McMurry 7e Ch19-23 Notes 5-29-07

Organic II McMurry 7th Edition
CHAPTER 19 ALDEHYDES AND KETONES: NUCLEOPHILIC ADDITION REACTIONS
Suggested Problems: ,30,32,34,45,48
Properties: Review the structure of the carbonyl group. The carbon is sp2 hybridized and is trigonal planar with a bond angle of 120. The bond is planar. The carbonyl group is polarized and therefore is weakly associated causing aldehydes and ketones to have higher boiling points than alkanes but not as high as alcohols. Carbonyl groups do not have hydrogen bonding and therefore their boiling points are lower than the alcohols.
19.1 Nomenclature: Aldehydes Replace the terminal "e" with the suffix "al". The longest carbon chain must include the CHO group and the CHO group is assigned the number one. If the CHO group is attached to a ring, then "carbaldehyde" is used to designate the aldehyde group. Ketone The terminal "e" is replaced by the suffix "one". The longest carbon chain must include the carbonyl group and the number must be done so that the carbonyl group has the lowest number. Examples:
CHO CH3CH2CH2CHO
butanal (butyraldehyde) cyclohexanecarbaldehyde
O CH3-C-CH2CH3
2-butanone (methyl ethyl ketone)
cyclohexanone
Watch out for the common names! 19.2 Preparation of Aldehydes and Ketones
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Aldehydes I. Oxidation of 1 Alcohols Using a Mild Oxidizing Agent, PCC: Pyridinium Chlorochromate PCC CH2Cl2
1o Alcohols
aldehydes + N CrO3ClH PCC
II. Oxidative Cleavage of Alkenes Using Ozone The work-up could be either Zn/H2O or H2O2. H H R-C=C-R H R-C=O H
1. O3 2. work-up
O=C-R
III. Reduction Reactions of More Highly Oxidized Compounds A. Acid Chlorides Using Rosenmund Catalyst and Hydrogen Gas O R-C-Cl O R-C-H
H2 Rosenmund catalyst
Rosenmund Catalyst - Pd/BaSO4, S8, quinoline B. Hydride Reductions of Esters and Acid Chlorides Using DIBAH. O i) R-C-OR' 1. DIBAH 2. H3O+ O R-C-H
O ii) Ketones I. Oxidation of 2 Alcohols by Any Oxidizing Agent 71 R-C-Cl 1. DIBAH 2. H3O+
O R-C-H
There are 4 common oxidizing agents employed: (1) CrO3/H2SO4 (2) Na2Cr2O7/H2SO4 (3) KMnO4/H+ (4) PCC, pyridinium chlorochromate, in a polar aprotic solvent.
2o Alcohols II. Oxidative Cleavage
any oxidizing agent
ketones
A. Ozonolysis of Di, Tri or Tetrasubstituted Alkenes The work-up could be either Zn/H2O or H2O2. R H(R) R-C=C-R(H) H(R)
1. O3 2. work-up
R R-C=O
O=C-R(H)
B. Basic Permanganate Note: If the alkene has a hydrogen on the sp2 carbon, then the aldehyde initially formed is further oxidized to the carboxylate ion. Terminal alkenes produce carbon dioxide as one of the products.
R H R-C=C-R'
hot KMnO4, -OH O R-C-X
R R-C=O
O=C-R' H AlCl3
O C-R
R H
HX
hot KMnO4, -OH R-C=O + CO R-C=C-H 2 III. Reactions with Aromatic Rings via Friedel-Crafts Acylation
IV. Reactions with Organocopper Reagents
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O R-C-X
2 R'2CuLi
R-C-R'
a ketone
Note: Organocopper reagents only react with acid halides. Reactivity Considerations: In comparison, aldehydes are generally more reactive than ketones. One factor contributing to this observation is steric hindrance. The least sterically hindered the carbonyl carbon, the more reactive it is. This can be seen in that, methanal (formaldehyde) is most reactive followed by other aldehydes and then ketones. The relative reactivities of the carbonyl compounds covered so far are given below.
acyl halides > anhydrides > aldehydes > ketones > carboxylic acids ~ esters > amides most reactive least reactive
19.4-11 Nucleophilic Addition Reactions of Aldehydes and Ketones: The main types of reactions involving aldehydes and ketones are Nucleophilic Addition Reactions. If the attacking nucleophilic atom has a pair of nonbonding electrons in the addition product, then it also undergoes elimination.
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Organic II McMurry 7th Edition Without Nonbonding Electrons O R-C-H(R) OH
HZ
R-C-H(R) Z
With Nonbonding Electrons O R-C-H(R) OH H + OH H+ R-C-H(R) :Z Z+ R-C-H(R)
.. HZ
R-C-H(R) :Z
Reactions: I. Oxidation A. Aldehydes Go to Carboxylic Acids There are a variety of oxidizing agents that can be used. Synthetically you must keep in mind the other functional groups present and their sensitivity to the oxidizing agent. Some common oxidizing agents include: hot nitric acid, KMnO4, CrO3/H2SO4, Ag2O/NH3 (Tollen's) and others.
B. Ketones are usually inert to oxidizing agents but will undergo cleavage with hot KMnO4 to form the diacid.
II. Nucleophilic Additions Nucleophiles can fall into two broad categories 1. Negatively Charged Nucleophiles: OH-, H-, R3C-, RO-, and CN2. Neutral Nucleophiles: H2O, ROH, NH3, and RNH2
The general reaction scheme showing both types of nucleophiles is shown below.
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O R O (neutral) :NuH2 C H (R) + NuH2
R C (R) H Nu
H2O
R-C-H(R) (negative) NuO R C H (R) Nu HA R OH C H (R) Nu
The relative reactivity of aldehydes and ketones depend upon the accessibility of the carbonyl carbon and the groups attached to the adjacent carbon atoms. Aldehydes only have one electron-releasing group attached to the carbonyl and therefore are less stable (more reactive) than ketones, which have two electron-releasing groups attached. If electron-withdrawing groups are attached, then this increases the electrophilicity of the carbonyl carbon.
A. Hydration of Carbonyls to Form Hydrates (Gemdiols) The gemdiol formation is reversible and can be catalyzed by either acid or base. Acid-Catalyzed
:O : C
+ : O :H
OH
OH - H+ C OH
H+
H2O
C + OH2
Base-Catalyzed :O : C O OH
-OH
C OH
H-O-H
C OH
-OH
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Examples: O CH3-C-CH3 99.99% OH H2O CH3-C-CH3 OH 0.01% 0.1% O H-C-H H2O OH H-C-H OH 99.9%
B. Cyanohydrin Formation (Addition of HCN) The first step is the protonation of the carbonyl oxygen followed by the attack of the cyanide ion. This is a very useful intermediate in the synthesis of amino acids. HCN :O : C + :O C H+ + CNgood nucleophile H O H
H+
CN-
C CN cyanohydrin
Reactions of Cyanohydrins O H 1. LAH O C CN H3O+ / heat H 2. H2O C hydroxy 10 amine CH2NH2 O H C CO2H hydroxy carboxylic acid
C. Addition of Grignard Reagents to form Alcohols Unlike hydration and cyanohydrin formation Grignard addition is generally irreversible. Grignard reagents are nucleophilic because the Mg-C bond is very polarized with the negative charge on the carbon. The carbon group acts as if it were a carbanion. Initially the magnesium complexes with the carbonyl oxygen making the
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carbonyl a better electrophile. The nucleophilic addition takes place via a tetrahedral intermediate. Subsequent reaction of this intermediate with aqueous acid yields the alcohol.
Examples: :O : R C H O 1. R'MgX 2. H3O+ R C R' R" R' 1. R"MgX 2. H3 O+ R C R' OH a 30 alcohol H H a 20 alcohol
:O : R C
D. Addition of Hydride Ion-Reduction to Alcohols The two most common reducing agents used are lithium aluminum hydride and sodium borohydride. The reducing agent acts as a hydride donor, thus adding the nucleophile. The subsequent addition of water or aqueous acid yields the alcohol. Examples: :O : R C H O 1. LAH 2. H3 O+ R C H H R' 1. NaBH4 2. H3 O+ R C R' OH a 20 alcohol H H a 10 alcohol
:O : R C
E. Addition of Amines to Form Imines and Enamines Primary amines (RNH2) react with carbonyls to form imines and secondary amines (R2NH) react with carbonyls to form enamines. Formation of Imines:
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In general:
C
Mechanism:
H2N-R
H+
N-R
H2O
Reaction is usually done in benzene because it forms an azeotrope with water and the therefore the water can be removed by using a Dean-Stark Trap. H+ + OH .. H2N-R - H+
OH
OH
+ NH2R H+ - H2O + - H+ N-R H iminium ion Examples:

