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تاريخ التسجيل : 02/10/2010
تاريخ الميلاد : 11/09/1992
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|موضوع: بحث كيميائي السبت 30 أكتوبر 2010 - 15:52|| |
Faculty Of Science
Departement of chemistry
The carboxyl functional group that characterizes the carboxylic acids is unusual in that it is composed of two functional groups described earlier in this text. As may be seen in the formula on the right, the carboxyl group is made up of a hydroxyl group bonded to a carbonyl group. It is often written in condensed form as –CO2H or –COOH. Other combinations of functional groups were described previously, and significant changes in chemical behavior as a result of group interactions were described (e.g. phenol & aniline). In this case, the change in chemical and physical properties resulting from the interaction of the hydroxyl and carbonyl group are so profound that the combination is customarily treated as a distinct and different functional group.
1. Nomenclature of Carboxylic Acids
As with aldehydes, the carboxyl group must be located at the end of a carbon chain. In the IUPAC system of nomenclature the carboxyl carbon is designated #1, and other substituents are located and named accordingly. The characteristic IUPAC suffix for a carboxyl group is "oic acid", and care must be taken not to confuse this systematic nomenclature with the similar common system. These two nomenclatures are illustrated in the following table, along with their melting and boiling points.
Formula Common Name Source IUPAC Name Melting Point Boiling Point
HCO2H formic acid ants (L. formica) methanoic acid 8.4 ºC 101 ºC
CH3CO2H acetic acid vinegar (L. acetum) ethanoic acid 16.6 ºC 118 ºC
CH3CH2CO2H propionic acid milk (Gk. protus prion) propanoic acid -20.8 ºC 141 ºC
CH3(CH2)2CO2H butyric acid butter (L. butyrum) butanoic acid -5.5 ºC 164 ºC
CH3(CH2)3CO2H valeric acid valerian root pentanoic acid -34.5 ºC 186 ºC
CH3(CH2)4CO2H caproic acid goats (L. caper) hexanoic acid -4.0 ºC 205 ºC
CH3(CH2)5CO2H enanthic acid vines (Gk. oenanthe) heptanoic acid -7.5 ºC 223 ºC
CH3(CH2)6CO2H caprylic acid goats (L. caper) octanoic acid 16.3 ºC 239 ºC
CH3(CH2)7CO2H pelargonic acid pelargonium (an herb) nonanoic acid 12.0 ºC 253 ºC
CH3(CH2)8CO2H capric acid goats (L. caper) decanoic acid 31.0 ºC 219 ºC
Substituted carboxylic acids are named either by the IUPAC system or by common names. If you are uncertain about the IUPAC rules for nomenclature you should review them now. Some common names, the amino acid threonine for example, do not have any systematic origin and must simply be memorized. In other cases, common names make use of the Greek letter notation for carbon atoms near the carboxyl group. Some examples of both nomenclatures are provided below.
Simple dicarboxylic acids having the general formula HO2C–(CH2)n–CO2H (where n = 0 to 5) are known by the common names: Oxalic (n=0), Malonic (n=1), Succinic (n=2), Glutaric (n=3), Adipic (n=4) and Pimelic (n=5) Acids. Common names, such as these can be troublesome to remember, so mnemonic aids, which take the form of a catchy phrase, have been devised. For this group of compounds one such phrase is: "Oh My Such Good Apple Pie".
2. Carboxylic Acid Natural Products
Carboxylic acids are widespread in nature, often combined with other functional groups. Simple alkyl carboxylic acids, composed of four to ten carbon atoms, are liquids or low melting solids having very unpleasant odors. The fatty acids are important components of the biomolecules known as lipids, especially fats and oils. As shown in the following table, these long-chain carboxylic acids are usually referred to by their common names, which in most cases reflect their sources. A mnemonic phrase for the C10 to C20 natural fatty acids capric, lauric, myristic, palmitic, stearic and arachidic is: "Curly, Larry & Moe Perform Silly Antics" (note that the names of the three stooges are in alphabetical order).
Interestingly, the molecules of most natural fatty acids have an even number of carbon atoms. Analogous compounds composed of odd numbers of carbon atoms are perfectly stable and have been made synthetically. Since nature makes these long-chain acids by linking together acetate units, it is not surprising that the carbon atoms composing the natural products are multiples of two. The double bonds in the unsaturated compounds listed on the right are all cis (or Z).
Formula Common Name Melting Point
CH3(CH2)10CO2H lauric acid 45 ºC
CH3(CH2)12CO2H myristic acid 55 ºC
CH3(CH2)14CO2H palmitic acid 63 ºC
CH3(CH2)16CO2H stearic acid 69 ºC
CH3(CH2)18CO2H arachidic acid 76 ºC
Formula Common Name Melting Point
CH3(CH2)5CH=CH(CH2)7CO2H palmitoleic acid 0 ºC
CH3(CH2)7CH=CH(CH2)7CO2H oleic acid 13 ºC
CH3(CH2)4CH=CHCH2CH=CH(CH2)7CO2H linoleic acid -5 ºC
CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7CO2H linolenic acid -11 ºC
CH3(CH2)4(CH=CHCH2)4(CH2)2CO2H arachidonic acid -49 ºC
The following formulas are examples of other naturally occurring carboxylic acids. The molecular structures range from simple to complex, often incorporate a variety of other functional groups, and many are chiral.
3. Related Carbonyl Derivatives
Other functional group combinations with the carbonyl group can be prepared from carboxylic acids, and are usually treated as related derivatives. Five common classes of these carboxylic acid derivatives are listed in the following table. Although nitriles do not have a carbonyl group, they are included here because the functional carbon atoms all have the same oxidation state. The top row (yellow shaded) shows the general formula for each class, and the bottom row (light blue) gives a specific example of each. As in the case of amines, amides are classified as 1º, 2º or 3º, depending on the number of alkyl groups bonded to the nitrogen.
Functional groups of this kind are found in many kinds of natural products. Some examples are shown below with the functional group colored red. Most of the functions are amides or esters, cantharidin being a rare example of a natural anhydride. Cyclic esters are called lactones, and cyclic amides are referred to as lactams. Penicillin G has two amide functions, one of which is a β-lactam. The Greek letter locates the nitrogen relative to the carbonyl group of the amide.
