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HOÁ HỌC HỮU CƠ
Organic Chemistry
CHƯƠNG 10
HỢP CHẤT CARBONYL
ALDEHYD VÀ CETON
Aldehydes and Ketones
Aldehydes and ketones are characterized by the the carbonyl functional group (C=O)
The compounds occur widely in nature as intermediates in metabolism and biosynthesis
They are also common as chemicals, as solvents, monomers, adhesives, agrichemicals and pharmaceuticals
DANH PHÁP
Naming Aldehydes and Ketones
Aldehydes are named by replacing the terminal -e of the corresponding alkane name with –al
The parent chain must contain the CHO group
The CHO carbon is numbered as C1
If the CHO group is attached to a ring, use the suffix See Table 19.1 for common names
Nomenclature - Aldehydes
IUPAC names: select as the parent alkane the longest chain of carbon atoms that contains the carbonyl group
because the carbonyl group of the aldehyde must be on carbon 1, there is no need to give it a number
For unsaturated aldehydes, show the presence of the C=C by changing the infix -an- to -en-
the location of the suffix determines the numbering pattern
Nomenclature - Aldehydes
DANH PHÁP
Nomenclature - Aldehydes
For cyclic molecules in which the -CHO group is attached to the ring, the name is derived by adding the suffix -carbaldehyde to the name of the ring
DANH PHÁP
DANH PHÁP
Nomenclature - Ketones
IUPAC names:
select as the parent alkane the longest chain that contains the carbonyl group,
changing the suffix -e to -one
number to give C=O the smaller number
Naming Ketones
Replace the terminal -e of the alkane name with –one
Parent chain is the longest one that contains the ketone group
Numbering begins at the end nearer the carbonyl carbon
DANH PHÁP
Nomenclature - Ketones
The IUPAC system retains these names
DANH PHÁP
DANH PHÁP
Ketones and Aldehydes as Substituents
The R–C=O as a substituent is an acyl group is used with the suffix -yl from the root of the carboxylic acid
CH3CO: acetyl; CHO: formyl; C6H5CO: benzoyl
The prefix oxo- is used if other functional groups are present and the doubly bonded oxygen is labeled as a substituent on a parent chain
Order of Precedence
For compounds that contain more than one functional group indicated by a suffix
DANH PHÁP
DANH PHÁP
IR of Molecules with C=O Groups
IR of Molecules with C=O Groups
Carbonyl groups
The position of C=O stretching vibration is sensitive to its molecular environment
as ring size decreases and angle strain increases, absorption shifts to a higher frequency





conjugation shifts the C=O absorption to lower frequency
O
O
O
O
O
O
H
O
19.2 Preparation of Aldehydes and Ketones
Preparing Aldehydes
Oxidize primary alcohols using pyridinium chlorochromate
Reduce an ester with diisobutylaluminum hydride (DIBAH)
Aldehydes and Ketones
IR spectrum of menthone (Fig 12.12)
Preparing Ketones
Oxidize a 2° alcohol (see Section 17.8)
Many reagents possible: choose for the specific situation (scale, cost, and acid/base sensitivity)
Ketones from Ozonolysis
Ozonolysis of alkenes yields ketones if one of the unsaturated carbon atoms is disubstituted (see Section 7.8)
Aryl Ketones by Acylation
Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl3 catalyst (see Section 16.4)
Methyl Ketones by Hydrating Alkynes
Hydration of terminal alkynes in the presence of Hg2+ (catalyst: Section 8.5)
Introduction
The carbonyl group is polarized



Carbonyl groups can undergo nucleophilic addition
The carbonyl group is an electrophile
Relative Reactivity of Aldehydes and Ketones
Aldehydes are generally more reactive than ketones in nucleophilic addition reactions
The transition state for addition is less crowded and lower in energy for an aldehyde (a) than for a ketone (b)
Aldehydes have one large substituent bonded to the C=O: ketones have two
Electrophilicity of Aldehydes and Ketones
Aldehyde C=O is more polarized than ketone C=O
As in carbocations, more alkyl groups stabilize + character
Ketone has more alkyl groups, stabilizing the C=O carbon inductively
Reactivity of Aromatic Aldehydes
Less reactive in nucleophilic addition reactions than aliphatic aldehydes
Electron-donating resonance effect of aromatic ring makes C=O less reactive electrophilic than the carbonyl group of an aliphatic aldehyde
Reaction Theme
One of the most common reaction themes of the carbonyl group is addition of a nucleophile to form a tetrahedral carbonyl addition compound
Oxidation and Reduction
Carbonyl groups and alcohols interconverted by oxidation and reduction reactions
Reduction: gain of hydrogen, loss of oxygen, …
Level of oxidation decreases
Oxidation: gain of oxygen, loss of hydrogen, …
Level of oxidation increases
Reduction
Any carbonyl compound can be reduced to alcohol





