, andKevlar arepolymers whose units are connected by amide groups (polyamides); these linkages are easily formed, confer structural rigidity, and resisthydrolysis. Amides include many other important biological compounds, as well as manydrugs likeparacetamol,penicillin andLSD.[8] Low-molecular-weight amides, such as dimethylformamide, are common solvents.
Structure of acetamidehydrogen-bonded dimer fromX-ray crystallography. Selected distances: C-O: 1.243, C-N, 1.325, N---O, 2.925 Å. Color code: red = O, blue = N, gray = C, white = H.[9]
The lone pair ofelectrons on the nitrogen atom is delocalized into theCarbonyl group, thus forming a partialdouble bond between nitrogen and carbon. In fact the O, C and N atoms havemolecular orbitals occupied bydelocalized electrons, forming aconjugated system. Consequently, the three bonds of the nitrogen in amides is not pyramidal (as in theamines) but planar. This planar restriction prevents rotations about the N linkage and thus has important consequences for the mechanical properties of bulk material of such molecules, and also for the configurational properties of macromolecules built by such bonds. The inability to rotate distinguishes amide groups fromester groups which allow rotation and thus create more flexible bulk material.
The C-C(O)NR2 core of amides is planar. The C=O distance is shorter than the C-N distance by almost 10%. The structure of an amide can be described also as aresonance between two alternative structures: neutral (A) andzwitterionic (B).
It is estimated that foracetamide, structure A makes a 62% contribution to the structure, while structure B makes a 28% contribution (these figures do not sum to 100% because there are additional less-important resonance forms that are not depicted above).[10] Resonance is largely prevented in the very strainedquinuclidone.
In their IR spectra, amides exhibit a moderately intenseνCO band near 1650 cm−1. The energy of this band is about 60 cm−1 lower than for theνCO of esters and ketones. This difference reflects the contribution of the zwitterionic resonance structure.
Compared toamines, amides are very weakbases. While theconjugate acid of anamine has apKa of about 9.5, theconjugate acid of an amide has a pKa around −0.5. Therefore, compared to amines, amides do not haveacid–base properties that are as noticeable inwater. This relative lack of basicity is explained by the withdrawing of electrons from the amine by the carbonyl. On the other hand, amides are much strongerbases thancarboxylic acids,esters,aldehydes, andketones (their conjugate acids' pKas are between −6 and −10).
The proton of a primary or secondary amide does not dissociate readily; its pKa is usually well above 15. Conversely, under extremely acidic conditions, the carbonyloxygen can become protonated with a pKa of roughly −1. It is not only because of the positive charge on the nitrogen but also because of the negative charge on the oxygen gained through resonance.
Because of the greater electronegativity of oxygen than nitrogen, the carbonyl (C=O) is a stronger dipole than the N–C dipole. The presence of a C=O dipole and, to a lesser extent a N–C dipole, allows amides to act as H-bond acceptors. In primary and secondary amides, the presence of N–H dipoles allows amides to function as H-bond donors as well. Thus amides can participate inhydrogen bonding with water and other protic solvents; the oxygen atom can accept hydrogen bonds from water and the N–H hydrogen atoms can donate H-bonds. As a result of interactions such as these, the water solubility of amides is greater than that of corresponding hydrocarbons. These hydrogen bonds also have an important role in thesecondary structure of proteins.
Thesolubilities of amides and esters are roughly comparable. Typically amides are less soluble than comparable amines and carboxylic acids since these compounds can both donate and accept hydrogen bonds. Tertiary amides, with the important exception ofN,N-dimethylformamide, exhibit low solubility in water.
Amides do not readily participate in nucleophilic substitution reactions. Amides are stable to water, and are roughly 100 times more stable towardshydrolysis than esters.[citation needed] Amides can, however, be hydrolyzed to carboxylic acids in the presence of acid or base. The stability ofamide bonds has biological implications, since theamino acids that make upproteins are linked with amide bonds. Amide bonds are resistant enough to hydrolysis to maintain protein structure inaqueous environments but are susceptible to catalyzed hydrolysis.[citation needed]
Primary and secondary amides do not react usefully with carbon nucleophiles. Instead,Grignard reagents and organolithiums deprotonate an amide N-H bond. Tertiary amides do not experience this problem, and react with carbon nucleophiles to giveketones; theamide anion (NR2−) is a very strong base and thus a very poor leaving group, so nucleophilic attack only occurs once. When reacted with carbon nucleophiles,N,N-dimethylformamide (DMF) can be used to introduce aformyl group.[11]
Because tertiary amides only react once with organolithiums, they can be used to introduce aldehyde and ketone functionalities. Here, DMF serves as a source of the formyl group in the synthesis of benzaldehyde.
Here,phenyllithium1 attacks the carbonyl group of DMF2, giving tetrahedral intermediate3. Because the dimethylamide anion is a poor leaving group, the intermediate does not collapse and another nucleophilic addition does not occur. Upon acidic workup, the alkoxide is protonated to give4, then the amine is protonated to give5. Elimination of a neutral molecule ofdimethylamine and loss of a proton give benzaldehyde,6.
A new class of amide reactions was discovered in 2015, showing that amides can be converted to esters using nickel catalysis.[12] Many other amide cross-couplings were subsequently developed using nickel or palladium catalysis,[13][14] includingSuzuki-Miyaura couplings.[15]
Mechanism for acid-mediated hydrolysis of an amide.[16]
Amides hydrolyse in hotalkali as well as in strongacidic conditions. Acidic conditions yield the carboxylic acid and the ammonium ion while basic hydrolysis yield the carboxylate ion and ammonia. The protonation of the initially generated amine under acidic conditions and the deprotonation of the initially generated carboxylic acid under basic conditions render these processes non-catalytic and irreversible. Electrophiles other than protons react with thecarbonyl oxygen. This step often precedes hydrolysis, which is catalyzed by bothBrønsted acids andLewis acids.Peptidase enzymes and some synthetic catalysts often operate by attachment of electrophiles to the carbonyl oxygen.
Amides are usually prepared by coupling acarboxylic acid with anamine. The direct reaction generally requires high temperatures to drive off the water:
^Bats, Jan W.; Haberecht, Monika C.; Wagner, Matthias (2003). "A new refinement of the orthorhombic polymorph of acetamide".Acta Crystallographica Section E.59 (10):o1483–o1485.doi:10.1107/S1600536803019494.
^Chapman, Arthur William (1925). "CCLXIX.—Imino-aryl ethers. Part III. The molecular rearrangement ofN-phenylbenziminophenyl ether".Journal of the Chemical Society, Transactions.127:1992–1998.doi:10.1039/CT9252701992.
^March, Jerry (1966).Advanced organic Chemistry, Reactions, mechanisms and structure (3rd ed.). Wiley.ISBN978-0-471-85472-2.
^T. A. Dineen; M. A. Zajac; A. G. Myers (2006). "Efficient Transamidation of Primary Carboxamides byin situ Activation with N,N-Dialkylformamide Dimethyl Acetals".J. Am. Chem. Soc.128 (50):16406–16409.Bibcode:2006JAChS.12816406D.doi:10.1021/ja066728i.PMID17165798.
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