Oxime
NHR
OH2+
N-R
NHR ..
imine
H2NOH
N-OH
H2O
H
Semicarbazone
N O
C O
NH2
CHO
H2NNHCNH2
H2O
2,4-Dinitrophenylhydrazone O2 N H3C C O + H2NNH H3C
NO2
H3 C H3 C C N-NH
O2N NO2
H2O
Preparation of Enamines:
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In general: R CH2 R' Examples: C O R C H C
HNR"2
H+ R'
NR"2
O H+
+ N H
N H
H3C HN(CH3)2 TiCl4 Et2O
CH3
TiO2
F. Wolff-Kishner Reaction-Addition of Hydrazine and Clemmensen Reduction This is a variation on the imine theme. The treatment of aldehydes or ketones with the primary amine, hydrazine in the presence of base transforms the carbonyl compound into an alkane. The overall reaction appears to be a complete reduction of the carbonyl group to an alkane. Usually the reaction is carried out at 240 C in boiling diethylene glycol. Recent advances have used DMSO as the solvent and carried the reaction out at room temperature. The Wolff-Kishner reaction is used when the molecule contains portions that are sensitive to acid. If the molecule contains segments that are sensitive to basic conditions of Wolff-Kishner, then the reduction can be done with amalgamated zinc in concentrated acid. This is known as the Clemmensen reduction. The Clemmensen reduction mechanism is not fully understood, but the Wolff-Kishner is. Examples are shown below.
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Wolf-Kishner
O C CH2CH3
H2NNH2 KOH
CH2CH2CH3
N2
Clemmenson O
C CH3
Zn(Hg) H3O+
CH2CH3
G. Acetal/Ketal Formation Aldehydes and ketones react reversibly with alcohols to form acetals (and in the older literature ketals). If only one molecule of alcohol reacts with the carbonyl, the prefix hemi is used. Like water alcohols react very slowly with carbonyls to form the nucleophilic product. In the presence of acid, the carbonyl is protonated and the nucleophilicity is greatly increased. Acetals are most often used as protecting groups for carbonyls because of the relative ease of formation and deprotection. The mechanism and examples are shown below. H. Formation of Thioacetals Mechanism O C O H+ C + O H H - H+ O C OR hemiacetal or hemiketal H
H-O-R H
C OR + OR
H+
+ OH2 C OR
H-O-R
- H2 O
C OR acetal or ketal
Example O
HOCH2CH2OH
H+
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The mechanism is the same as that of acetal formation. In this case, the thiol ethanedithiol is used to form the cyclic thioacetal. Thioacetals are however, stronger than their oxygen counterparts and deprotection is accomplished using Raney nickel in a protic solvent like ethanol. Example:
O S S Raney Ni EtOH
HSCH2CH2SH
H+
NiS
I. Wittig Reaction the Formation of Alkenes The reaction is very useful in producing alkenes that are mono, di or tri substituted. Tetrasubstituted are not formed due to the high degree of steric hindrance. The overall reaction is that a carbon group is attached to the carbonyl carbon with a double bond. There is no mixture of stereochemical isomers other than E and Z. The Wittig reagent is a phosphorus ylide. The ylide is formed from the SN2 reaction of triphenylphosphine with an appropriate primary or secondary alkyl halide. The phosphonium salts are reacted with a strong base such as NaH or n-BuLi. The proton on the carbon next to the positively charged phosphorus is slightly acidic. This forms a neutral zwitterion, a betaine. The mechanism involves the formation of a cyclic intermediate known as an oxaphosphatane. Because of this cyclic intermediate, there is considerable stereochemical control.
General Scheme:
O +
+ _ Ph 3P-C
Ph 3P=O
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Mechanism: Formation of Ylide R' Ph3P R' + Ph3P-C-H R" :B R' + _ Ph3P-C R" Ph3P=C
X-C-H R"
R' R"
Mechanism O R C H(R) R' O R-C (R) H + PPh3 C R" R' O R-C (R) H PPh3 C R" R' (R) H R C C R" R'
+ C-PPh3 R"
Ph3P=O
betaine
oxaphosphatane
Example: O O O C-H + _ Ph3P-CH(CH2)6CH3
H O O H C C-(CH2)6CH3 + Ph3P=O
J. Cannizzaro Reaction The Cannizzaro Reaction is a special kind of reaction known as a disproportionation reaction. The reaction occurs by the nucleophilic addition of OH- to an aldehyde that does not contain any alpha hydrogens to form a tetrahedral intermediate. This tetrahedral intermediate expels a hydride ion as the leaving group thus forming a carboxylic acid from the original aldehyde. The hydride ion nucleophilically attacks another aldehyde carbonyl carbon and after acid water work up affords an alcohol. The net result of this reaction is that two aldehydes without alpha hydrogens are reacted in aqueous hydroxide solution to form an oxidized product, the carboxylic acid and a reduced product, the alcohol. This reaction works well only on formaldehyde and benzaldehyde. It also has physiological applications and is the basis behind NADH catalyzed reactions. The reaction using benzaldehyde is shown below. 82
O 1.
H O C
OH
O C H HO-
O C
_ OH H
(oxidized)
+
2. H3O+ OH C H H (reduced)
tetrahedral intermediate
19.13 Conjugate Nucleophilic Additions to ,-Unsaturated Aldehydes and Ketones Up to this point, the nucleophilic addition reactions have been directly to the carbonyl carbon of the aldehyde or ketone. The nucleophilic addition reactions can be expanded to include additions to carbonyl compounds that have a double bond adjacent to the carbonyl carbon. These compounds are generally referred to as ,-unsaturated carbonyl compounds. The conjugated carbon-carbon double bond sets up alternating sites of positive and negative charges. When we studied conjugated dienes, we looked at the two sites of nucleophilic attack, 1,2 or 1,4. Whenever the carbonyl compound does not have an unsaturated conjugated bond, the attack is 1,2. However, under certain conditions the attack on the conjugated system can be 1,4. The beta carbon of the conjugated carbon-carbon double bond is said to be activated by the carbonyl group, since carbonyl groups are electron withdrawing. The nucleophiles that attack the beta carbon site can be neutral as in the case of primary and secondary amines or they can be negatively charged as in the case of carbanions. The following reactions illustrate these types of reactions.
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I. Conjugate Addition of Neutral Amines O CH3-C-CH=CH2 O O
HN(CH2CH3)2
EtOH
CH3-C-CH2CH2-N(CH2CH3)2 O
CH3NH2
EtOH
NHCH3
II. Conjugate Addition of Carbanions If the carbanion is from a Grignard reagent, it is a strong carbanion and will most likely attack the O O 1. "R-" C C C C C C R 2. H3O+ H carbonyl carbon in the 1,2 addition. However, if the carbanion comes from a weaker reagent such as a lithium cuprate, then the attack is primarily at the beta carbon of the conjugated double bond (1,4). Below are some examples showing this. HO 1. CH3MgBr O 2. H3O+ 1,2 Addition O 1. Li(CH3)2Cu 2. H3O+ CH3 CH3
1,4 Addition The organocuprates are generated by the reaction of one equivalent of copper(I) iodide and two equivalents of organolithium reagent. Primary, secondary and even tertiary groups as well as aryl and vinyl (alkenyl) groups undergo the addition reaction.
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CHAPTERS 20 & 21 Chapter 20: 21,22,25,26,30,31,32,33,34,35,36,38,39,52 Chapter 21: 32,33,36,37,46,60
CARBOXYLIC ACIDS Derivatives and Reactions

