第四军医大学药学课件

1、第四军医大学药学,General consideration:,第四军医大学药学,Summary,Nomenclature and Structure 1.1. Nomenclature: UIPAC names, Common Names 1.2. Structure 2. Physical Properties and Spectroscopy 2.1. Physical Properties 2.2. Spectroscopy: IR, 1HNMR, 13CNMR, MS, UV 3. Chemical Properties: 4. Synthesis of Aldehydes and

2、Ketones 5. ,-Unsaturated Carbonyl Compounds: 1,4-Addtion, Diels-Alder Reaction,第四军医大学药学,Chapter 10 Carboxylic Acids and Substituted Carboxylic Acids,第四军医大学药学,Carboxyl group is usually written COOH Aliphatic acids have an alkyl group bonded to -COOH Aromatic acids have an aryl group Fatty acids are l

3、ong-chain aliphatic acids,A carboxylic acid consists of three parts: a hydroxyl group, a carbonyl group, and the “remainder.”,第四军医大学药学,1. Nomenclature,In naming, the carboxyl group takes priority over any of the other functional groups we have discussed,1.1. UIPAC Names: Monocarboxylic acids: The al

4、iphatic carboxylic acids are named by replacing the ending -e in the name of the alkane by -oic acid The alkanoic acid stem is numbered by assigning the number 1 to the carboxy carbon Substituents are labeled along the longest chain incorporating the CO2H group,第四军医大学药学,Cycloalkanes with -COOH subst

5、ituents are generally named as cycloalkanecarboxylic acids,第四军医大学药学,Unsaturated acids Unsaturated acids are named using the name of the corresponding alkene, with the final -e replaced by -oic acid. The carbon chain is numbered starting with the carboxyl carbon, and a number gives the location of th

6、e double bond The stereochemical terms cis and trans (and Z and E) are used as they are with other alkenes,第四军医大学药学,Many simple carboxylic acids have common names accepted by IUPAC,Aromatic acids of the form Ar-COOH are named as derivatives of benzoic acid,第四军医大学药学,Dicarboxylic Acids:,Aliphatic dica

7、rboxylic acids are named simply by adding the suffix -dioic acid to the name of the parent alkane,第四军医大学药学,Aromatic dicarboxylic acids are named by adding the words dicarboxylic acid to “benzene”,Many diacids have common names accepted by IUPAC,第四军医大学药学,1.1.2. Common Names,Aliphatic carboxylic acids

8、 are named according to their source or for some characteristic property The Greek letters , , , , and so forth are often added as a prefix to locate substituents The -position in a carboxylic acid is the one next to the carboxyl group,第四军医大学药学,The nasty odor of ginkgo seeds,A chemical signal of dea

9、d ants,The tart taste of many fruits and vegetables,Vinegar,Ants weapon,HCO2H Formic acid,CH3CO2H Acetic acid,第四军医大学药学,1.3. Structure,The carbonyl carbon is sp2 hybridized and trigonal planar, making it relatively uncrowded. The electronegative oxygen atom polarizes the carbonyl group, making the ca

10、rbonyl carbon electrophilic.,第四军医大学药学,The carboxyl group is planar, with one of its carbonoxygen bonds shorter than the other, and with bond angles at carbon close to 120. sp2 Hybridization at carbon, and a +carbonoxygen double bond analogous to that of aldehydes and ketones. sp2 Hybridization of th

11、e hydroxyl oxygen allows one of its unshared electron pairs to be delocalized by orbital overlap with the system of the carbonyl group Lone-pair donation from the hydroxyl oxygen makes the carbonyl group less electrophilic than that of an aldehyde or ketone.,第四军医大学药学,The electrostatic potential map

12、of formic acid shows the most electron-rich site to be the oxygen of the carbonyl group and the most electron-poor one to be, as expected, the OH hydrogen.,第四军医大学药学,2. Physical Properties and Spectroscopy,2.1. Physical Properties,Boiling Points,Higher boiling points than similar alcohols, due to dim

13、er formation,第四军医大学药学,Melting Points,Aliphatic acids with more than 8 carbons are solids at room temperature. Double bonds (especially cis) lower the melting point. Note these 18-C acids:,Stearic acid (saturated): 72C Oleic acid (one cis double bond): 16C Linoleic acid (two cis double bonds): -5C,第四