Reduction
Reduction of carboxylic acids
With powerful reducing agents such as lithium aluminum hydride (LiAlH4 also abbreviated LAH)
LAH is an hydride (H-) source and therefore basic.
H- is also a nucleophile
Reduction
Esters, aldehydes and ketones to primary and secondary alcohols
Reduction
Esters, aldehydes and ketones to primary and secondary alcohols
Reduction
Acids and esters less reactive than ketones and aldehydes







LAH is very reactive with water and must be used in an anhydrous solvent such as ether
NaBH4 is considerably less reactive and can be used in solvents such as water or an alcohol
Reduction
An aldehyde can be reduced to a 1° alcohol and a ketone to a 2° alcohol
Catalytic Reduction
Catalytic reductions are generally carried out from 25° to 100°C under 1 to 5 atm H2
Catalytic Reduction
A carbon-carbon double bond may also be reduced under these conditions





by careful choice of experimental conditions, it is often possible to selectively reduce a carbon-carbon double in the presence of an aldehyde or ketone
Metal Hydride Reduction
The most common laboratory reagents for the reduction of aldehydes and ketones are NaBH4 and LiAlH4
both reagents are sources of hydride ion, H:-, a very powerful nucleophile
NaBH4 Reduction
Reductions with NaBH4 are most commonly carried out in aqueous methanol, in pure methanol, or in ethanol
one mol of NaBH4 reduces four mol of aldehyde or ketone
NaBH4 Reduction
the key step in metal hydride reduction is transfer of a hydride ion to the C=O group to form a tetrahedral carbonyl addition compound
LiAlH4 Reduction
Unlike NaBH4, LiAlH4 reacts violently with water, methanol, and other protic solvents
reductions using this reagent are carried out in diethyl ether or tetrahydrofuran (THF)
Metal Hydride Reduction
Metal hydride reducing agents do not normally reduce carbon-carbon double bonds, and selective reduction of C=O or C=C is often possible
Reductive Amination
A value of imines is that the carbon-nitrogen double bond can be reduced to a carbon-nitrogen single bond
Oxidation
A primary alcohol can be oxidized to an aldehyde or a carboxylic acid




pyridinium chlorochromate (PCC) stops the oxidation at the aldehyde stage
Oxidation
Oxidation of Primary Alcohols to Carboxylic Acids
Potassium permanganate (KMnO4) and chromic acid (H2CrO4) oxidizes a primary alcohol to a carboxylic acid



Oxidation of Secondary Alcohols to Ketones
chromic acid (H2CrO4) and Jones reagent (CrO3 in acetone) oxidize a secondary alcohol to a ketone
Oxidation of Aldehydes and Ketones
CrO3 in aqueous acid oxidizes aldehydes to carboxylic acids efficiently
Silver oxide, Ag2O, in aqueous ammonia (Tollens’ reagent) oxidizes aldehydes (no acid)
Hydration of Aldehydes
Aldehyde oxidations occur through 1,1-diols (“hydrates”)
Reversible addition of water to the carbonyl group
Aldehyde hydrate is oxidized to a carboxylic acid by usual reagents for alcohols
Oxidation of Aldehydes
Aldehydes are oxidized to carboxylic acids by a variety of oxidizing agents, including chromic acid
Oxidation of Aldehydes
aldehydes are oxidized by molecular oxygen and by hydrogen peroxide



Ketones Oxidize with Difficulty
Undergo slow cleavage with hot, alkaline KMnO4
C–C bond next to C=O is broken to give carboxylic acids
Reaction is practical for cleaving symmetrical ketones
Oxidation
Mechanism of chromate oxidation
Oxidation
Mechanism of chromate oxidation
Aldehydes form hydrates in water
Oxidation
H2CrO4, H2O:
Aldehydes form hydrates in water and are further oxidized into carboxylic acids
PCC, CH2Cl2:
The aldehyde cannot form a hydrate
The oxidation of a primary alcohol stops at the aldehyde stage
Tertiary alcohols can form the chromate ester but cannot eliminate (they have no hydrogen on the alcohol carbon) and are therefore not oxidized by chromium based reagents
Organolithium and Grignard Reagents
Organolithium and Grignard reagents can be used to form alkynides by acid-base reactions
Grignard Reagents
Formally: conversion of halides to hydrogen