RCOO- NH4+ Ammonium salt NH3 (aq) RCOOH Carboxylic acid RCOO- Na+ Sodium salt
H3O+
NaOH (aq) Neutralization H3O+
H2O RCOCl Acid chloride PCl3, PCl5 or SOCl2
- H 2O H2O (RCO)2O Acid anhydride
R'OH (H+) Fischer Esterification R'OH
H2O R'OH
NH3
RCOOR' Ester NH3 heat
NH3
RCONH2 Amide - H 2O heat H3O+ heat RCOO-NH4+ Ammonium salt Reactions with conc. H2SO4 or H2O2/OHH3O+ heat RCN Nitrile P2O5
H2O are called hydrolysis ROH are called alcoholysis NH3 are called ammonolysis
Nomenclature: 85
Carboxylic Acids IUPAC rules allow for two systems of nomenclature depending on the complexity of the molecule. Carboxylic acids derived from open chains are systematically named by replacing the "e" at the end of the parent chain with "oic acid". The carboxyl group is always C1 in the numbering scheme. Examples: CH3CO2H ethanoic acid (acetic acid) CO2H CH3CH2CO2H benzoic acid propanoic acid CH3CH2CH2CH2CH2CH2CO2H heptanoic acid H HO2CCO2H HO2CCH2CO2H HO2CCH2CH2CO2H H oxalic acid malonic acid succinic acid C C CO2H HO2C CO2H H C C H CO2H
(cis) maleic acid
(trans) fumaric acid
If the carboxylic acid has a more complex unit, then name the complex unit and add the words carboxylic acid. O C-OH
CH3 3-methylcyclohexanecarboxylic acid
Acyl Halides
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The acyl group is derived from the carboxylic acid name by replacing the ic acid with yl or the carboxylic acid with carbonyl and then the halide name follows. COCl COCl
CH3COCl ethanoyl chloride (acetyl chloride) Acid Anhydrides
benzoyl chloride
cyclopentanecarbonyl chloride
Symmetrical anhydrides of straight-chain monocarboxylic acids and cyclic anhydrides of dicarboxylic acids are named by replacing the word acid with anhydride. O O O O (CH3(CH2)5C)2O heptanoic anhydride O O ethanoic anhydride (acetic anhydride) phthalic anhydride CH3C-O-CCH3 O O O maleic anhydride
Asymmetric (mixed) anhydrides are named by naming each acid and then adding the word anhydride. O O
C-O-CCH3 cyclohexanecarboxylic ethanoic anhydride
Esters The systematic names for esters are derived from the alkyl group attached to oxygen through a single bond (which comes from the alcohol) and then the name of the carboxylic acid with the ending ate on it. This is the actual name of the conjugate base ion of the carboxylic acid.
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O CH3C-OCH3
O C-O
CH3 C-CH3 CH3
CH3CH2O-C-CH2-C-OCH2CH3
methyl ethanoate (methyl acetate) Amides
diethyl malonate
t-butyl cyclohexanecarboxylate
Amides formed from unsubstituted NH2 groups are named by replacing the oic acid or ic acid ending with amide or by replacing the carboxylic acid with carboxamide. If the nitrogen has substituents on it, they are designated by using N and the alkyl name. O O CH3C-NH2 ethanamide (acetamide) O CH3(CH2)4C-NH2 hexanamide C-NH2
cyclopentanecarboxamide
O O CH3CH2-C-NHCH3 N-methylpropanamide Nitriles C-N
CH2CH3 CH2CH3
N,N-diethylcyclobutanecarboxamide
Simple acyclic nitriles are named by adding the ending nitrile as a suffix to the alkane name with the nitrile carbon counting as position number 1. More complex nitriles are named as derivatives as the carboxylic acids by replacing ic acid or carboxylic acid with onitrile or carbonitrile. CN CH3CN
CN CH3 CH3
acetonitrile
benzonitrile
2,2-dimethylcyclohexanecarbonitrile
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Structure and Physical Properties of Carboxylic Acids: Carboxylic acids resemble both aldehydes/ketones and alcohols. Like aldehydes and ketones the carbonyl carbon is sp2 hybridized with bond angles of 120. Like alcohols, carboxylic acids are strongly associated with each other through hydrogen bonds. Because of the strong hydrogen bonding capabilities, carboxylic acids normally exist as dimers. These strong hydrogen bonds have a noticeable effect on the physical property of boiling point. The boiling points are much higher than those of alcohols.
Dissociation of Carboxylic Acids Compare the dissociations of a carboxylic acid, water and an alcohol. O R-C-OH H2O R-OH O R-C-O-
H+
pKa = 4-5 pKa = 15 pKa = 16-18
H+ + OHR-O- + H+
Carboxylic acids are more acidic than alcohols (1011), but less than mineral acids. Since they are acids, they react with bases (both strong and weak) to yield salts. Most undissociated carboxylic acids are insoluble in water (>C6) but their salts are very soluble in water. In practice, this is exploited to extract and purify carboxylic acids. What is commonly done in the laboratory is to react the insoluble carboxylic acid with base so that it is soluble in water and remove all of the water insoluble impurities. Then re-acidify the salt with strong mineral acid to make it more soluble in the organic solvent. Why are carboxylic acids stronger acids than alcohols? The answer lies in the structure of the conjugate bases. The carboxylic acid forms a carboxylate ion that has both resonance stabilization and delocalization of the negative charge. The alkoxide ion formed from alcohols cannot be resonance stabilized nor delocalized. Evidence for the resonance stabilized structures came from x-ray crystallographic studies of sodium formate. The x-ray data showed that the bond lengths were equal and somewhere in-between a pure single and pure double bond length. The resonance stabilized structures of the carboxylate ion are shown below.
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O R-C O-
OR-C O
Substituent Effects on Acidity: Any substituent that will stabilize the negative carboxylate ion charge, will increase the acidity. A brief comparison is given below:
Carboxylic Acid CH3CH2CO2H ClCH2CH2CO2H ClCH2CO2H Cl2CHICO2H Cl3CCO2H F3CCO2H
pKa 4.87 3.98 2.85 1.26 0.64 0.23
Electron-withdrawing groups will stabilize the anion and therefore increase acidity. There is also an increased effect based on the number of electron-withdrawing groups, their electronegativity values, and their relative position to the carboxyl group.
Substituent Effects on Substituted Benzoic Acids: Recall the discussion concerning the effect of certain groups (activating/deactivating) on the reactivity of substituted benzenes and electrophilic aromatic substitution reactions. These same groups will also have an effect on the relative acidity of benzoic acid derivatives because of their inductive or resonance effects. If the group is electron-withdrawing (inductively), it will lower the pKa of the substituted benzoic acid relative to benzoic acid. If the group is electron-donating, then it will increase the pKa of the substituted benzoic acid relative to benzoic acid.
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Deactivating groups such as NO2, CN, CHO, Cl, and Br will increase the acidity relative to benzoic acid. Activating groups such as CH3, OCH3, and OH will decrease the acidity relative to benzoic acid. Hammett proposed a numerical treatment of the effect of substituents on the reactivity of certain compounds. The compounds used were benzoic esters, namely substituted ethyl benzoates. Hammett proposed a Linear Free Energy Relationship to relate the rate constants for the hydrolysis of the benzoic esters (both substituted and unsubstituted) to the ratio of the equilibrium constants of benzoic acids (both substituted and unsubstituted). He used benzoic acids and esters that the substituents located in the meta and para positions. This precluded the interference of steric factors caused by substituents in the ortho positions. The logarithm of the ratio of the rates of ester hydrolysis (substituted/unsubstituted) was plotted against the logarithm of the ratio of the dissociation constants for the substituted and unsubstituted benzoic acids. The two differed by a constant, . Rho was assigned a value of 1.00 for the ionization of XC6H4COOH in water at 25o C and the values (log K/Ko) were calculated for each type of substituent group. Once a set of values could be obtained, then values could be obtained from the rates of just two other substituted compounds. This then was a way of predicting the rate of reactions that had not yet been run. The most familiar form of the Hammett equation is shown below.
lg o