Physical Properties & Acidity
Properties of Carboxylic Acids
1. Physical Properties of Carboxylic Acids
The table at the beginning of this page gave the melting and boiling points for a homologous group of carboxylic acids having from one to ten carbon atoms. The boiling points increased with size in a regular manner, but the melting points did not. Unbranched acids made up of an even number of carbon atoms have melting points higher than the odd numbered homologs having one more or one less carbon. This reflects differences in intermolecular attractive forces in the crystalline state. In the table of fatty acids we see that the presence of a cis-double bond significantly lowers the melting point of a compound. Thus, palmitoleic acid melts over 60º lower than palmitic acid, and similar decreases occur for the C18 and C20 compounds. Again, changes in crystal packing and intermolecular forces are responsible.
The factors that influence the relative boiling points and water solubilities of various types of compounds were discussed earlier. In general, dipolar attractive forces between molecules act to increase the boiling point of a given compound, with hydrogen bonds being an extreme example. Hydrogen bonding is also a major factor in the water solubility of covalent compounds To refresh your understanding of these principles Click Here. The following table lists a few examples of these properties for some similar sized polar compounds (the non-polar hydrocarbon hexane is provided for comparison).
Physical Properties of Some Organic Compounds
Formula IUPAC Name Molecular Weight Boiling Point Water Solubility
CH3(CH2)2CO2H butanoic acid 88 164 ºC very soluble
CH3(CH2)4OH 1-pentanol 88 138 ºC slightly soluble
CH3(CH2)3CHO pentanal 86 103 ºC slightly soluble
CH3CO2C2H5 ethyl ethanoate 88 77 ºC moderately soluble
CH3CH2CO2CH3 methyl propanoate 88 80 ºC slightly soluble
CH3(CH2)2CONH2 butanamide 87 216 ºC soluble
CH3CON(CH3)2 N,N-dimethylethanamide 87 165 ºC very soluble
CH3(CH2)4NH2 1-aminobutane 87 103 ºC very soluble
CH3(CH2)3CN pentanenitrile 83 140 ºC slightly soluble
CH3(CH2)4C hexane 86 69 ºC insoluble
he first five entries all have oxygen functional groups, and the relatively high boiling points of the first two is clearly due to hydrogen bonding. Carboxylic acids have exceptionally high boiling points, due in large part to dimeric associations involving two hydrogen bonds. A structural formula for the dimer of acetic acid is shown here. When the mouse pointer passes over the drawing, an electron cloud diagram will appear. The high boiling points of the amides and nitriles are due in large part to strong dipole attractions, supplemented in some cases by hydrogen bonding.
2. Acidity of Carboxylic Acids
The pKa 's of some typical carboxylic acids are listed in the following table. When we compare these values with those of comparable alcohols, such as ethanol (pKa = 16) and 2-methyl-2-propanol (pKa = 19), it is clear that carboxylic acids are stronger acids by over ten powers of ten! Furthermore, electronegative substituents near the carboxyl group act to increase the acidity.
Compound pKa Compound pKa
HCO2H 3.75 CH3CH2CH2CO2H 4.82
CH3CO2H 4.74 ClCH2CH2CH2CO2H 4.53
FCH2CO2H 2.65 CH3CHClCH2CO2H 4.05
ClCH2CO2H 2.85 CH3CH2CHClCO2H 2.89
BrCH2CO2H 2.90 C6H5CO2H 4.20
ICH2CO2H 3.10 p-O2NC6H4CO2H 3.45
Cl3CCO2H 0.77 p-CH3OC6H4CO2H 4.45
Why should the presence of a carbonyl group adjacent to a hydroxyl group have such a profound effect on the acidity of the hydroxyl proton? To answer this question we must return to the nature of acid-base equilibria and the definition of pKa , illustrated by the general equations given below. These relationships were described in an previous section of this text.
We know that an equilibrium favors the thermodynamically more stable side, and that the magnitude of the equilibrium constant reflects the energy difference between the components of each side. In an acid base equilibrium the equilibrium always favors the weaker acid and base (these are the more stable components). Water is the standard base used for pKa measurements; consequently, anything that stabilizes the conjugate base (A:(–)) of an acid will necessarily make that acid (H–A) stronger and shift the equilibrium to the right. Both the carboxyl group and the carboxylate anion are stabilized by resonance, but the stabilization of the anion is much greater than that of the neutral function, as shown in the following diagram. In the carboxylate anion the two contributing structures have equal weight in the hybrid, and the C–O bonds are of equal length (between a double and a single bond). This stabilization leads to a markedly increased acidity, as illustrated by the energy diagram displayed by clicking the "Toggle Display" button.
Compounds in which an enolic hydroxyl group is conjugated with a carbonyl group also show enhanced acidity.
To see examples of such compounds Click Here
The resonance effect described here is undoubtedly the major contributor to the exceptional acidity of carboxylic acids. However, inductive effects also play a role. For example, alcohols have pKa's of 16 or greater but their acidity is increased by electron withdrawing substituents on the alkyl group. The following diagram illustrates this factor for several simple inorganic and organic compounds (row #1), and shows how inductive electron withdrawal may also increase the acidity of carboxylic acids (rows #2 & 3). The acidic hydrogen is colored red in all examples.
Water is less acidic than hydrogen peroxide because hydrogen is less electronegative than oxygen, and the covalent bond joining these atoms is polarized in the manner shown. Alcohols are slightly less acidic than water, due to the poor electronegativity of carbon, but chloral hydrate, Cl3CCH(OH)2, and 2,2,2,-trifluoroethanol are significantly more acidic than water, due to inductive electron withdrawal by the electronegative halogens (and the second oxygen in chloral hydrate). In the case of carboxylic acids, if the electrophilic character of the carbonyl carbon is decreased the acidity of the carboxylic acid will also decrease. Similarly, an increase in its electrophilicity will increase the acidity of the acid. Acetic acid is ten times weaker an acid than formic acid (first two entries in the second row), confirming the electron donating character of an alkyl group relative to hydrogen, as noted earlier in a discussion of carbocation stability. Electronegative substituents increase acidity by inductive electron withdrawal. As expected, the higher the electronegativity of the substituent the greater the increase in acidity (F > Cl > Br > I), and the closer the substituent is to the carboxyl group the greater is its effect (isomers in the 3rd row). Substituents also influence the acidity of benzoic acid derivatives, but resonance effects compete with inductive effects. The methoxy group is electron donating and the nitro group is electron withdrawing (last three entries in the table of pKa values).
For additional information about substituent effects on the acidity of carboxylic acids Click Here
Preparation of Carboxylic Acids
Preparation of Carboxylic Acids
The carbon atom of a carboxyl group has a high oxidation state. It is not surprising, therefore, that many of the chemical reactions used for their preparation are oxidations. Such reactions have been discussed in previous sections of this text, and the following diagram summarizes most of these. To review the previous discussion of any of these reaction classes simply click on the number (1 to 4) or descriptive heading for the group.
