6o6mo3ceea2ag88ohrthmomco0ah CHAPTER 20 d-Fm Cabenyic Acd Derivatives Carboxylic Acid Derivatives and Mass Spectrometry 8osaaa8 0 RCOOM X HC RCOOM RC0OM yur 20-1 Relative Reac atives eaterth the xtn N.-Dt The amideithybridiz 1
1 CHAPTER 20 Carboxylic Acid Derivatives and Mass Spectrometry Relative Reactivities, Structures and Spectra of Carboxylic Acid Derivatives 20-1 Carboxylic acid derivatives undergo substitution reactions via the (often acid- or base-catalyzed) addition-elimination sequence: The relative reactivities of the substrates follow a consistent order: The order of reactivity depends upon the ability of L to act as a leaving group and what effect it has on the adjacent carbonyl function. Lone pairs on L can be delocalized onto the carbonyl oxygen: The resonance form on the right is most important in amides and somewhat less important in esters. Amides and esters are strongly stabilized by resonance. Anhydrides are more reactive than esters because the lone pairs on the central oxygen are shared over two carbonyl groups. Alkanoyl halides are least stable because of their electronegatives and the poor overlap between their p-orbitals and those of carbon. Relative Reactivities, Structures and Spectra of Carboxylic Acid Derivatives 20-1 The greater the resonance, the shorter the C-L bond. The structures of carboxylic acid derivatives are directly related to the extent of resonance. In progressing from alkanoyl halides to esters and amides, the CL bond becomes progressively shorter (increased double-bond character). The NMR spectra of N,N-dimethylformamide at room temperature exhibits two singles for the two methyl groups. •Bond rotation about the C-N bond in this molecule is very slow on the NMR time scale. •The measured barrier to this rotation is about 21 kcal mol-1. The amide nitrogen possesses sp2 hybridization. The resultant planarity of the amide group is the most important determinator of structure (thus, function) in peptides and proteins
IeSehoeeareeTeeheaieanSoreponaia w82 ABLE 20-2 CA CC o on ogn oa o eRgeanono980aeta8asato4e boxylic acid derivat ives are basic and acidic ”2oea。 of the 20-2 Chemistry of Alkanoyl Halides Toenakh2Rlheygeaeaneanedanertheakanocacd Aanmlhaidesundeo3aiton-ennato dditioo-Elimination Reactions of Alkanoyl Halides xylic acids are called H、 CH.CHCH.CB 2
2 IR spectra of amides and esters also indicate the presence of resonance in the structures. The C=O bond is weakened, which causes a corresponding decrease in the carbonyl stretching frequency. The IR spectra of monomeric acetic acid displays a carbonyl stretching frequency of 1780 cm-1, similar to that of anhydrides. The 13C NMR signals of the carbonyl carbons in carboxylic acid derivatives are less sensitive and fall into a narrow range near 170 ppm. The mass spectra of carboxylic acid derivatives typically contain peaks resulting from both α-cleavage and McLafferty rearrangement. Carboxylic acid derivatives are basic and acidic. Resonance in carboxylic acid derivatives affects their basicity (protonation at the carbonyl oxygen) and their acidity (enolate formation). Protonation becomes easier as L becomes more electrondonating. The acidity of the α-hydrogens also increases along the series: 20-2 Chemistry of Alkanoyl Halides The alkanoyl halides are named after the alkanoic acid from which they are derived. The halides of cycloalkanecarboxylic acids are called cycloalkanecarbonyl halides. Alkanoyl halides undergo addition-elimination reactions:
Cierhydrotyzesalkanoychloridestoearbogyic Alcohols convert alkanoyl chlorides into esters. ealo9lchagnaCoenagaarethecamesponding ernhegereyproducedbythereactionotalkanoy 0 ma+一+ 流一牌。海。 Ieetinsmgamdefomatonfomakano1hioides 中 s convert alkanoyl chlorides uction of alkanoyl chlo rides results in aldehydes 08rn9dne2oreS8eR8eaeedrey. 3
3 Water hydrolyzes alkanoyl chlorides to carboxylic acids. Alkanoyl chlorides react with water to give the corresponding carboxylic acids and hydrogen chloride. Alcohols convert alkanoyl chlorides into esters. Esters can be effectively produced by the reaction of alkanoyl chlorides with alcohols. An alkali metal hydroxide, pyridine or a tertiary amine is usually added to neutralize the HCl produced by the reaction. The basic or neutral conditions employed in this method avoid the equilibrium problem of acid-catalyzed ester formation. Amines convert alkanoyl chlorides into amides. Ammonia, primary amines and secondary amines convert alkanoyl chlorides into amides. Aqueous ammonia can be used for the synthesis of simple amines since it is a much stronger nucleophile than water. The HCl formed is neutralized by a base, which can be excess amine. The mechanism of amide formation from alkanoyl chlorides is addition-elimination: Tertiary amines cannot form amides since they do not possess a proton to lose during the last step of the reaction. Organometallic reagents convert alkanoyl chlorides into ketones. Ketone formation is best achieved by using diorganocuprates rather than RLi or RMgX. The latter are unselective and tend to attack more than once leading to alcohol formation. Reduction of alkanoyl chlorides results in aldehydes. Alkanoyl chlorides are reduced to alcohols when sodium borohydride or lithium aluminum hydride are used directly. The reaction stops at the aldehyde if LiAlH4 is first reacted with three molecules of 2-methyl-2-propanol (tert-butyl alcohol), which reduces the nucleophilicity of the remaining hydride ion