k =o g l k0
K = K0
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Preparation of Carboxylic Acids A. Oxidation of Alkylbenzenes Using KMnO4 R KMnO4(AQ) heat B. Oxidative Cleavage of Alkenes Using KMnO4 or Na2Cr2O7 KMnO4(aq) K2CO3 CH3CH=CHCH2CH3 Na2Cr2O7 C. Jones Oxidation of Primary Alcohols CH3CO2H + HO2CCH2CH3 CO2-
CH3CH2CH2OH
CrO3/H2SO4
CH3CH2CO2H
D. Oxidation of Aldehydes via Jones' Reagent or Tollen's Reagent CrO3/H2SO4 O CH3CH2CH2C-H Ag2O/NH4OH E. Hydrolysis of Nitriles Formed From Alkyl Halides Using Strong Acid or Base Acid: R-C Base: N H3O+ R-CO2H + NH4+ CH3CH2CH2CO2H
R-C
HO-
R-CO- + NH3 2
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F. Haloform Reaction of Methyl Ketones (to be covered in more detail later)
O HOG. Carboxylation of Grignard Reagents R-C-CH3 I2 / KI
_ R-CO2 + CHI3
Practically in the laboratory, the reaction is carried out by either pouring the Grignard reagent over dry ice or by bubbling CO2 through the Grignard reagent. The reaction is limited to alkyl halides that can form good Grignard reagents to begin with. Mechanism:
_ + R-Mg-X
Examples: H3C
O _ H3 O+ R-C-OH
O=C=O
R-C-O
+MgX
Br CH3 Mg Et2O H3C
MgBr CH3 1. CO2 2. H3O+ H3C
CO2H CH3
CH3
CH3 Mg Et2O
CH3 1. CO2 2. H3O+ CH3CH2CH2CO2H
CH3CH2CH2Cl
CH3CH2CH2MgCl
Reactions of Carboxylic Acids and Carboxylic Acid Derivatives There are 4 general reactions of carboxylic acids. They are: 1. Reduction 2. Deprotonation 3. Alpha Substitution 4. Nucleophilic Acyl Substitution
1. Reduction reactions of carboxylic acids and derivatives
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A. Using Hydrogen Gas Note: Carboxylic acids, ester and amides are not reduced using hydrogen gas. However, nitriles and acid chlorides are reduced using hydrogen gas. 1. Nitrile Reduction R-C N H2 Pd R-CH2NH2 a 1o amine
2. Acid Chloride Reduction
i) Catalytic (Full Strength) O R-C-Cl H2 Pd O R-C-H R-CH2OH a 1o alcohol
ii) Weakened Catalyst (Rosenmund - Pd/BaSO4, S8, quinoline) O R-C-Cl H2 Rosenmund catalyst O R-C-H
B. Hydride Reductions Note: LiAlH4 and NaBH4 both reactions are worked up in H3O+. NaBH4 is a weaker reducing agent compared to LAH. NaBH4 cannot reduce esters, carboxylic acids and amides. It can reduce aldehydes and ketones to alcohols. Hydrides do not reduce carbon-carbon multiple bonds.
1. Carboxylic Acids/Esters O R-C-OH
1. LAH 2. H3O+
RCH2OH + H2O
O R-C-OR' 1. LAH 2. H3O+ RCH2OH + HOR' 94
2. Amides to Amines O R-C-NH(R) H 1. LAH 2. H3O+
RCH2NH(R) H
3. Using Bulky Aluminum Hydrides Produces Aldehydes O i) R-C-OR' 1. DIBAH 2. H3O+ O R-C-H
O ii) R-C-Cl 1. DIBAH 2. H3O+
O R-C-H
2. Deprotonation O R-C OH O
:B-
R-C O
H:B
3. Alpha Substitution: The Hell-Volhard-Zelinskii Reaction This reaction is also known as an -halogenation of carboxylic acids. The halogenating reagent can be a phosphorus trihalide, such as PCl3 or PBr3 and the halogen or it can be the N-halosuccinimide, like NBS or NCS, with the corresponding hydrohalic acid. General Scheme:
O R-CH2-C-OH
1. Br2 PBr3 2. H2O
O R-CH-C-OH Br
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Examples Br CH2CO2H Br2 PCl3 CH-CO2H
CO2H
Br2 PCl3
CO2H Br
4. Nucleophilic Acyl Substitution Reactivity Considerations in a General Nucleophilic Acyl Substitution: 1. Tetrahedral Intermediate 2. Weaker Base is Eliminated 3. Three Possible Scenarios a. Incoming nucleophile is weaker than leaving group: No Reaction b. Incoming nucleophile is stronger than leaving group: Reaction c. Incoming nucleophile and leaving group are similar: Equilibrium
Introduction: Relative Reactivities of Acyl Derivatives: Nucleophilic acyl substitution reactions take place in two steps: addition of a nucleophile to the acyl carbon and elimination of the leaving group. The step that is generally the rate-limiting step is the attack of the nucleophile on the acyl carbon. Thus, any factor that makes the acyl carbon easily attacked by the nucleophile will enhance the reactivity. Steric and electronic factors play the major roles in determining the reactivity rates. Sterically the acyl carbon must be easily accessible to the incoming attack of the nucleophile. For this reason the less substituted the alpha carbon is the faster the reaction. In light of this then, a CH3 group is more reactive than a CR3 group. Electronically, strongly polarized derivatives are more reactive than less polar derivatives. Thus, acid chlorides 96
are the most reactive because of the electronegativity of the chlorine atom polarizing the acyl group more strongly. Amides and esters are not as reactive because they polarize the acyl group much less. The order of reactivity is: acid chloride> acid anhydride> ester> amide. The way the various groups enhance the polarization of the acyl group is very similar to the way they effect the reactivity of the benzene ring toward aromatic substitution.
General Mechanism of Acyl Nucleophilic Substitution: O R-C Y OO R-C Nu
Nu-
R-C-Y Nu tetrahedral intermediate
Y-
If the nucleophile is neutral, like water, then an additional step is added. It is a proton transfer step. O R-C Y OO-H+ H+ R-C-Y OH O R-C OH
H2O
R-C-Y + OH2
Y-
tetrahedral intermediates Conversions of Carboxylic Acids into Various Derivatives:
Conversion Into Acid Chlorides:
97
This conversion can be achieved by reacting the carboxylic acid with thionyl chloride (SOCl2), phosphorus trichloride (PCl3) or oxalyl chloride (ClCOCOCl). Thionyl chloride is both inexpensive and convenient to use but is very acidic and therefore can only be used on acid stable compounds. Oxalyl chloride is very expensive but gives much higher yields and reacts under milder conditions. The mechanisms of these reactions involve initially the conversion of the carboxylic acid into an activated derivative. This activated derivative is then attacked by the nucleophilic chloride ion thus yielding the acyl chloride. The mechanisms involving thionyl chloride and oxalyl chloride are shown below.
SOCl2
O R-C-OH O O Cl O O
Cl-S-Cl
+ R-C-O-S-OH Cl
+ R-C-O-S=O H Cl
O Cl
H+
R-C-O-S=O Cl O R-C-Cl
Cl-
R-C-O-S=O
SO2 + Cl-
C2O2Cl2
O R-C-OH OO
Cl O OO O OO O OO
+ Cl-C-C-Cl
+ R-C-O-C-C-Cl H Cl
+ R-C-O-C-C-Cl H
O OO
H+
R-C-O-C-C-Cl O R-C-Cl
Cl-
OO
R-C-O-C-C-Cl Cl
-O-C-C-Cl
Conversion Into Acid Anhydrides: Acid anhydrides are formed from two molecules of carboxylic acids with the removal of one molecule of water. Acyclic anhydrides other than acetic anhydride are difficult to prepare, but cyclic anhydrides that form rings of 5 and 6-members are readily obtained from the high temperature dehydration reaction. The mechanism for the formation of a cyclic anhydride is shown below.
98
O C H2C H2C C O OH OH
O C H2C H2C C O OH + O H H+ H2 C H2 C
OH C OH O C O H2 C H2 C
+ OH C O C O H+ H 2C H 2C
O C O C O
Conversion Into Amides: Carboxylic acids are not converted into amides by directly reacting them with amines. This is because since amines are bases the overwhelming reaction is the acid base reaction. The amino-carboxylate salt produced is a very poor electrophile and is essentially unreactive with nucleophiles.
Conversion Into Esters: There are many methods used to prepare one of the most important conversion reactions. One method is the SN2 reaction between the carboxylate ion and an alkyl halide, such as an alkyl iodide. O R-C-OO
R'CH2-I
SN2
R-C-OCH2R'
I-
The most common and productive method is the Fischer esterification reaction. This is the reaction between a carboxylic acid and an alcohol in the presence of mineral acid catalyst. The reaction is governed by the equilibrium between reactants, carboxylic acid and alcohol and products, ester and water. The yields are good but must be pushed by using an excess of alcohol. Because of this, the reaction is normally limited to the formation of methyl, ethyl, and propyl esters. The mechanism of the Fischer esterification reaction is the reverse reaction of one we have seen before, the Acid Catalyzed Ester Hydrolysis. The mechanistic pathway was established from isotopic labeling experiments using 18O alcohol. This showed that the carboxylic oxygen came from the alcohol and not water, because the 18O label was incorporated into the ester and not the water.
99