Two other useful procedures for preparing carboxylic acids involve hydrolysis of nitriles and carboxylation of organometallic intermediates. As shown in the following diagram, both methods begin with an organic halogen compound and the carboxyl group eventually replaces the halogen. Both methods require two steps, but are complementary in that the nitrile intermediate in the first procedure is generated by a SN2 reaction, in which cyanide anion is a nucleophilic precursor of the carboxyl group. The hydrolysis may be either acid or base-catalyzed, but the latter give a carboxylate salt as the initial product.
In the second procedure the electrophilic halide is first transformed into a strongly nucleophilic metal derivative, and this adds to carbon dioxide (an electrophile). The initial product is a salt of the carboxylic acid, which must then be released by treatment with strong aqueous acid.
An existing carboxylic acid may be elongated by one methylene group, using a homologation procedure called the Arndt-Eistert reaction.. To learn about this useful method Click Here.
Reactions of Carboxylic Acids
1. Salt Formation
Because of their enhanced acidity, carboxylic acids react with bases to form ionic salts, as shown in the following equations. In the case of alkali metal hydroxides and simple amines (or ammonia) the resulting salts have pronounced ionic character and are usually soluble in water. Heavy metals such as silver, mercury and lead form salts having more covalent character (3rd example), and the water solubility is reduced, especially for acids composed of four or more carbon atoms.
RCO2H + NaHCO3
RCO2(–) Na(+) + CO2 + H2O
RCO2H + (CH3)3N:
RCO2H + AgOH
RCO2δ(-) Agδ(+) + H2O
Carboxylic acids and salts having alkyl chains longer than six carbons exhibit unusual behavior in water due to the presence of both hydrophilic (CO2) and hydrophobic (alkyl) regions in the same molecule. Such molecules are termed amphiphilic (Gk. amphi = both) or amphipathic. Depending on the nature of the hydrophilic portion these compounds may form monolayers on the water surface or sphere-like clusters, called micelles, in solution.
2. Substitution of the Hydroxyl Hydrogen
This reaction class could be termed electrophilic substitution at oxygen, and is defined as follows (E is an electrophile). Some examples of this substitution are provided in equations (1) through (4).
RCO2–H + E(+)
RCO2–E + H(+)
If E is a strong electrophile, as in the first equation, it will attack the nucleophilic oxygen of the carboxylic acid directly, giving a positively charged intermediate which then loses a proton. If E is a weak electrophile, such as an alkyl halide, it is necessary to convert the carboxylic acid to the more nucleophilic carboxylate anion to facilitate the substitution. This is the procedure used in reactions 2 and 3. Equation 4 illustrates the use of the reagent diazomethane (CH2N2) for the preparation of methyl esters. This toxic and explosive gas is always used as an ether solution (bright yellow in color). The reaction is easily followed by the evolution of nitrogen gas and the disappearance of the reagent's color. This reaction is believed to proceed by the rapid bonding of a strong electrophile to a carboxylate anion.
The nature of SN2 reactions, as in equations 2 & 3, has been described elsewhere. The mechanisms of reactions 1 & 4 will be displayed by clicking the "Toggle Mechanism" button below the diagram.
Alkynes may also serve as electrophiles in substitution reactions of this kind, as illustrated by the synthesis of vinyl acetate from acetylene. Intramolecular carboxyl group additions to alkenes generate cyclic esters known as lactones. Five-membered (gamma) and six-membered (delta) lactones are most commonly formed. Electrophilic species such as acids or halogens are necessary initiators of lactonizations. Even the weak electrophile iodine initiates iodolactonization of γ,δ- and δ,ε-unsaturated acids. Examples of these reactions will be displayed by clicking the "Other Examples" button.
3. Substitution of the Hydroxyl Group
Reactions in which the hydroxyl group of a carboxylic acid is replaced by another nucleophilic group are important for preparing functional derivatives of carboxylic acids. The alcohols provide a useful reference chemistry against which this class of transformations may be evaluated. In general, the hydroxyl group proved to be a poor leaving group, and virtually all alcohol reactions in which it was lost involved a prior conversion of –OH to a better leaving group. This has proven to be true for the carboxylic acids as well.
Four examples of these hydroxyl substitution reactions are presented by the following equations. In each example, the new bond to the carbonyl group is colored magenta and the nucleophilic atom that has replaced the hydroxyl oxygen is colored green. The hydroxyl moiety is often lost as water, but in reaction #1 the hydrogen is lost as HCl and the oxygen as SO2. This reaction parallels a similar transformation of alcohols to alkyl chlorides, although its mechanism is different. Other reagents that produce a similar conversion to acyl halides are PCl5 and SOBr2.
The amide and anhydride formations shown in equations #2 & 3 require strong heating, and milder procedures that accomplish these transformations will be described in the next chapter.
Reaction #4 is called esterification, since it is commonly used to convert carboxylic acids to their ester derivatives. Esters may be prepared in many different ways; indeed, equations #1 and #4 in the previous diagram illustrate the formation of tert-butyl and methyl esters respectively. The acid-catalyzed formation of ethyl acetate from acetic acid and ethanol shown here is reversible, with an equilibrium constant near 2. The reaction can be forced to completion by removing the water as it is formed. This type of esterification is often referred to as Fischer esterification. As expected, the reverse reaction, acid-catalyzed ester hydrolysis, can be carried out by adding excess water.
A thoughtful examination of this reaction (#4) leads one to question why it is classified as a hydroxyl substitution rather than a hydrogen substitution. The following equations, in which the hydroxyl oxygen atom of the carboxylic acid is colored red and that of the alcohol is colored blue, illustrate this distinction (note that the starting compounds are in the center).
H2O + CH3CO-OCH2CH3 H-substitution
CH3CO-OH + CH3CH2-OH
CH3CO-OCH2CH3 + H2O
In order to classify this reaction correctly and establish a plausible mechanism, the oxygen atom of the alcohol was isotopically labeled as 18O (colored blue in our equation). Since this oxygen is found in the ester product and not the water, the hydroxyl group of the acid must have been replaced in the substitution. A mechanism for this general esterification reaction will be displayed on clicking the "Esterification Mechanism" button; also, once the mechanism diagram is displayed, a reaction coordinate for it can be seen by clicking the head of the green "energy diagram" arrow. Addition-elimination mechanisms of this kind proceed by way of tetrahedral intermediates (such as A and B in the mechanism diagram) and are common in acyl substitution reactions. Acid catalysis is necessary to increase the electrophilic character of the carboxyl carbon atom, so it will bond more rapidly to the nucleophilic oxygen of the alcohol. Base catalysis is not useful because base converts the acid to its carboxylate anion conjugate base, a species in which the electrophilic character of the carbon is reduced.