20-3 Chemistry of Carboxylic Anhydrides The leavinggroucabylte nsted of a halide. Aeee ash dde 0 0H,+o yyndesndergsmhiceadtong 20-4 Chemistry of Esters Esters are alkyl alkanoates 0 ca eae0gogfieeoocntgpaiotwhou bea9emaoesmr8eaenuceophlesarem enbr8oecaae 5tesMpemetenrhpandpbyboogcalrolesnthe 89 roethane as a cleaning aheromoheestesaeusedassotenesoastcaesjo 4
4 20-3 Chemistry of Carboxylic Anhydrides Carboxylic anhydrides are named by adding the term “anhydride” to the acid name (or names, if a mixed anhydride). This method also applies to cyclic derivatives. The reactions of anhydrides with nucleophiles are the same as for alkanoyl halide, only less vigorous. The leaving group is a carboxylate instead of a halide. Cyclic anhydrides undergo similar reactions which lead to ring opening. Alkanoyl halides are difficult to store for extended periods without undergoing hydrolysis from atmospheric moisture. Anhydrides, although less reactive towards nucleophiles, are more stable and many are commercially available. For these reasons, anhydrides are often preferred for the preparation of many carboxylic acid derivatives. 20-4 Chemistry of Esters Esters are alkyl alkanoates. Esters are named alkyl alkanoates, and the ester grouping as a substituent is called “alkoxycarbonyl.” Cyclical esters are named oxa-2-cycloalkanone (common name, lactone). The common name is preceded by α,β,γ,etc., depending upon ring size. Esters are prevalent in plants and play biological roles in the animal kingdom, often as pheromones. (Z)-7-dodecenyl acetate is a component in the pheromone mixture of several species of moths, as well as the mating pheromone of the elephant. In industry, lower esters such as ethyl acetate and butyl acetate are used as solvents. Butyl butanoate has replaced trichloroethane as a cleaning solvent in the electronics industry. Higher nonvolatile esters are used as softeners (plasticizers) for brittle polymers
bas ce the hy Esters hydrolyze to carboxylic acids. 默+用一0H+B- via the revers 一 2 theydroe on terfication takes place with alcohols actmay be ring opened by. rd rea ansform esters into 5
5 Esters hydrolyze to carboxylic acids. Esters undergo nucleophilic substitution reactions by means of addition-elimination pathways, although with reduced reactivity compared to halides and anhydrides. In the presence of excess water and a strong acid, esters are cleaved to carboxylic acids and alcohols. This reaction requires heating to proceed at a reasonable rate, however. The acid-catalyzed hydrolysis of esters proceeds via the reverse of the acid-catalyzed esterification mechanism. Strong bases catalyze the hydrolysis of esters through an addition-elimination mechanism. The strong base converts the poor nucleophile H2O into the higher nucleophilic ion OH- . Unlike acid-catalyzed hydrolysis, base-catalyzed hydrolysis is driven to completion by the last step, which converts the carboxylic acid into a carboxylate ion. Ester hydrolysis is often carried out using the hydroxide ion itself, in at least stoichiometric amounts. Transesterfication takes place with alcohols. The direct conversion of one ester into another without proceeding through the free carboxylic acid can be carried out by reacting a second alcohol with an ester in the presence of strong acid. This process is called transesterification and is reversible. To shift the equilibrium, a large excess of the second alcohol is used. Lactones may be ring opened by transesterification. Acid-catalyzed transesterifications proceed by protonation of the carbonyl oxygen and subsequent attack by the alcohol. Base-catalyzed transesterifications proceed by deprotonation of the alcohol and subsequent attack at the carbonyl carbon. Amines convert esters into amides. Amines are more nucleophilic than alcohols. Esters readily transform into amides by treatment with an amine and subsequent heating. (A catalyst is not required.) Grignard reagents transform esters into alcohols. Two equivalents of a Grignard reagent will react with a normal ester to form a tertiary alcohol. In the case of a formate ester, a secondary alcohol is formed