+O H +O H
O R-C-OH
OH
H+
R-C-OH
H O R'
17
R-C
17
OH
O R' H
OH R-C
17
O O R'
H+
O R'
R-C
17
R-C
17
O R'
OH2
proton transfer
A final method that is considered for forming methyl esters is the diazomethane reaction of carboxylic acids. The reaction and its mechanism are shown below. O R-C-OH O N R-C-OO
- + :CH2N
+ CH3-N
R-C-OCH3
N2
Reactions of Acid Halides: One of the most reactive acid derivative and most of the reactions are conversions. 1. Hydrolysis to Carboxylic Acids
O R-C-X
O -
O -H+ R-C-X OH
O R-C-OH
H2O
R-C-X OH2+
HX
2. Reactions with Aromatic Rings via Friedel-Crafts Acylation O O R-C-X H
AlCl3
C-R
HX
3. Alcoholysis to Esters O R-C-X O O -H+ pyr or Et3N R-C-X OR' O R-C-OR'
R'OH
R-C-X H OR'+
ammonium halide salt
100
4. Aminolysis to Amides O R-C-X O R-C-X O
2 NH3
R-C-NH2 O
NH4+X-
2 NHR'2
R-C-NR'2
NH2R'2+X-
5. Reduction to Alcohols and Aldehydes O R-C-X 1. LiAlH4 O R-C-H not isolated O R-C-X 1. LiAlH(OtBu)3 2. H3 O+ O R-C-H [3 tBuOH + LiAlH4 LiAlH(OtBu)3] O R-CH2 2. H3O+ OH R-CH2
6. Hydrogenation via Rosenmund Reduction
O R-C-X
H2 Pd-BaSO4
O R-C-H an aldehyde
7. Reactions with Grignard Reagents and Organocopper Reagents O R-C-X 1. Et2O 2. H3O+ OH R-C-R' a tertiary alcohol R' O
2 R'MgX
O R-C-X
2 R'2CuLi
R-C-R'
a ketone
Note: Organocopper reagents only react with acid halides. 101
Reactions of Acid Anhydrides: The chemistry of acid anhydrides is very similar to that of acid halides. The difference being that acid anhydrides react more slowly. 1. Hydrolysis to Carboxylic Acids
O H+
O R-C-OH
O + H+ R-C-OH
R-C-O-C-R
H2O
R-C-O-C-R OH2+
R-C-O-C-R OH
+ -OC-R
2. Reaction with Aromatics via Friedel-Crafts Acylation O O O H R-C-O-C-R
AlCl3 or TiCl4 or PPA
C-R
3. Alcoholysis to Form Esters O O O O - H+ O O O O O + H+ R-C-OH
R-C-O-C-R
R'OH
R-C-O-C-R H OR' +
R-C-O-C-R OR'
R-C-OR' + -OC-R
4. Aminolysis to Form Amides
R-C-O-C-R
HNR'2
H2NR' or NH3
pyridine or excess amine
R-C-NR2'
-OC-R
102
5. Reduction to Alcohols and Aldehydes
Reactions of Esters: Esters show the same kinds of reactions that were seen for the other derivatives except that they are less reactive toward nucleophilic attack. All of the following reactions are applicable to acyclic and cyclic O O 1. LAH 2. H3O+ 2 R-CH2OH
R-C-O-C-R
O Na2Fe(CO)4 disodium tetracarbonyl ferrate
O 2 R-C-H
R-C-O-C-R
(lactones) esters. 1. Hydrolysis to Carboxylic Acids and Alcohols Base Catalyzed (Saponification): O R-C
17
O O R'
_
17
O O R' R-C-OH
HO-
R-C
17
O R'
R-C-O-
H 17O R'
OH Acid Catalyzed (Reverse Fischer Esterification): 2. Aminolysis to Amides H +O O O H+ R-C 17O R' H2O 17 R-C O R' HNR2 R-C OR' OH O O - H+ 17 17 + R-C O R' R-C O R' R-C-OH R-C-NR2 + HOR' + H OH + OH2 Note: Not normally used because higher yields are seen using acid halides. proton transfer OH
H 17O R'
3. Reduction to Alcohols and Aldehydes O R-C OR' O C O 1. LAH 2. H3 O+ HOCH2 103 OH 1. LAH 2. H3O+ RCH2OH + HOR'
4. Reaction with Grignard Reagents
O R-C OR' 1. 2 eq R"MgX 2. H3O+
R" R-C-OH R" R" 1. 2 eq R"Li 2. H3O+ R-C-OH R" tertiary alcohol tertiary alcohol
O R-C OR'
5. Decarboxylation, the Hunsdieker Reaction The reaction involves the loss of carbon dioxide and the formation of an alkyl halide with one less carbon than the starting acid. O R-C OH HgO or Ag2O or Pb(IV) X2 and heat or light
RX + CO2
This is a free radical mechanism and needs energy for initiation. Reactions of Amides: Amides are much less reactive than acid chlorides, anhydrides and esters. This is a good thing since protein primary structure is made of these amide linkages and it is beneficial to have them somewhat inert. 1. Hydrolysis to Carboxylic Acids and Ammonia or Amines Acid Catalyzed: O R-C-NR2 H+ OH+ R-C-NR2 OH O-H + R-C-NR2 HO H O R-C-OH
H2O
R-C-NR2 OH2+ proton transfer
+ H2NR2
Base Catalyzed:
O R-C-NR2
-OH
O R-C-NR2 OH
O R-C-OH + -NR2
O R-C-O-
HNR2
104
2. Reduction to Amines O R-C-NH2 O-AlH3 H R-C=NH2 H iminium ion from AlH4 or AlH3+ Reactions of Nitriles: The reactions of nitriles are very similar to the chemistry of carbonyl compounds. This is because the nitrile group is strongly polarized like the carbonyl group. When nitrile carbons are attacked by nucleophiles they form an sp2 imine anion intermediate analogous to the sp3 alkoxide ion intermediate from carbonyls. HR-C-NH2 H
+
H
AlH3
R-C-NH2 H
1. Hydrolysis to Carboxylic Acids and Amines via Amides Base Catalyzed: -OH OH R-C=N _ OH O R-C-NH2 amide 1. HO2. H3O+ amide hydrolysis O R-C-OH
R-C N
H2O
R-C=NH hydroxy amine tautomers
NH4+
Acid Catalyzed:
R-C N
H+
+ R-C N H OH H2O
OH2+
OH - H+ R-C=NH hydroxy amine
H2O
R-C=NH OH
H+
OH R-C=NH2
O-H H+ R-C-NH3+ OH proton transfer
O R-C-OH
R-C-NH2 OH2+
- H+
R-C-NH2 OH
NH4+
105
2. Reduction to Amines R-C N 1. LAH 2. H3O+ R-CH2NH2 primary amine O R-C N 1. DIBAH 2. H2O 3. Reaction with Grignard Reagents R'MgX R-CH + NH3 aldehyde
R-C N
R-C=N R'
+MgX
H+ H2O
R-C=NH R' Schiff Base (imine)
H2O
R-C=O R'
NH3
106
CHAPTER 22 CARBONYL SUBSTITUTION REACTIONS
Suggested problems at the end of the chapter: 20,21,22,23,24,25,28,29,30,35,44
22.1 Keto-Enol Tautomerism: Carbonyl compounds that have hydrogen atoms on the carbon adjacent to the carbonyl (the alpha position) are in rapid equilibrium with their enol form. This rapid interconversion produces two chemically distinct species, known as tautomers. O C H C O H C C
keto tautomer enol tautomer Most carbonyl compounds exist almost exclusively in the keto form at equilibrium. Keto-enol tautomerism is catalyzed by both acids and bases. The acid catalyzed formation produces the enol. Whereas the base catalyzed produces the enolate ion. This enolate ion can be readily protonated by water to form the enol or it can react with other reagents, as we shall see later. Acid Catalyzed Enol Formation: O C + H O H C C H2O - H3 O+
H C
H+
H H
O H C C
C + C
Base Catalyzed Enolate-Enol Formation:
O C
H C
-OH
O_ C C
O C _ .. C - H2 O
O H C C
107
Acidity of Alpha-Hydrogen Atoms: Enolate Formation The topic of this chapter is reactions involving the alpha hydrogen of carbonyl compounds. Let's look at how these are formed and their relative reactivity. The acidity of the -hydrogen is due to the alignment of the C-H orbital with the carbonyl p orbitals. The negative charge formed can overlap with the bond and delocalize (stabilize). If 2 carbonyl groups are present, then the acidity is greatly enhanced. The -hydrogen are only weakly acidic and therefore require strong bases to cause the abstraction. The strong bases required are usually either metal hydrides or metal amides. Examples of these types of bases include NaH, NaNH2 and LDA (lithium diisopropylamide). Refer to Table 18.1 to compare some acidity values of organic compounds.
Enolates Enolates are more reactive than enols because of the full negative charge. The two resonance forms are shown below.
O C _ C O C _ .. C
Reactions can take place either at the oxygen site or the -carbon site. Most of the time the reactions happen at the carbon site. This is because oxygen is quickly protonated. This makes the position of the enol or enolate the nucleophile.
22.2 Reactivity of Enols: The Mechanism of -Substitution Reactions The general mechanism for this reaction type is given below:
O C
H C
H+
+ H O H C C
H H
H2O
O H C C
C + C
E+
+ H O E C C
H E
:B
O C
E C
C + C
22.3 Alpha Halogenation of Aldehydes and Ketones: 108
The reaction usually takes place with an acid catalyst and is limited to aldehydes and ketones. Bromine is most often used, but the reaction will take place with iodine and chlorine also. There is a great deal of evidence supporting the following mechanism. Mechanistic Evidence 1. The rate of halogenation is independent of the halogen. This indicates that the same ratedetermining step is involved for all halogenation reactions. 2. Acid-catalyzed ketone halogenations exhibit second-order kinetics in which the rate depends on the concentrations of H+ and ketone. Since the rate is independent of the concentration of halogen, the halogen therefore must not be involved in the rate-determining step. 3. Placing the ketone in D3O+ instead of H3O+ places a deuterium on the -carbon. The rate of deuteration is identical to the rate of halogenation for a given ketone. This suggests that the same intermediate exists in both mechanisms. This common intermediate is the enol.
O R-CH2C-H(R)
X2
H+, H2O
R-CH-C-H(R) X
{X=Br, Cl, I}
-Bromoketones are useful in organic synthesis because they can be dehydrobrominated using base to form ,-unsaturated ketones.
O CH3 Br2, HOAc
O CH3 Br pyridine heat
O CH3
Halogenation of Enolate Ions: Haloform Reaction
109
If excess halogen and base are used, then the halogenated ketone (of which the -hydrogens are more acidic) can further halogenate. If the ketone is a methyl ketone, then the triply halogenated enolate forms which is cleaved by base to form haloform. In the laboratory, this is known as the Iodoform Test for methyl ketones. An example is below:
O R-C-CH3
I2 HO-
O R-C-CH2I
I2 HO-
O R-C-CHI2
I2 HO-
O R-C-CI3
HOH2O
O R-C-O-
+ CHI3
iodoform
Formation of ,-Unsaturated Carbonyls A. Halogenation Followed by Elimination

O Br2 H3O+ O Br
-OH
This is limited by the competing substitution reaction and aldol condensation (in base). B. Phenylselenenylation Followed by Oxidation In order to accomplish the selenenylation the carbonyl compound must react with a strong base to form the enolate. The enolate solution is then treated with one equivalent of benzeneselenenyl bromide. The selenenylated carbonyl is then reduced using peroxide.
General Scheme: O
O 1. LDA 2. PhSeBr R-C-C C H SePh H2O2
O R-C-C C
R-C-C-C HH
Examples
HOSePh
O 1. LDA 2. PhSeBr
O SePh H2O2
O 110 C-CH2CH3
1. LDA 2. PhSeBr 3. H2O2
O C-CH=CH2
This reaction works well for ketones, esters and nitriles. Aldehydes give a poor yield due to aldol condensations. LDA is a strong base used to create enolates. Another strong base often used is nBuLi or other alkyl lithiums.
LDA
Li N
22.4 Alpha Bromination of Carboxylic Acids: Hell-Volhard-Zelinskii Reaction This reaction is also known as an -halogenation of carboxylic acids. The halogenating reagent can be a phosphorus trihalide, such as PCl3 or PBr3 and the halogen or it can be the N-halosuccinimide, like NBS or NCS, with the corresponding hydrohalic acid. General Scheme:
O R-CH2-C-OH 1. Br2 PBr3 2. H2O
O R-CH-C-OH Br
Examples Br CH2CO2H Br2 PCl3 CH-CO2H
CO2H
Br2 PCl3
CO2H Br
22.7 Alkylation at the Carbon Site of Enolates 111
The alkylation reaction is under the normal constraints of any SN2 reaction. The leaving group can be Cl, Br, I, or tosylate and the alkyl group must be 1 or CH3 but preferably, allylic or benzylic. Vinylic and aryl halides are unreactive because of steric hindrance. The order of reactivity is as follows: -Y: Tosylate > I > Br > Cl R-Y R: Allylic = benzylic > CH3 > 1
General Mechanistic Scheme: O C C O C O _ C
SN2 attack Ketones, esters and nitriles can be alkylated this way. Aldehydes give poor yields. Alkylation of unsymmetrical ketones gives 2 products. The product formed is based on the energetics of the reaction. We describe these reactions as either being under kinetic control or thermodynamic control.
enolate formation
Kinetic Control The conditions that are used to produce kinetic control are strong base and low temperatures. These are considered to be mild conditions and the result is that the enolate ion formation is irreversible. Kinetically controlled reactions will form enolate ions at the least hindered site, alpha to the carbonyl.
Thermodynamic Control The conditions used to produce thermodynamic control are weak base and higher temperatures. These are considered to be harsh conditions and the result is that the enolate ion formation is reversible. Thermodynamically controlled reactions will form the enolate ion that is the most thermodynamically stable. Some examples are shown below.
112
Kinetic Control O CH3 1. LDA, - 78o 2. CH3I Thermodynamic Control O CH3 1. t-BuO-, heat 2. CH3I H3C O CH3
O CH3 CH3
There are two alternative approaches to forming the kinetic product without having to use the strong base and low temperatures. They are (1) forming a hydrazone intermediate and (2) forming an enamine. Both of these form activated derivatives which produce the least hindered enolate ion. 1. Using a hydrazone intermediate: O CH3 CH3 CH3-N-NH2 N(CH3)2 N CH3 n-BuLi _ N CH3 N(CH3)2
N(CH3)2 CH3CH2Br CH3CH2 N CH3 H3O+ CH3CH2 O CH3
2. Using an enamine derivative: Enamines can react with alkyl halides and acid chlorides and ,unsaturated carbonyls.
.. N
O
1. R-C-Cl 2. H3O+
O C-R
O
.. N 1. R-CH=CH-C-R(H) 2. H3O+
O CH-CH2C-R(H) R
113
.. N N
O CH3Br N CH3 H3 O+ CH3
Specific Types of Alkylations A. Malonic Ester Synthesis This reaction prepares substituted acetic acids from alkyl halides. There are 4 steps involved: 1. Enolate of malonic ester 2. Nucleophilic attack onto alkyl halide 3. Hydrolysis of esters 4. Decarboxylation CO2Et CH2 CO2Et NaOEt (1 eq) EtOH CO2Et H-CNa+ CO2Et R-X CO2Et H-C-R CO2Et This could further alkylate or undergo decomposition
malonic ester -hydrogens are very acidic due to the 2 C=O s Malonic Ester Decomposition
sodio malonic ester is a very good nucleophile
Overall Reaction
CO2Et H-C-R CO2Et H3O+ heat CO2H R-C-R H
CO2 + 2 EtOH
114
Mechanism (Decarboxylation requires a -Keto acid)
O R C R CO2Et CO2Et
H3O+ heat
R C R
C C HO
O O H
- CO2
R C R C
OH OH
R C R
CO2H H
diacid
acid enol
Examples
CO2Et CH2 CO2Et CHCH2(CH2)2CH3 CO2Et CO2H CO2Et
+ CH3(CH2)2CH2Br
NaOEt (1 eq) EtOH
CO2Et
1. NaOEt (1 eq) CH3-C-CH2(CH2)2CH3 2. CH3I CO Et

2
H3O+ heat
CH3-C-CH2(CH2)2CH3 H
CO2Et CH2
CH3(CH2)2CH2Br
CO2Et Intramolecular CH2-Br CH2 CH2 CH2-Br
NaOEt (1 eq) EtOH
CO2Et CHCH2(CH2)2CH3 CO2Et
H3O+ heat
CH3(CH2)4CO2H
CO2Et CH2 CO2Et NaOEt (2 eq) EtOH
CO2Et CO2Et
H3O+ heat
CO2H
B. Acetoacetic Ester Synthesis This is the preparation of -substituted acetone derivatives from alkyl halides. There are 3 steps involved:
115
1. Enolate formation' 2. Alkylation 3. Hydrolysis-Decarboxylation Overall Reaction
CO2Et R-X
O Base H3 heat O+ R-CH2-C-CH3 -substituted acetone
CH2 C CH3 O
This reaction follows the same mechanistic pathway as the malonic ester synthesis except one of the ethyl esters is replaced with a methyl ketone.
Examples CO2Et Br O 1. NaOEt (1eq) 2. H3O+ heat CH3
CH2 C CH3 O
O OEt 1. NaOEt (1eq) 2. PhCH2Br 3. H3O+ heat
116
CHAPTER 23 CARBONYL CONDENSATION REACTIONS
Suggested problems at the end of the chapter: 25,27,33,35,39,42,45,53,56
General Mechanism of Carbonyl Condensations There are three types of carbonyl additions/condensations we will discuss. They are the aldol addition, the Claisen condensation and the Dieckmann condensation. The requirements of these reactions and their variations are that at least one of the carbonyl compounds must have an acidic -hydrogen and a strong base is employed.
General Mechanism: O O R-C H C :B O R-C C C O R-C O C C H2O O R-C OH C C
HO-
Carbonyl condensation reactions take place between two carbonyl components and involve a combination of nucleophilic and alpha substitution steps. All types of carbonyl compounds (aldehydes, ketones, esters, amides, anhydrides, thiol esters, and nitriles) can undergo these condensation reactions.
23.1 Aldol Addition/Condensation (For All Aldehydes and Ketones with -Hydrogens): General Scheme: O R-C-C-H O O base R
R-C-C-H
R-C-C-C-C-H OH
Mechanism: 117
O O R-C H C :B O R-C C C O R-C O C C H2O O R-C OH C C
HO-
Examples O 2
-OH
OH
O 2 CH3-C-CH3
OH
-OH
CH3-C-CH2-C-CH3 CH3
O 2 CH3-C-H
-OH
OH
CH3-C-CH2-C-H H
23.3 Dehydration of Aldol Products (-Hydroxyaldehydes and Ketones): The -hydroxy aldehydes and -hydroxy ketones formed can be dehydrated to yield conjugated enones (,unsaturated aldehydes and ketones). The condensation of the water out of the reaction is what gives the aldol condensation reaction its name. The general reaction is shown below. O C H OH C C H+ or
-OH
O C C C
H2O
-Hydroxy groups to carbonyls are more reactive than normal alcohols. Therefore, milder conditions are needed for dehydration. Often the dehydration reaction only requires a lightly elevated temperature over the
O C _ C C 118
original aldol conditions. Because of this, the -hydroxy intermediate is not isolated. Conjugated enones are more stable than nonconjugated ones for the same reasons that conjugated dienes are more stable than isolate dienes. Interaction between the pi electrons of the carbon-carbon double bond and the pi electrons of the carbonyl group leads to a molecular orbital description of conjugated enones that shows a partial delocalization of the pi electrons over all four atomic centers.
The real driving force of the aldol condensation reaction is the dehydration step. The initial condensation to form the -hydroxy intermediate is an equilibrium, step that is in favor of the single compounds. However, when the condensation takes place the conjugated enone is more favored over the -hydroxy intermediate.
23.5 Mixed Aldol Reactions: Normally mixed aldol reactions between similar carbonyl compounds leads to four possible products. Two of the products are from the symmetrical condensation and the other two from the mixed condensation.
Mixed aldol reactions can lead to a single product if one of two conditions is met. 1. If one of the carbonyl components does not contain any -hydrogens and therefore cannot form an enolate ion. This carbonyl compound will act as the electrophilic site for attack by the other enolate ion. Carbonyl compounds that fit this requirement and that are usually used in mixed aldol reactions are benzaldehyde and formaldehyde. Of course any carbonyl compound without -hydrogens will work, for example trichloroacetophenone. 2. If one of the carbonyl compounds is exceptionally acidic as in the case with ethyl acetoacetate. Then it will be easily transformed into the enolate and will serve as the nucleophile. The other carbonyl compound will only form its corresponding enolate in small amounts with the equilibrium favoring the carbonyl form. An example is illustrated below.
O NaOEt EtOH
CH3-C-CH2-C-OEt
CH3-C-C-C-OEt
H2O
very acidic
119
80%
23.6 Intramolecular Aldol Condensations: These reactions lead to cyclic enones. The most common ring sizes formed are 5 and 6-membered rings. This is due to the increased stability of these two ring sizes. The mechanism of the intramolecular aldol is similar to the mechanism for the intermolecular. The only difference is that the intramolecular reaction requires that the reactant contain the nucleophilic carbonyl anion donor and the electrophilic carbonyl acceptor. 1,4-Diketones react intramolecularly to form cyclopentenones and 1,5-diketones yield cyclohexenone products.
23.7 Claisen Condensation Reactions: The reaction involves the condensation of an ester with an -hydrogen with the carbonyl of a second ester to yield the -keto ester. The activated ester is often ethyl acetate. The mechanism is very similar to the aldol reaction. This reaction like aldol is reversible. General Scheme: O 2 R-CH2-C-OEt 1. :B 2. H3O+ O C-CH2-R R CH-C-OEt O a -keto ester Example O 2 CH3-CH2-C-OEt 1. NaOEt 2. H3O+ O C-CH2-CH3 H3C CH-C-OEt O 23.8 Mixed Claisen Reactions: This is very similar to mixed aldol reactions. In this case, two different esters are used. The reaction is only successful when one of the two esters does not have -hydrogens. In addition, the condensation can take
HOEt
HOEt
120
place between the ester and an aldehyde without any -hydrogens. Usually the -hydroxy ester formed undergoes elimination to form the ,-unsaturated ester.
Examples O CO2Et O 1. NaOEt 2. H3O+ O C CH2CO2Et
CH3CO2Et
H3C H3C
O O
H-C-OEt
1. NaOEt 2. H3O+
H3C H3C
O C-H
23.9 Dieckmann Cyclization (Intramolecular Claisen): These intramolecular Claisen reactions involving diesters are analogous to the intramolecular aldol reactions noted before. The cyclization works best with 1,6-diesters and 1,7-diesters. The 1,6-diesters produce the 5-membered -keto cyclic ester and the 1,7-diesters produce the 6-membered -keto cyclic ester. The mechanism is similar to the Claisen mechanism. The Dieckmann cyclic ester products can be further alkylated and decarboxylated by reactions analogous to the acetoacetic ester reactions.
General Scheme: O C-OEt CH2CO2Et 1. :B 2. H3O+ O C CHCO2Et
121
Examples
23.10-12 Special reactions of Carbonyls and ,Unsaturated Carbonyls:
Michael Addition: O C-OCH3 O MeO 1. NaOCH3 2. H3O+ O O C-OCH3
O C-OCH3 O 1. NaOCH3 2. H3O+
O C-OCH3
OMe The Michael addition reactions are conjugate addition reactions in which a nucleophile adds to the carbon-carbon double bond of an ,-unsaturated ketone. The only requirement of the Michael acceptors is that they must have a conjugated double bond with an electron-withdrawing group attached. These electronwithdrawing groups could be aldehydes, esters, nitriles, ketones, nitro groups and amide groups. In the same sense, the Michael donor must have an acidic hydrogen which means it must have an electron-withdrawing group attached to it. These could be compounds such as -diketones, -keto esters, malonic esters, -keto nitriles, and nitro compounds.
General Reaction: EWG EWG-CH2-R EWG EWG :B H-C-C-C-H R Michael Donor Michael Acceptor 122
Examples
Michael Donors
Michael Acceptors O HOCH2CH2-C-H CH3-C-CH-C-CH3 O O O
CH3-C-CH2-C-CH3
CH2=CH-C-H
CH3-CH-CH2-C-NH2 CH3OCH3-C-CH-C-OCH3 O O O CH2CH2-C-OCH3 CH3OCH3-C-CH-CN O
CH3-C-CH2-C-OCH3
CH3-CH=CH-C-NH2
O CH3-C-CH2-CN
CH2=CH-C-OCH3
Stork Enamine Addition to ,Unsaturated Carbonyl Groups This is an adaptation to the Michael Addition reaction. The enamine can also react with acid chlorides. Some examples are shown below.
123
O N
CH2=CH-C-H
O CH2-CH=C-H
H2O
O CH2-CH2-C-H
H3O+
O CH2-CH2-C-H
O N
O
H3O+
O C-R
R-C-Cl
Robinson Annulation The Robinson annulation reaction is used to prepare polycyclic compounds. The reaction takes place in two steps: 1. Michael addition reaction between a Michael-type donor such as a -keto ester or a -diketone and an ,-unsaturated ketone, a Michael acceptor 2. The ring closure takes place via an intramolecular aldol condensation followed by the elimination reaction to form the substituted cyclic ,-unsaturated ketone. The Michael donor, the enolate, can be prepared from both acid and base.
General Scheme:
+
O O
EWG
Na+ -OEt Michael Addition O O
EWG
Na+ -OEt Aldol Reaction O
EWG
Michael Product
Annulation Product
124

McMurry 7e Ch19-23 Notes 5-29-07

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Organic II McMurry 7th Edition

CHAPTER 19 ALDEHYDES AND KETONES: NUCLEOPHILIC ADDITION REACTIONS

Suggested Problems: ,30,32,34,45,48

Organic II McMurry 7th Edition

aldehydes + N CrO3ClH PCC

Organic II McMurry 7th Edition

2o Alcohols II. Oxidative Cleavage

any oxidizing agent

hot KMnO4, -OH O R-C-X

IV. Reactions with Organocopper Reagents

Organic II McMurry 7th Edition

Organic II McMurry 7th Edition Without Nonbonding Electrons O R-C-H(R) OH

With Nonbonding Electrons O R-C-H(R) OH H + OH H+ R-C-H(R) :Z Z+ R-C-H(R)

Organic II McMurry 7th Edition

O R O (neutral) :NuH2 C H (R) + NuH2

R-C-H(R) (negative) NuO R C H (R) Nu HA R OH C H (R) Nu

Organic II McMurry 7th Edition

Organic II McMurry 7th Edition

Organic II McMurry 7th Edition

+ NH2R H+ - H2O + - H+ N-R H iminium ion Examples:

2,4-Dinitrophenylhydrazone O2 N H3C C O + H2NNH H3C

Organic II McMurry 7th Edition

In general: R CH2 R' Examples: C O R C H C

H3C HN(CH3)2 TiCl4 Et2O

Organic II McMurry 7th Edition

Organic II McMurry 7th Edition

Organic II McMurry 7th Edition

Example: O O O C-H + _ Ph3P-CH(CH2)6CH3

Organic II McMurry 7th Edition

Organic II McMurry 7th Edition

I. Conjugate Addition of Neutral Amines O CH3-C-CH=CH2 O O

Organic II McMurry 7th Edition

CHAPTERS 20 & 21 Chapter 20: 21,22,25,26,30,31,32,33,34,35,36,38,39,52 Chapter 21: 32,33,36,37,46,60

CARBOXYLIC ACIDS Derivatives and Reactions

NaOH (aq) Neutralization H3O+

H2O RCOCl Acid chloride PCl3, PCl5 or SOCl2

- H 2O H2O (RCO)2O Acid anhydride

R'OH (H+) Fischer Esterification R'OH

RCOOR' Ester NH3 heat

Organic II McMurry 7th Edition

(cis) maleic acid

(trans) fumaric acid

CH3 3-methylcyclohexanecarboxylic acid

Organic II McMurry 7th Edition

CH3COCl ethanoyl chloride (acetyl chloride) Acid Anhydrides

C-O-CCH3 cyclohexanecarboxylic ethanoic anhydride

Organic II McMurry 7th Edition

CH3 C-CH3 CH3

methyl ethanoate (methyl acetate) Amides

O O CH3CH2-C-NHCH3 N-methylpropanamide Nitriles C-N

Organic II McMurry 7th Edition

pKa = 4-5 pKa = 15 pKa = 16-18

Organic II McMurry 7th Edition

Carboxylic Acid CH3CH2CO2H ClCH2CH2CO2H ClCH2CO2H Cl2CHICO2H Cl3CCO2H F3CCO2H

pKa 4.87 3.98 2.85 1.26 0.64 0.23

Organic II McMurry 7th Edition

Organic II McMurry 7th Edition

Organic II McMurry 7th Edition

F. Haloform Reaction of Methyl Ketones (to be covered in more detail later)

O HOG. Carboxylation of Grignard Reagents R-C-CH3 I2 / KI

Br CH3 Mg Et2O H3C

MgBr CH3 1. CO2 2. H3O+ H3C

CH3 1. CO2 2. H3O+ CH3CH2CH2CO2H