Since a tetrahedral intermediate occupies more space than a planar carbonyl group, we would expect the rate of this reaction to be retarded when bulky reactants are used. To test this prediction the esterification of acetic acid was compared with that of 2,2-dimethylpropanoic acid, (CH3)3CO2H. Here the relatively small methyl group of acetic acid is replaced by a larger tert-butyl group, and the bulkier acid reacted fifty times slower than acetic acid. Increasing the bulk of the alcohol reactant results in a similar rate reduction.
Reduction & Oxidation Reactions
Reductions & Oxidations of Carboxylic Acids
The carbon atom of a carboxyl group is in a relatively high oxidation state. Reduction to a 1º-alcohol takes place rapidly on treatment with the powerful metal hydride reagent, lithium aluminum hydride, as shown by the following equation. One third of the hydride is lost as hydrogen gas, and the initial product consists of metal salts which must be hydrolyzed to generate the alcohol. These reductions take place by the addition of hydride to the carbonyl carbon, in the same manner noted earlier for aldehydes and ketones. The resulting salt of a carbonyl hydrate then breaks down to an aldehyde that undergoes further reduction.
4 RCO2H + 3 LiAlH4 ether
4 H2 + 4 RCH2OM + metal oxides H2O
4 RCH2OH + metal hydroxides
Diborane, B2H6, reduces the carboxyl group in a similar fashion. Sodium borohydride, NaBH4, does not reduce carboxylic acids; however, hydrogen gas is liberated and salts of the acid are formed. Partial reduction of carboxylic acids directly to aldehydes is not possible, but such conversions have been achieved in two steps by way of certain carboxyl derivatives. These will be described later.
Because it is already in a high oxidation state, further oxidation removes the carboxyl carbon as carbon dioxide. Depending on the reaction conditions, the oxidation state of the remaining organic structure may be higher, lower or unchanged. The following reactions are all examples of decarboxylation (loss of CO2). In the first, bromine replaces the carboxyl group, so both the carboxyl carbon atom and the remaining organic moiety are oxidized. Silver salts have also been used to initiate this transformation, which is known as the Hunsdiecker reaction. The second reaction is an interesting bis-decarboxylation, in which the atoms of the organic residue retain their original oxidation states. Lead tetraacetate will also oxidize mono-carboxylic acids in a manner similar to reaction #1. Finally, the third example illustrates the general decarboxylation of β-keto acids, which leaves the organic residue in a reduced state (note that the CO2 carbon has increased its oxidation state.).
Three additional examples of the Hunsdiecker reaction and a proposed mechanism for the transformation will be shown above by clicking on the diagram. Note that the meta- dihalobenzene formed in reaction 4 could not be made by direct halogenation reactions, since chlorine and bromine are ortho/para-directing substituents. Also, various iodide derivatives may be prepared directly from the corresponding carboxylic acids. A heavy metal carboxylate salt is transformed into an acyl hypohalide by the action of a halogen. The weak oxygen-halogen bond in this intermediate cleaves homolytically when heated or exposed to light, and the resulting carboxy radical decarboxylates to an alkyl or aryl radical. A chain reaction then repeats these events. Since acyl hypohalites are a source of electrophilic halogen, this reaction takes a different course when double bonds and reactive benzene derivatives are present. In this respect remember the addition of hypohalous reagents to double bonds and the facile bromination of
Chemistry of Amines
1. Nomenclature and Structure of Amines
In the IUPAC system of nomenclature, functional groups are normally designated in one of two ways. The presence of the function may be indicated by a characteristic suffix and a location number. This is common for the carbon-carbon double and triple bonds which have the respective suffixes ene and yne. Halogens, on the other hand, do not have a suffix and are named as substituents, for example: (CH3)2C=CHCHClCH3 is 4-chloro-2-methyl-2-pentene. If you are uncertain about the IUPAC rules for nomenclature you should review them now.
Amines are derivatives of ammonia in which one or more of the hydrogens has been replaced by an alkyl or aryl group. The nomenclature of amines is complicated by the fact that several different nomenclature systems exist, and there is no clear preference for one over the others. Furthermore, the terms primary (1º), secondary (2º) & tertiary (3º) are used to classify amines in a completely different manner than they were used for alcohols or alkyl halides. When applied to amines these terms refer to the number of alkyl (or aryl) substituents bonded to the nitrogen atom, whereas in other cases they refer to the nature of an alkyl group. The four compounds shown in the top row of the following diagram are all C4H11N isomers. The first two are classified as 1º-amines, since only one alkyl group is bonded to the nitrogen; however, the alkyl group is primary in the first example and tertiary in the second. The third and fourth compounds in the row are 2º and 3º-amines respectively. A nitrogen bonded to four alkyl groups will necessarily be positively charged, and is called a 4º-ammonium cation. For example, (CH3)4N(+) Br(–) is tetramethylammonium bromide.
The IUPAC names are listed first and colored blue. This system names amine functions as substituents on the largest alkyl group. The simple -NH2 substituent found in 1º-amines is called an amino group. For 2º and 3º-amines a compound prefix (e.g. dimethylamino in the fourth example) includes the names of all but the root alkyl group.
The Chemical Abstract Service has adopted a nomenclature system in which the suffix -amine is attached to the root alkyl name. For 1º-amines such as butanamine (first example) this is analogous to IUPAC alcohol nomenclature (-ol suffix). The additional nitrogen substituents in 2º and 3º-amines are designated by the prefix N- before the group name. These CA names are colored magenta in the diagram.
Finally, a common system for simple amines names each alkyl substituent on nitrogen in alphabetical order, followed by the suffix -amine. These are the names given in the last row (colored black).
Many aromatic and heterocyclic amines are known by unique common names, the origins of which are often unknown to the chemists that use them frequently. Since these names are not based on a rational system, it is necessary to memorize them. There is a systematic nomenclature of heterocyclic compounds, but it will not be discussed here.
Natural Nitrogen Compounds
Nature abounds with nitrogen compounds, many of which occur in plants and are referred to as alkaloids. Structural formulas for some representative alkaloids and other nitrogen containing natural products are displayed below, and we can recognize many of the basic structural features listed above in their formulas. Thus, Serotonin and Thiamine are 1º-amines, Coniine is a 2º-amine, Atropine, Morphine and Quinine are 3º-amines, and Muscarine is a 4º-ammonium salt.
The reader should be able to recognize indole, imidazole, piperidine, pyridine, pyrimidine & pyrrolidine moieties among these structures. These will be identified by pressing the "Show Structures" button under the diagram.