14、军医大学药学,Solubility,Water solubility decreases with the length of the carbon chain. Up to 4 carbons, acid is miscible in water. More soluble in alcohol. Also soluble in relatively nonpolar solvents like chloroform because it dissolves as a dimer.,第四军医大学药学,2.2. Spectroscopic Properties,Infrared:,The O-

15、H and C-H stretching frequencies overlap to produce a broad absorption in the 35002500 cm-1 region A strong band for C=O stretching between 1710 to 1760 cm-1 Free carboxyl groups absorb at 1760 cm-1, but the more commonly encountered dimeric carboxyl groups absorb in a broad band centered around 171

16、0 cm-1,第四军医大学药学,第四军医大学药学,1H NMR,The acidic proton of a carboxylic acid produces a signal that is usually broad and appears in the region 1013 This proton is exchangeable with deuterium of a solvent containing the OD linkage, such as D2O Protons of the -carbon position come into resonance in the same

17、 region as do those of aldehydes and ketones ( 22.5),第四军医大学药学,第四军医大学药学,13C NMR,The carbonyl group of a carboxylic acid derivative generally appears in the region between 160 and 185 ppm,第四军医大学药学,Mass Spectrometry,第四军医大学药学,第四军医大学药学,UV Spectroscopy,Saturated carboxylic acids absorb very weakly around

18、200-215 nm. If C=C is conjugated with C=O, molar absorptivity = 10,000 at 200 nm. An additional conjugated double bond increases the absorption wavelength to 250 nm.,第四军医大学药学,3. Chemical Properties,sp2 Hybridization of the hydroxyl oxygen allows one of its unshared electron pairs to be delocalized b

19、y orbital overlap with the system of the carbonyl group Lone-pair donation from the hydroxyl oxygen makes the carbonyl group less electrophilic than that of an aldehyde or ketone.,第四军医大学药学,General consideration:,第四军医大学药学,3.1. Acidity,Carboxylic acids are the most acidic class of compounds that conta

20、in only carbon, hydrogen, and oxygen,Resonance Stabilization,第四军医大学药学,Acidity Compared to Alcohols,Carboxylic acids are better proton donors than are alcohols (The pKa of ethanol is 16, compared to 5 for acetic acid) In an alkoxide ion, the negative charge is localized on oxygen while in a carboxyla

21、te ion the negative charge is delocalized over two equivalent oxygen atoms, giving resonance stabilization,第四军医大学药学,Acidity Constant and pKa,Carboxylic acids transfer a proton to water to give H3O+ and carboxylate anions, RCO2, but H3O+ is a much stronger acid The acidity constant, Ka, is about 10-5

22、 for a typical carboxylic acid (pKa 5),第四军医大学药学,Substituent Effects,An electronegative group will drive the ionization equilibrium toward dissociation, increasing acidity An electron-donating group destabilizes the carboxylate anion and decreases acidity,第四军医大学药学,Alkyl groups have little effect. The

23、 ionization constants of all acids that have the general formula CnH2n+1CO2H are very similar to one another and equal approximately 10 5 (pKa 5). An electronegative substituent, particularly if it is attached to the carbon, increases the acidity of a carboxylic acid. Monohaloacetic acids is about 1

24、00 times more acidic than acetic acid. Multiple halogen substitution increases the acidity even more; trichloroacetic acid is 7000 times more acidic than acetic acid!,Substituent Effects on Acidity,第四军医大学药学,Substituent Effects on Acidity,Electronegative substituents promote formation of the carboxyl

25、ate ion,第四军医大学药学,Examples of Inductive Effects on Acidity,Fluoroacetic, chloroacetic, bromoacetic, and iodoaceticacids are stronger acids than acetic acid Multiple electronegative substituents have synergistic effects on acidity,第四军医大学药学,Inductive effects depend on the electronegativity of the subst

26、ituent and the number of bonds between it and the affected site. As the number of bonds increases, the inductive effect decreases,第四军医大学药学,Acidity of Substituted Benzoic Acids,Benzoic acid itself is a somewhat stronger acid than acetic acid. Carbon becomes more electron-withdrawing as its s characte

27、r increases,The largest effects are observed when strongly electron-withdrawing substituents are ortho to the carboxyl group,第四军医大学药学,Substituent at meta position: An inductive effect; Substituent at para position: An resonance effect and inductive effect, and resonance effect outweighs the inductiv