The Grignard reaction: addition of Grignard reagents to carbonyls
Grignard Reagents
Nucleophilic attack of Grignard reagents at carbonyl carbons is the most important reaction of Grignard reagents



Mechanism
Grignard Reagents
Reaction with esters



Mechanism (ketones are more reactive than esters)
Grignard Reagents
Synthesis of 1O, 2O and 3O alcohols
Grignard Reagents
addition of a Grignard reagent to formaldehyde followed by H3O+ gives a 1° alcohol
Grignard Reagents
addition to any other RCHO gives a 2° alcohol
Grignard Reagents
addition to a ketone gives a 3° alcohol
Grignard Reagents
addition to CO2 gives a carboxylic acid
Formation of Acetals
Alcohols are weak nucleophiles but acid promotes addition forming the conjugate acid of C=O
Addition yields a hydroxy ether, called a hemiacetal (reversible); further reaction can occur
Protonation of the OH and loss of water leads to an oxonium ion, R2C=OR+ to which a second alcohol adds to form the acetal
Addition of Alcohols
Addition of one molecule of alcohol to the C=O group of an aldehyde or ketone gives a hemiacetal
Hemiacetal: a molecule containing an -OH and an -OR or -OAr bonded to the same carbon
Addition of Alcohols
Hemiacetals are only minor components of an equilibrium mixture, except where a five- or six-membered ring can form
Addition of Alcohols
Hemiacetals react with alcohols to form acetals
Acetal: a molecule containing two -OR or -OAr groups bonded to the same carbon
Addition of Alcohols
Steps 1 and 2: proton transfer from the acid catalyst, HA, to the carbonyl oxygen followed by loss of H2O
Addition of Alcohols
Steps 3 and 4: reaction of the oxonium ion with ROH followed by proton transfer to A-
Addition of Alcohols
with a glycol, such as ethylene glycol, the product is a five-membered cyclic acetal
Uses of Acetals
Acetals can serve as protecting groups for aldehydes and ketones
It is convenient to use a diol, to form a cyclic acetal (the reaction goes even more readily)
Add’n of N Nucleophiles
Ammonia, 1° aliphatic amines, and 1° aromatic amines react with the C=O group of aldehydes and ketones to give imines (Schiff bases)
Add`n of N Nucleophiles
Formation of an imine occurs in two steps
Step 1: formation of a TCAI
Step 2: loss of water

Add`n of N Nucleophiles
Rhodopsin (visual purple) is the imine formed between 11-cis-retinal (vitamin A aldehyde) and the protein opsin
Keto-Enol Tautomerism
Keto-Enol Tautomerism
Keto-Enol Tautomerism
keto-enol equilibria for simple aldehydes and ketones lie far toward the keto form
Keto-Enol Tautomerism
Keto-enol tautomerism is acid catalyzed
Step 1: proton transfer from H-A




Step 2: proton transfer to A-
Racemization
Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction
The sequence converts C=O is to C=C
A phosphorus ylide adds to an aldehyde or ketone to yield a dipolar intermediate called a betaine
The intermediate spontaneously decomposes through a four-membered ring to yield alkene and triphenylphosphine oxide, (Ph)3P=O
Formation of the ylide is shown below
A Note on the Word “Betaines”
The term “betaines” is an extension from a specific substance (betaine) that has permanent + and – charges (as in a zwitterion) that cannot be neutralized by proton transfers (as in normal amino acids). Webster`s Revised Unabridged Dictionary lists: Betaine Be"ta*ine, n. [From beta, generic name of the beet.] (Chem.) A nitrogenous base, {C5H11NO2}, produced artificially, and also occurring naturally in beet-root molasses and its residues. The listed pronunciation indicates it has the exact same emphasis as “cocaine”.
Cocaine Co"ca*ine, n. (Chem.) A powerful alkaloid, {C17H21NO4}, obtained from the leaves of coca
So – if you say “co-ca-een” (as this dictionary suggests) then you would also say “bee-ta-een”. If you sat “co-cayn” then say “beet-ayn”.
Whatever you say, the “beta” in “betaine” refers to beets and not a letter in the Greek alphabet. There have been a lot of wagers on this over the years.
RK
Uses of the Wittig Reaction
Can be used for monosubstituted, disubstituted, and trisubstituted alkenes but not tetrasubstituted alkenes The reaction yields a pure alkene of known structure
For comparison, addition of CH3MgBr to cyclohexanone and dehydration with, yields a mixture of two alkenes
Mechanism of the Wittig Reaction
Retrosynthetic Analysis
Example: Synthesize the following compound using an alcohol of not more than 4 carbons as the only organic starting material
Summary
Carboxylic acid to alcohol
LiAlH4
Ester to alcohol
LiAlH4
H2, [Cu]
Ketone to alcohol
LiAlH4
NaBH4
Aldehyde to alcohol
LiAlH4
NaBH4
1O Alcohol to Aldehyde
PCC
1O Alcohol to carboxylic acid
H2CrO4
2O Alcohol to ketone
PCC
H2CrO4
Summary
Synthesis of alcohols and carbon-carbon bond formation
The Cannizzaro Reaction: Biological Reductions
The adduct of an aldehyde and OH can transfer hydride ion to another aldehyde C=O resulting in a simultaneous oxidation and reduction (disproportionation)
The Biological Analogue of the Canizzaro Reaction
Enzymes catalyze the reduction of aldehydes and ketones using NADH as the source of the equivalent of H-
The transfer resembles that in the Cannizzaro reaction but the carbonyl of the acceptor is polarized by an acid from the enzyme, lowering the barrier
Enzymes are chiral and the reactions are stereospecific. The stereochemistry depends on the particular enzyme involved.
Conjugate Addition of Amines
Conjugate Addition of Alkyl Groups: Organocopper Reactions
Mechanism of Alkyl Conjugate Addition
Conjugate nucleophilic addition of a diorganocopper anion, R2Cu, an enone
Transfer of an R group and elimination of a neutral organocopper species, RCu
Biological Nucleophilic Addition Reactions
Example: Many enzyme reactions involve pyridoxal phosphate (PLP), a derivative of vitamin B6, as a co-catalyst
PLP is an aldehyde that readily forms imines from amino groups of substrates, such as amino acids
The imine undergoes a proton shift that leads to the net conversion of the amino group of the substrate into a carbonyl group
Spectroscopy of Aldehydes and Ketones
Infrared Spectroscopy
Aldehydes and ketones show a strong C=O peak 1660 to 1770 cm1
aldehydes show two characteristic C–H absorptions in the 2720 to 2820 cm1 range.
C=O Peak Position in the IR Spectrum
The precise position of the peak reveals the exact nature of the carbonyl group
NMR Spectra of Aldehydes
Aldehyde proton signals are at  10 in 1H NMR - distinctive spin–spin coupling with protons on the neighboring carbon, J  3 Hz
Protons on Carbons Adjacent to C=O
Slightly deshielded and normally absorb near  2.0 to 2.3
Methyl ketones always show a sharp three-proton singlet near  2.1
13C NMR of C=O
C=O signal is at  190 to  215
No other kinds of carbons absorb in this range
Mass Spectrometry – McLafferty Rearrangement
Aliphatic aldehydes and ketones that have hydrogens on their gamma () carbon atoms rearrange as shown
Mass Spectroscopy: -Cleavage
Cleavage of the bond between the carbonyl group and the  carbon
Yields a neutral radical and an oxygen-containing cation
Enantioselective Synthesis
When a chiral product is formed achiral reagents, we get both enantiomers in equal amounts - the transition states are mirror images and are equal in energy
However, if the reaction is subject to catalysis, a chiral catalyst can create a lower energy pathway for one enantiomer - called an enantionselective synthesis
Reaction of benzaldehyde with diethylzinc with a chiral titanium-containing catalyst, gives 97% of the S product and only 3% of the R
Summary
Aldehydes are from oxidative cleavage of alkenes, oxidation of 1° alcohols, or partial reduction of esters
Ketones are from oxidative cleavage of alkenes, oxidation of 2° alcohols, or by addition of diorganocopper reagents to acid chlorides.
Aldehydes and ketones are reduced to yield 1° and 2° alcohols , respectively
Grignard reagents also gives alcohols
Addition of HCN yields cyanohydrins
1° amines add to form imines, and 2° amines yield enamines
Reaction of an aldehyde or ketone with hydrazine and base yields an alkane
Alcohols add to yield acetals
Phosphoranes add to aldehydes and ketones to give alkenes (the Wittig reaction)
-Unsaturated aldehydes and ketones are subject to conjugate addition (1,4 addition)
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