Nitrogen atoms that are part of aromatic rings , such as pyridine, pyrrole & imidazole, have planar configurations (sp2 hybridization), and are not stereogenic centers. Nitrogen atoms bonded to carbonyl groups, as in caffeine, also tend to be planar. In contrast, atropine, coniine, morphine, nicotine and quinine have stereogenic pyramidal nitrogen atoms in their structural formulas (think of the non-bonding electron pair as a fourth substituent on a sp3 hybridized nitrogen). In quinine this nitrogen is restricted to one configuration by the bridged ring system. The other stereogenic nitrogens are free to assume two pyramidal configurations, but these are in rapid equilibrium so that distinct stereoisomers reflecting these sites cannot be easily isolated.
It should be noted that structural factors may serve to permit the resolution of pyramidal chiral amines. Two examples of such 3º-amines, compared with similar non-resolvable analogs, are shown in the following diagram. The two nitrogen atoms in Trögers base are the only stereogenic centers in the molecule. Because of the molecule's bridged structure, the nitrogens have the same configuration and cannot undergo inversion. The chloro aziridine can invert, but requires a higher activation energy to do so, compared with larger heterocyclic amines. It has in fact been resolved, and pure enantiomers isolated. An increase in angle strain in the sp2-hybridized planar transition state is responsible for the greater stability of the pyramidal configuration. The rough estimate of angle strain is made using a C-N-C angle of 60º as an arbitrary value for the three-membered heterocycle.
To see these features Click on the Diagram.
Of course, quaternary ammonium salts, such as that in muscarine, have a tetrahedral configuration that is incapable of inversion. With four different substituents, such a nitrogen would be a stable stereogenic center.
2. A Structure Formula Relationship
Recall that the molecular formula of a hydrocarbon (CnHm) provides information about the number of rings and/or double bonds that must be present in its structural formula. In the formula shown below a triple bond is counted as two double bonds.
Rings + Double Bonds
in a CnHm Hydrocarbon = (2n + 2 - m)
Rings + C=Z
Coniine C8H17N C9H18 1
Nicotine C10H14N2 C12H16 5
Morphine C17H19NO3 C18H20 9
This molecular formula analysis may be extended beyond hydrocarbons by a few simple corrections. These are illustrated by the examples in the table above, taken from the previous list of naturally occurring amines.
• The presence of oxygen does not alter the relationship.
• All halogens present in the molecular formula must be replaced by hydrogen.
• Each nitrogen in the formula must be replaced by a CH moiety.
Properties of Amines
Properties of Amines
1. Boiling Point and Water Solubility
It is instructive to compare the boiling points and water solubility of amines with those of corresponding alcohols and ethers. The dominant factor here is hydrogen bonding, and the first table below documents the powerful intermolecular attraction that results from -O-H---O- hydrogen bonding in alcohols (light blue columns). Corresponding -N-H---N- hydrogen bonding is weaker, as the lower boiling points of similarly sized amines (light green columns) demonstrate. Alkanes provide reference compounds in which hydrogen bonding is not possible, and the increase in boiling point for equivalent 1º-amines is roughly half the increase observed for equivalent alcohols.
Compound CH3CH3 CH3OH CH3NH2 CH3CH2CH3 CH3CH2OH CH3CH2NH2
Mol.Wt. 30 32 31 44 46 45
Point ºC -88.6º 65º -6.0º -42º 78.5º 16.6º
The second table illustrates differences associated with isomeric 1º, 2º & 3º-amines, as well as the influence of chain branching. Since 1º-amines have two hydrogens available for hydrogen bonding, we expect them to have higher boiling points than isomeric 2º-amines, which in turn should boil higher than isomeric 3º-amines (no hydrogen bonding). Indeed, 3º-amines have boiling points similar to equivalent sized ethers; and in all but the smallest compounds, corresponding ethers, 3º-amines and alkanes have similar boiling points. In the examples shown here, it is further demonstrated that chain branching reduces boiling points by 10 to 15 ºC.
Compound CH3(CH2)2CH3 CH3(CH2)2OH CH3(CH2)2NH2 CH3CH2NHCH3 (CH3)3CH (CH3)2CHOH (CH3)2CHNH2 (CH3)3N
Mol.Wt. 58 60 59 59 58 60 59 59
Point ºC -0.5º 97º 48º 37º -12º 82º 34º 3º
The water solubility of 1º and 2º-amines is similar to that of comparable alcohols. As expected, the water solubility of 3º-amines and ethers is also similar. These comparisons, however, are valid only for pure compounds in neutral water. The basicity of amines (next section) allows them to be dissolved in dilute mineral acid solutions, and this property facilitates their separation from neutral compounds such as alcohols and hydrocarbons by partitioning between the phases of non-miscible solvents.
2. 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 pKa's of their conjugate acids rather than their pKb's. Since pKa + pKb = 14, the higher the pKa the stronger the base, in contrast to the usual inverse relationship of pKa with acidity. Most simple alkyl amines have pKa'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. The first of these is the hybridization of the nitrogen. In pyridine the nitrogen is sp2 hybridized, and in nitriles (last entry) an sp hybrid nitrogen is part of the triple bond. 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.
pKa 11.0 10.7 10.7 9.3 5.2 4.6 1.0 0.0 -1.0 -10.0
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). This is the same delocalization that results in activation of a benzene ring toward electrophilic substitution. The following resonance equations, which are similar to those used to explain the enhanced acidity of ortho and para-nitrophenols illustrate electron pair delocalization in p-nitroaniline. Indeed, aniline is a weaker base than cyclohexyl amine by roughly a million fold, the same factor by which phenol is a stronger acid than cyclohexanol. This 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. A similar electron pair delocalization is responsible for the very low basicity (and nucleophilic reactivity) of amide nitrogen atoms (last green shaded structure). This feature was instrumental in moderating the influence of amine substituents on aromatic ring substitution, and will be discussed further in the section devoted to carboxylic acid derivatives.
By clicking on the above diagram, the influence of a conjugated amine group on the basicity of an existing amine will be displayed. 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. 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.
Finally, the very low basicity of pyrrole (shaded blue) reflects the exceptional delocalization of the nitrogen electron pair associated with its incorporation in an aromatic ring. Indole (pKa = -2) and imidazole (pKa = 7.0), see above, also have similar heterocyclic aromatic rings. 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.
Although resonance delocalization generally reduces the basicity of amines, a dramatic example of the reverse effect is found in the compound guanidine (pKa = 13.6). 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. Consequently, aqueous solutions of guanidine are nearly as basic as are solutions of sodium hydroxide.
The relationship of amine basicity to the acidity of the corresponding conjugate acids may be summarized in a fashion analogous to that noted earlier for acids.
Strong bases have weak conjugate acids, and weak bases have strong conjugate acids.
3. Acidity of Amines
We normally think of amines as bases, but it must be remembered that 1º and 2º-amines are also very weak acids (ammonia has a pKa = 34). In this respect it should be noted that pKa is being used as a measure of the acidity of the amine itself rather than its conjugate acid, as in the previous section. For ammonia this is expressed by the following hypothetical equation:
NH3 + H2O ____> NH2(–) + H2O-H(+)
The same factors that decreased the basicity of amines increase their acidity. This is illustrated by the following examples, which are shown in order of increasing acidity. It should be noted that the first four examples have the same order and degree of increased acidity as they exhibited decreased basicity in the previous table. The first compound is a typical 2º-amine, and the three next to it are characterized by varying degrees of nitrogen electron pair delocalization. The last two compounds (shaded blue) show the influence of adjacent sulfonyl and carbonyl groups on N-H acidity. From previous discussion it should be clear that the basicity of these nitrogens is correspondingly reduced.
pKa 33 27 19 15 10 9.6
The acids shown here may be converted to their conjugate bases by reaction with bases derived from weaker acids (stronger bases). Three examples of such reactions are shown below, with the acidic hydrogen colored red in each case. For complete conversion to the conjugate base, as shown, a reagent base roughly a million times stronger is required.
C6H5SO2NH2 + KOH C6H5SO2NH(–) K(+) + H2O a sulfonamide base
(CH3)3COH + NaH (CH3)3CO(–) Na(+) + H2 an alkoxide base
(C2H5)2NH + C4H9Li (C2H5)2N(–) Li(+) + C4H10 an amide base
4. Important Reagent Bases
The significance of all these acid-base relationships to practical organic chemistry lies in the need for organic bases of varying strength, as reagents tailored to the requirements of specific reactions. The common base sodium hydroxide is not soluble in many organic solvents, and is therefore not widely used as a reagent in organic reactions. Most base reagents are alkoxide salts, amines or amide salts. Since alcohols are much stronger acids than amines, their conjugate bases are weaker than amide bases, and fill the gap in base strength between amines and amide salts. In the following table, pKa again refers to the conjugate acid of the base drawn above it.
Base Name Pyridine Triethyl
Amine Hünig's Base DBU Barton's
t-Butoxide Sodium HMDS LDA
(CH3)3CO(–) K(+) [(CH3)3Si]2N(–) Na(+) [(CH3)2CH]2N(–) Li(+)
pKa 5.3 10.7 11.4 12 14 19 26 35.7
Pyridine is commonly used as an acid scavenger in reactions that produce mineral acid co-products. Its basicity and nucleophilicity may be modified by steric hindrance, as in the case of 2,6-dimethylpyridine (pKa=6.7), or resonance stabilization, as in the case of 4-dimethylaminopyridine (pKa=9.7). Hünig's base is relatively non-nucleophilic (due to steric hindrance), and like DBU is often used as the base in E2 elimination reactions conducted in non-polar solvents. Barton's base is a strong, poorly-nucleophilic, neutral base that serves in cases where electrophilic substitution of DBU or other amine bases is a problem. The alkoxides are stronger bases that are often used in the corresponding alcohol as solvent, or for greater reactivity in DMSO. Finally, the two amide bases see widespread use in generating enolate bases from carbonyl compounds and other weak carbon acids.
An interesting group of neutral, highly basic compounds of nitrogen and phosphorus have been prepared, and are referred to as superbases.
To see examples of these compounds Click Here.
Reactions of Amines
1. Electrophilic Substitution at Nitrogen
Ammonia and many amines are not only bases in the Brønsted sense, they are also nucleophiles that bond to and form products with a variety of electrophiles. A general equation for such electrophilic substitution of nitrogen is:
2 R2ÑH + E(+) R2NHE(+) R2ÑE + H(+) (bonded to a base)
A list of some electrophiles that are known to react with amines is shown here. In each case the electrophilic atom or site is colored red.
Electrophile RCH2–X RCH2–OSO2R R2C=O R(C=O)X RSO2–Cl HO–N=O
Name Alkyl Halide Alkyl Sulfonate Aldehyde
or Ketone Acid Halide
or Anhydride Sulfonyl Chloride Nitrous Acid
It is instructive to examine these nitrogen substitution reactions, using the common alkyl halide class of electrophiles. Thus, reaction of a primary alkyl bromide with a large excess of ammonia yields the corresponding 1º-amine, presumably by a SN2 mechanism. The hydrogen bromide produced in the reaction combines with some of the excess ammonia, giving ammonium bromide as a by-product. Water does not normally react with 1º-alkyl halides to give alcohols, so the enhanced nucleophilicity of nitrogen relative to oxygen is clearly demonstrated.
2 RCH2Br + NH3 (large excess) RCH2NH2 + NH4(+) Br(–)
It follows that simple amines should also be more nucleophilic than their alcohol or ether equivalents. If, for example, we wish to carry out a SN2 reaction of an alcohol with an alkyl halide to produce an ether (the Williamson synthesis), it is necessary to convert the weakly nucleophilic alcohol to its more nucleophilic conjugate base for the reaction to occur. In contrast, amines react with alkyl halides directly to give N-alkylated products. Since this reaction produces HBr as a co-product, hydrobromide salts of the alkylated amine or unreacted starting amine (in equilibrium) will also be formed.
2 RNH2 + C2H5Br RNHC2H5 + RNH3(+) Br(–) RNH2C2H5(+) Br(–) + RNH2
Unfortunately, the direct alkylation of 1º or 2º-amines to give a more substituted product does not proceed cleanly. If a 1:1 ratio of amine to alkyl halide is used, only 50% of the amine will react because the remaining amine will be tied up as an ammonium halide salt (remember that one equivalent of the strong acid HX is produced). If a 2:1 ratio of amine to alkylating agent is used, as in the above equation, the HX issue is solved, but another problem arises. Both the starting amine and the product amine are nucleophiles. Consequently, once the reaction has started, the product amine competes with the starting material in the later stages of alkylation, and some higher alkylated products are also formed. Even 3º-amines may be alkylated to form quaternary (4º) ammonium salts. When tetraalkyl ammonium salts are desired, as shown in the following example, Hünig's base may be used to scavenge the HI produced in the three SN2 reactions. Steric hindrance prevents this 3º-amine (Hünig's base) from being methylated.
C6H5NH2 + 3 CH3I + Hünig's base C6H5N(CH3)3(+) I(–) + HI salt of Hünig's base
Reaction with Benzenesulfonyl chloride (The Hinsberg test)
Another electrophilic reagent, benzenesulfonyl chloride, reacts with amines in a fashion that provides a useful test for distinguishing primary, secondary and tertiary amines (the Hinsberg test). As shown in the following equations, 1º and 2º-amines react to give sulfonamide derivatives with loss of HCl, whereas 3º-amines do not give any isolable products other than the starting amine. In the latter case a quaternary "onium" salt may be formed as an intermediate, but this rapidly breaks down in water to liberate the original 3º-amine (lower right equation).
The Hinsberg test is conducted in aqueous base (NaOH or KOH), and the benzenesulfonyl chloride reagent is present as an insoluble oil. Because of the heterogeneous nature of this system, the rate at which the sulfonyl chloride reagent is hydrolyzed to its sulfonate salt in the absence of amines is relatively slow. The amine dissolves in the reagent phase, and immediately reacts (if it is 1º or 2º), with the resulting HCl being neutralized by the base. The sulfonamide derivative from 2º-amines is usually an insoluble solid. However, the sulfonamide derivative from 1º-amines is acidic and dissolves in the aqueous base. Acidification of this solution then precipitates the sulfonamide of the 1º-amine.
2. Preparation of 1º-Amines
Although direct alkylation of ammonia by alkyl halides leads to 1º-amines, alternative procedures are preferred in many cases. These methods require two steps, but they provide pure product, usually in good yield. The general strategy is to first form a carbon-nitrogen bond by reacting a nitrogen nucleophile with a carbon electrophile. The following table lists several general examples of this strategy in the rough order of decreasing nucleophilicity of the nitrogen reagent. In the second step, extraneous nitrogen substituents that may have facilitated this bonding are removed to give the amine product.
Reactant 1st Reaction
Type Initial Product 2nd Reaction
Conditions 2nd Reaction
Type Final Product
1. N3(–) RCH2-X or
R2CH-X SN2 RCH2-N3 or
R2CH-N3 LiAlH4 or
4 H2 & Pd Hydrogenolysis RCH2-NH2 or
2. C6H5SO2NH(–) RCH2-X or
R2CH-X SN2 RCH2-NHSO2C6H5 or
R2CH-NHSO2C6H5 Na in NH3 (liq) Hydrogenolysis RCH2-NH2 or
3. CN(–) RCH2-X or
R2CH-X SN2 RCH2-CN or
R2CH-CN LiAlH4 Reduction RCH2-CH2NH2 or
4. NH3 RCH=O or
R2C=O Addition /
Elimination RCH=NH or
R2C=NH H2 & Ni
or NaBH3CN Reduction RCH2-NH2 or
5. NH3 RCOX Addition /
Elimination RCO-NH2 LiAlH4 Reduction RCH2-NH2
(urea) R3C(+) SN1 R3C-NHCONH2 NaOH soln. Hydrolysis R3C-NH2
A specific example of each general class is provided in the diagram below. In the first two, an anionic nitrogen species undergoes a SN2 reaction with a modestly electrophilic alkyl halide reactant. For example #2 an acidic phthalimide derivative of ammonia has been substituted for the sulfonamide analog listed in the table. The principle is the same for the two cases, as will be noted later. Example #3 is similar in nature, but extends the carbon system by a methylene group (CH2). In all three of these methods 3º-alkyl halides cannot be used because the major reaction path is an E2 elimination.
The methods illustrated by examples #4 and #5 proceed by attack of ammonia, or equivalent nitrogen nucleophiles, at the electrophilic carbon of a carbonyl group. A full discussion of carbonyl chemistry is presented later, but for present purposes it is sufficient to recognize that the C=O double bond is polarized so that the carbon atom is electrophilic. Nucleophile addition to aldehydes and ketones is often catalyzed by acids. Acid halides and anhydrides are even more electrophilic, and do not normally require catalysts to react with nucleophiles. The reaction of ammonia with aldehydes or ketones occurs by a reversible addition-elimination pathway to give imines (compounds having a C=N function). These intermediates are not usually isolated, but are reduced as they are formed (i.e. in situ). Acid chlorides react with ammonia to give amides, also by an addition-elimination path, and these are reduced to amines by LiAlH4.
The 6th example is a specialized procedure for bonding an amino group to a 3º-alkyl group (none of the previous methods accomplishes this). Since a carbocation is the electrophilic species, rather poorly nucleophilic nitrogen reactants can be used. Urea, the diamide of carbonic acid, fits this requirement nicely. The resulting 3º-alkyl-substituted urea is then hydrolyzed to give the amine.
One important method of preparing 1º-amines, especially aryl amines, uses a reverse strategy. Here a strongly electrophilic nitrogen species (NO2(+)) bonds to a nucleophilic carbon compound. This nitration reaction gives a nitro group that can be reduced to a 1º-amine by any of several reduction procedures.
The Hofmann rearrangement of 1º-amides provides an additional synthesis of 1º-amines.
To learn about this useful procedure Click Here.
3. Preparation of 2º & 3º-Amines
Of the six methods described above, three are suitable for the preparation of 2º and/or 3º-amines. These are:
(i) Alkylation of the sulfonamide derivative of a 1º-amine. Gives 2º-amines.
(ii) Reduction of alkyl imines and dialkyl iminium salts. Gives 2º & 3º-amines.
(iii) Reduction of amide derivatives of 1º & 2º-amines. Gives 2º & 3º-amines.
Examples showing the application of these methods to the preparation of specific amines are shown in the following diagram. The sulfonamide procedure used in the first example is similar in concept to the phthalimide example #2 presented in the previous diagram. In both cases the acidity of the nitrogen reactant (ammonia or amine) is greatly enhanced by conversion to an imide or sulfonamide derivative. The nucleophilic conjugate base of this acidic nitrogen species is then prepared by treatment with sodium or potassium hydroxide, and this undergoes a SN2 reaction with a 1º or 2º-alkyl halide. Finally, the activating group is removed by hydrolysis (phthalimide) or reductive cleavage (sulfonamide) to give the desired amine. The phthalimide method is only useful for preparing 1º-amines, whereas the sulfonamide procedure may be used to make either 1º or 2º-amines.
Examples #2 & #3 make use of the carbonyl reductive amination reaction (method #4 in the preceding table. This versatile procedure may be used to prepare all classes of amines (1º, 2º & 3º), as shown here and above. A weak acid catalyst is necessary for imine formation, which takes place by amine addition to the carbonyl group, giving a 1-aminoalcohol intermediate, followed by loss of water. The final reduction of the C=N double bond may be carried out catalytically (Pt & Pd catalysts may be used instead of Ni) or chemically (by NaBH3CN). The imine or enamine intermediates are normally not isolated, but are immediately reduced to the amine product.
Carboxylic Acid Derivatives
A Substitution Reaction Which Starts With Addition
Structures of Carboxylic Acid Derivatives
Substitution by Addition-Elimination
Esters - Preparation and Mechanisms
Amides - Preparations
Last time we completed our study of the reactions of aldehydes and ketones, compounds in which a carbonyl group is bonded either to carbons or hydrogens. The typical reaction pattern for these compounds was addition, with a nucleophile adding to the carbonyl carbon and an electrophile adding to the carbonyl oxygen.
Today we'll look at carboxylic acid derivatives. This group of compounds also contains a carbonyl group, but now there is an electronegative atom (oxygen, nitrogen, or a halogen) attached to the carbonyl carbon. This difference in structure leads to a major change in reactivity. Here we find that the reactions of this group of compounds typically involve substitution of the electronegative atom by a nucleophile. Before looking at that reaction in detail, though, let's see what kind of compounds we're talking about.
Notice that each of these functional groups has either an oxygen, a nitrogen, or a halogen attached to the carbonyl carbon.
The typical reactions of these compounds are substitutions -- replacing one of these heteroatoms by a another atom. Here's an example:
The chlorine of the acyl chloride has been replaced by the -OCH2CH3, more specifically by the oxygen atom of that group. This type of reaction, in which an atom or group is replaced by another atom or group, is called a substitution reaction.
We can begin to connect this reaction type with what we have seen earlier by thinking about the mechanism. We notice that the O- end of the group (called an alkoxide) which is doing the substituting is very much like the oxygen in an OH-. Since we've seen the OH- act as a nucleophile when it attacked the electrophilic carbon of a carbonyl group, let's begin by seeing what happens if we use the same approach here.
The first step is familiar from aldehyde and ketone chemistry. The nucleophilic oxygen uses its electrons to make a new bond to the electrophilic carbonyl carbon while the pi bond's electrons move to the carbonyl oxygen. We've made the necessary oxygen-carbon bond. In the next step, the pi bond is reformed, and the carbon-chlorine bond is broken. This is a new type of step, and it happens when breaking this bond is eased by the electron pair being attracted to an electronegative atom such as oxygen, nitrogen or a halogen. This step is called an elimination. The overall substitution process occurs by an addition-elimination mechanism which begins with a nucleophilic addition to the carbonyl group and finishes with the departure of an atom with the bonding pair of electrons. This atom or group is called a "leaving group."
Here's a general statement of the mechanism:
As we look at some specific examples, keep this pattern in mind. There will be some elaborations on it, but we will always find an addition step in which the nucleophile attacks and an elimination step in which the leaving group leaves.
The conversion of acyl chlorides to esters is more commonly carried out by using an alcohol rather than an alkoxide (RO-).
The mechanism of this reaction starts just the same way the earlier one did; the first step is attack of the nucleophile at the carbonyl carbon. In this instance, the nucleophile is an unshared electron pair on a neutral oxygen atom. The intermediate formed in this step rapidly shifts a proton (H+) to the O-. Such transfers of protons between oxygen atoms or nitrogen atoms are fast. (These intermediates are called "tetrahedral intermediates" since carbonyl carbon has been changed to a tetrahedral geometry and an sp3 hybridization.)
The tetrahedral intermediate loses HCl in a single step, one in which the H+ is transferred to a second molecule of alcohol and the Cl comes off as Cl-. It is important to notice that the neutral alcohol oxygen serves as the nucleophile. The O-H bond is not broken until after the C-O bond is formed. There is never any alkoxide in this reaction. Indeed, an alkoxide ion could not survive in the strongly acidic (HCl) solution. This pattern, neutral nucleophile attacks first, then the proton is removed, is very common for neutral nucleophiles and must be followed.
This is a practical and useful method for making esters, but it does make the strong acid HCl, which is often troublesome. A more practical variation is to add a weak base such as pyridine to react with the HCl and neutralize it. This gives us a procedure for making esters from acyl chlorides which uses the following reaction statement:
A similar procedure is used to make amides from acyl chlorides and amines (the amine must have at least one hydrogen attached to the nitrogen).
Acyl chlorides are the most reactive carboxylic acid derivatives. The electronegative chlorine atom pulls electrons toward it in the C-Cl bond, which makes the carbonyl carbon more electrophilic. This makes nucleophilic attack easier. Also, the Cl- is an excellent leaving group, so that step is also fast. Because of their reactivity, acyl chlorides are easily converted into esters and amides and are thus valuable synthetic intermediates. They are made from carboxylic acids by this reaction (Atkins & Carey, Sec 12:10):
In the mechanism we just looked at, the key steps (attack of a nucleophile and departure of a leaving group) were accompanied by steps in which protons moved from one location to another. Such proton transfers are very common in acid catalyzed reactions. Here's the mechanism for the acid catalyzed formation of an ester from a carboxylic acid and an alcohol:
Notice that the nucleophilic attack is preceded by protonation of the carbonyl oxygen. We've seen this step before in the acid-catalyzed additions of nucleophiles to carbonyl groups. Its purpose is to increase the reactivity of the carbonyl carbon as an electrophile, so that it can be easily attacked by the alcohol oxygen. After nucleophilic attack, there is a proton transfer. Its purpose is to make one of the OH groups (either will do) into a good leaving group, water.
Think back to the addition of alcohols to aldehydes to produce hemiacetals. The two mechanisms start off identically. Compare them in detail, and work out the reasons for the different outcome.
Notice that each step in this mechanism is presented as an equilibrium. That means that the whole reaction represents an equilibrium in which significant amounts of carboxylic acid and alcohol co-exist with ester and water.
This allows us to push the reaction one way or the other by controlling concentrations, particularly of water. If we remove water from the reaction mixture, more ester is formed because carboxylic acid and alcohol react to replace the water we have removed. The resulting formation of ester is called Fischer esterification.
If we add water to the reaction mixture, equilibrium is restored by the production of more carboxylic acid and alcohol. This is called acid catalyzed ester hydrolysis.
Esters can also react with amines or ammonia to form amides. This reaction doesn't involve acid catalysis, so the first step is nucleophilic attack at the carbonyl carbon. Proton transfer follows and loss of the alcohol portion of the ester.
This gives us two ways to make amides, this one from esters and the earlier one from acyl chlorides. Here's a third and very direct way to make amides, by heating carboxylic acids and amines together.
South valley university
Faculty of science
Rfer to Dr: Rgaab Faheem fendy
Prepared by : antonios nagah kelayd[ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذه الصورة]