28、e effect Substituent at ortho position: Nearly all ortho substituents exert an effect of the same kind acid-strengthening whether they are electron-withdrawing or electron-releasing, and the effect is unusually large.,Substituent Effects in Substituted Benzoic Acids,第四军医大学药学,Aromatic Substituent Eff

29、ects,An electron-withdrawing group (-NO2) increases acidity by stabilizing the carboxylate anion An electron-donating (activating) group (OCH3) decreases acidity by destabilizing the carboxylate anion,第四军医大学药学,If we want to know the effect of a certain substituent on electrophilic reactivity, we can

30、 simply find the acidity of the corresponding benzoic acid.,第四军医大学药学,Substituent Effects in Substituted Benzoic Acids,第四军医大学药学,Diacids have two dissociation constants: Ka1 is for the first dissociation, and Ka2 is for the second dissociation, to give a dianion. The second carboxyl group is much less

31、 acidic than the first ( Ka2 Ka1) because extra energy is required to create a second negative charge close to another, mutually repulsive, negative charge. This repulsive effect decreases as the chain gets longer.,第四军医大学药学,“Field Effects”: The Electrostatic Interpretation,第四军医大学药学,Formation of Salt

32、s,In the presence of bases such as NaOH, Na2CO3 and NaHCO3, carboxylic acids are neutralized rapidly and quantitatively,Adding a strong acid, like HCl, regenerates the carboxylic acid.,第四军医大学药学,Properties of Acid Salts,Usually solids with no odor. Carboxylate salts of Na+, K+, Li+, and NH4+ are solu

33、ble in water. Soap is the soluble sodium salt of a long chain fatty acid. Salts can be formed by the reaction of an acid with NaHCO3, releasing CO2.,第四军医大学药学,Purifying an Acid,第四军医大学药学,3.2. Substitution at the Carboxy Carbon,3.2.1. Fischer Esterification:,The reaction of a carboxylic acid with an al

34、cohol in the presence of an acid catalyst to form an ester,Emil Fischer (1852-1919) was a German Chemist and won the Nobel Prize in Chemistry in 1902. He discovered the Fischer esterification, and developed the Fischer projection, a symbolic way of drawing asymmetric carbon atoms,第四军医大学药学,Acid-catal

35、yzed esterification is reversible A large excess of alcohol Removal of water (azeotropic distillation and a Dean-Stark trap),第四军医大学药学,In 1938, Irving Roberts and Harold C. Urey of Columbia University confirmed that the C-O bond of the alcohol is preserved during esterification, and the oxygen that i

36、s lost as a water molecule must come from the carboxylic acid.,Harold Clayton Urey (1893 1981) was an American physical chemist whose pioneering work on isotopes earned him the Nobel Prize in Chemistry in 1934. He played a significant role in the development of the atom bomb.,Harold Urey,第四军医大学药学,Me

37、chanism of Fischer esterification,第四军医大学药学,The presence of bulky groups near the site of reaction, whether in the alcohol or in the acid, slows down esterification (as well as its reverse, hydrolysis). Reactivity in esterification: CH3OH 1 2 ( 3) HCOOH CH3COOH RCH2COOH R2CHCOOH R3CCOOH This steric h

38、indrance can be so marked that special methods are required to prepare esters of tertiary alcohols or esters of acids like 2,4,6-trimethylbenzoic acid (mesitoic acid).,第四军医大学药学,Synthesis of tert-butyl esters:,Mechanism:,第四军医大学药学,Esterification of 2,4,6-trimethylbezoic acid:,第四军医大学药学,The three elemen

39、ts of the chemistry of carboxylic acid derivatives. These elements are 1. Activation of the carbonyl group by protonation of the carbonyl oxygen 2. Nucleophilic addition to the protonated carbonyl to form a tetrahedral intermediate 3. Elimination from the tetrahedral intermediate to restore the carb

40、onyl group This sequence is fundamental to the carbonyl-group chemistry of carboxylic acids, acyl chlorides, anhydrides, esters, and amides.,第四军医大学药学,3. 2. 2. Formation of Acyl Halides, Acid Anhydrides and Amides,The functional group of an acyl halide is a carbonyl group bonded to a halogen atom,The conversion of carboxylic acids into acyl halides employs the same reagents used in the synthesis of haloalkanes from alcohols,General Reactions:,第四军医大学药学,Mechanism,第四军医大学药学,An acid anhydride