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Hydrolysis of an Ester
forms a carboxylic acid and an alcohol
Catalyzed by an acid
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Transesterification
turns one ester into another, a type of alcoholysis
ester + alcohol
catalyzed by an acid
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aminolysis
Not catalyzed by an acid, it will protonate the amine
forms another amine
ester + amine
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Ester + Cl-
No reaction
Leaving Group on ester (RO-) is a stroner base than Cl-
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Acyl chloride + alcohol
Forms an ester
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Acyl Chloride + H2O
forms an alcohol
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Acyl Chloride + 2amine
forms an amide
requires twice the amine as chloride because the HCl formed will protonate the amine, making it unable to react
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Relative Reactivities of Caboxylic Acid Derivatives
- Acyl Chloride > Ester ~ Corboxylic Acid > amide
- LG: (Cl-) (RO-) (HO-) (-NH2)
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Steps in Nucleophilic Acyl Subsitution Reaction
- 1.) Tetrahedral Intermediate is formed.
- B/C C=O bond is polar
- 2.) Tetrahedral Intermediate collapses.
- Expels the group that is the weakest base
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Best Leaving Groups
- Weak bases.
- Characteristics:
- More stable than strong bases
- More electronegative than strong bases
- -Electron withdrawling (adds to polarity)
- Form weaker bonds than strong bases
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Relative Boiling Points of Carboxylic Acid Derivatives
Amide > Carboxylic Acid >> Ester ~ Acyl Chloride ~ aldehyde ~ Ketone
- Amides --> strong dipole interactions (resonance)
- Carboxylic Acid --> forms 2 hydrogen bonds
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Carboxylic Acid Derivative + 1. stronger base
2. weaker base
3. similar base
(Compared to leaving group)
1. Forms a new carboxylic acid derivative
2. No reaction
3. After reaction both reatant and product present
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Carbonyl Carbon
The carbon double bonded to an oxygen in the acyl group
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Acyl Chloride + 1. nuetral nucleophile
Important Steps
1. Formation of a tetrahedral intermediate (slow)
2. Proton dissociation (equilibrium)
3. Weaker base is expelled and intermediate collapses
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Acyl Chloride + 2. Negatively Charged Nucleophile
Important Steps
1. Nucleophile attacks carbonyl carbon, forming tetrahedral intermediate
2. Intermediate collapses, expelling the weaker base
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Mechanism:
Acid Catalyzed Hydrolysis of Ester
- 1. Acid protonates the carbonyl oxygen
- 2. Nucleophile attacks the carbony carbon
- - Forms a protonated Tetrahedral Intermediate I
- 3. Proton dissociation
- - Forms T.I. II
- 4. 2 possible protonation sites for H+
- - Forms T.I I or III (weak base is protonated)
- 5. Weaker base is expelled
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Acid Protonation Selectivity
Acids will protonate the atom in the compound with the highest electron density, the most basic atom
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Relative Reactivities toward nucleophilic acyl substition
Carboxylic Acids
Leaving Group
OH > NH2 > O-
In acidic form has approximately same reactivity as an ester
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Carboxylic Acid + Alcohol
- Forms an Ester
- Must be carried out in acidic solution
- - Catalyzes reaction
- - Keeps Carboxylic acid in acid form
Mechanism is exact opposite of acid catalyzed hydrolysis of an Ester
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Carboxylic Acid + Amine
No nucleophilic acyl substitution reaction
- Carboxylic acid is and Acid, amine is a base
- - Acid will protonate amine immediately
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Nucleophilic substitution reactions of epoxides under acidic conditions
Under acidic conditions, the nucleophile attacks the more substituted ring-carbon
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Nucleophilic substitution reactions of epoxides under basic conditions
Under basic conditions, the nucleophile attacks the less sterically hindered (or least substituted) ring carbon
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Acid-catalyzed amide hydrolysis
- 1. Acid protonates the carbonyl oxygen
- 2. Nucleophile attacks the carbony carbon
- - Forms a protonated Tetrahedral Intermediate I
- 3. Proton dissociation - Forms T.I. II
- 4. 2 possible protonation sites for H+
- - Forms T.I I or III
- 5. Weaker base is expelled
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Carboxylic Acid ---> acyl chloride
- reagent: SOCl2 Thionyl Chloride
- Heat required to activate
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Nitriles
- Contain a C=N functional group
- Considered carboxylic acid derivatives
- - react with H2O to form carboxylic acids
- Less Reactive than Amides
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Naming Nitriles
Add "nitrile" to parent alkane name
ex: ethanenitrile
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Nitrile + H2O
Catalyst - Acid and Heat
--> carboxylic acid
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Preparation of a Nitrile
Sn2 reaction of akyl Halide and cyanide ion (-C=N)
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Reduction of an alkyne to an alkane
Reagent: H2
catalyst: Pt/C or Pd/C
works for nitriles also
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Activation of Carboxylic Acids
Reagent SOCl2
Add Heat
Forms an Acyl Chloride
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Class II Carbonyl Compounds
Do not have a group that can be replaced by a nucleophile.
- Aldehydes and Ketones
- - