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1、Chapter 20: Carboxylic Acid Derivatives,OH bad leaving group,What is the relative reactivity of these carboxylic acid derivatives?,Most reactive,Least reactive,L to the right, when acting as Nu, displaces that to the left,,= L,,,,,Origins of Reactivity Trends,Inductive effects,Elements to the right

2、in a row of PT are more electronegative (nuclear charge increase). Elements down a column in PT are less electronegative (size), but bonds to them get weaker.,Donating ability of L decreases from left to right in the periodic table. The greater the resonance, the shorter the C-L bond.,2. Resonance e

3、ffects,At the extreme: Hindered rotation in amides on the NMR time scale. The nitrogen is sp2-hybridized to maximize resonance.,Acetyl chloride,Acetamide,Differences reflected in pKa values,Basicity,Protonation gets easier from L = X to O to N,For the same reason, deprotonation gets more difficult,C

4、omparing Reactivity,A. Alkanoyl Halides B. Anhydrides C. Esters D. Amides E. Alkanenitriles,A. Alkanoyl Halides,Names: Alkanoic acid alkanoyl halide Cycloalkanecarboxylic acid cycloalkanecarbonyl halide,Cyclohexanecarbonyl fluoride,In a nutshell.......,Mechanism:,Example:,,1. Water: Hydrolysis gives

5、 RCOOH,General Reaction,Example:,60%,2. Alcohol: ROH converts alkanoyl chlorides into esters,Works for NH3, RNH2, and RNHR,Reaction:,3. Amines turn alkanoyl chlorides into amides,Mechanism:,RMgX at low temperature, or R2CuLi,4. Organometallic reagents transform alkanoyl chlorides into ketones,Exampl

6、es:,,1. THF, -78 C 2. H+, H2O,5. Reduction of alkanoyl chlorides results in aldehydes,Use modified (less reactive form of) LiAlH4,Does not touch the aldehyde product,B. Anhydrides,Names: Add anhydride to the acid name,Acetic anhydride,Pentanedioic anhydride,,= Leaving group,,,,+,,+,React

7、ions:,Similar to alkanoyl halides, but anhydrides are less corrosive, cheaper,Mechanism:,Examples:,,Regioselective reaction?,Cyclic anhydrides react by ring opening: Allows the regioselective functionalization of a dioic acid.,For example, problem:,,Heating the dioic acid produces the cyclic anhydri

8、de:,,Now, treat with nucleophile to ring open:,:,C. Esters,Names: Alkyl alkanoate,-C(O)OR substituent called alkoxycarbonyl,Methyl acetate,Cyclic: Lactone,-Propiolactone Common naming,1,1-Dimethylethyl butanoate,,Note space,Esters in Nature: Waxes, Fats, and Oils,Fats and oils,Fatty acid

9、s are unbranched and contain an even number of carbon atoms; unsaturated fats are usually cis. Fats are biological energy reserves.,Triesters of 1,2,3-propanetriol (glycerol),,Example:,Mechanisms: a. Base-mediated,1. Water: Hydrolysis gives carboxylic acids,Reactions of Esters,Work up with acidic wa

10、ter gives RCOOH,b. Acid-catalyzed (as applied to a lactone),2. Alcohols effect transesterification,3. Amines convert esters into amides,Example:,,Use 2 equivalents of Grignard reagent,4. Grignard reagents: Esters turn into alcohols,Mechanism:,5. Hydride reagents: Reduce esters to alcohols or aldehyd

11、es,LiAlH4 goes all the way:,The milder DIBAL stops at aldehyde stage:,NaBH4 is too unreactive.,Mechanisms: Double or single hydride additions,6. Ester enolates can be alkylated,Similar to aldehyde and ketone enolates. Limitation: Basic!,:,,,,,Other alkylating agents:,-,Aldol-like,Intramolecular tran

12、sesterification,D. Amides,Amide linkage is what holds proteins together.,Names: Alkane Alkanamide Substituents on N labeled N -or N,N - Cycloalkane amides: Cycloalkanecarboxamide Cyclic amides: Lactams,Formamide,Primary,Secondary,N-Methylacetamide,Tertiary,4-Bromo-N-ethyl-N-methyl

13、pentanamide,Reactions,1. Hydrolysis to component carboxylic acid and amine,Acid:,Base:,Mechanism of hydrolysis by aqueous base:,,Neutralized by aqueous work-up.,2. Reduction to an amine,Mechanism:,3. Reduction to an aldehyde,Mechanism goes by single hydride addition to hemiaminal stage, then hydroly

14、sis.,Acidic, like carboxylic acid,pKa Values higher because amide carbonyl is relatively stabilized by resonance and N is less e-negative than O.,Amide Enolates and Amidates,,Acidic, like other carbonyl compounds,,Allows alkylation at N or C (if N is blocked):,Only for primary amines:,This constitut

15、es a one-carbon degradation of a chain: Topologically, CO is excised.,4. Hofmann rearrangement,Example:,Mechanism:,Recall: CHCl3 + base -CCl3,,6e species,Recall: -CCl3 CCl2 + -Cl,E. Alkanenitriles: RCN,Names: Alkanoic acid alkanenitrile Substituent CN is called cyano Cyanocycloalkanes

16、 are called cycloalkanecarbonitriles,Retained by IUPAC,Structure,C and N sp-hybridized like C in alkynes,,1H NMR:,,Spectra,13C NMR:,, 112-126 ppm (close to alkene region),,Higher than (65-85 ppm), because N is more electronegative,IR:,Stretch 2250 cm-1,,Compare 2120 cm-1 weaker bond,Nitriles are Aci

17、dic and Basic,pKa -10,RCH2CN,pKa 25,,Alkylation of anion with RX, RC(O)H is possible: Like enolates,Acidic:,Basic,Example:,Hydrolysis: H+ or HO- to carboxylic acids,Recall:,General: RH RX RCN RCOOH,,Mechanisms: H+-catalyzed,HO--”catalyzed” (actually need stoichiometric base, because it makes carboxy

18、late first, before acidic work-up),Amide,Use RLi or RMgX reagents,Organometallic reagents attack nitriles to give ketones,General:,,,,Ketone synthesis,Example:,,C,N,,,,R,,General: RX RCN RCHO,Use LiAlH(OR)3 or,Reduction of nitriles by modified hydrides leads to aldehydes,Example:,LiAlH4 + RCN RCH2NH

19、2 H2 + RCN RCH2NH2,General: RX RCN RCH2NH2,Reduction of nitriles by LiAlH4 or catalytic hydrogenation leads to amines,PtO2,,Examples:,Mass Spectrometry,,,Ionization,,Deflection,,m/z = Molecular weight per charge (charge usually one),The mass spectrometer distinguishes ions by weight,1 eV 23 kcal

20、 mol-1,High-resolution mass spectrometry reveals molecular formulas,High Resolution Mass Spectrometry,Molecular ions with 70 eV ( 1600 kcal mol-1) undergo fragmentation,There are two ways of fragmenting a radical cation to a radical (uncharged, hence undetected) and a cation.,Fragmentation,Mass Spec

21、trum of CH4,Largest peak (base peak): defined as 100%. Not always the molecular ion!,Due to 13C natural abundance,,,,,Mass spectra reveal the presence of isotopes:,13C natural abundance is 1.1%; therefore relative height of M+1 peak = n x 1.1%, where n = number of carbons. Other isotopes: 18O: 0.204

22、%; 35Cl : 37Cl = 3:1; 79Br : 81Br = 1:1,Mass spectrum of 1-bromopropane,m/z = 43; due to propyl,Fragmentation is more likely at a highly substituted center: Follows carbocation stabilities: tertiary secondary primary,Examples: C5H12 isomers,All C-C bonds are ruptured with roughly equal probability.

23、Note: Fragments have odd weight.,Mass spectrum of pentane,The peaks at m/z = 43 and 57 result from preferred fragmentation around C2 to give secondary carbocations.,Mass spectrum of 2-methylbutane,,,,Only a very weak molecular ion peak is seen, because the fragmentation to give a tertiary cation is

24、favored.,Mass spectrum of 2,2-dimethylpropane,Alcohols:,M+ often not observed,Fragmentation also helps to identify functional groups,Alcohol Fragmentation by Dehydration and Cleavage:,,Characteristic of water; fragment ion is even,Mass spectrum of 1-butanol,The parent ion, at m/z = 74, gives rise to

25、 a small peak because of ready loss of water to give the ion at m/z = 56.,,Alkenes fragment to give resonance-stabilized cations,Mass spectrum of 1-butene,Mass spectrum of 2-hexene,Ketones:,Acylium ions,Mass Spectrum of 2-Pentanone,Shows two peaks for cleavage and one for “McLafferty rearrangement” (m/z = 58), coming up.,Mass Spectrum of 3-pentanone,Shows only a single cleavage peak because of symmetry,General:,McLafferty Rearrangement,Example: 2-Pentanone,Ethene and acetone enol are produced.,Needs an H in position to carbonyl: Allows aromatic, 6 e TS,The Mass Spectrum of Estrone,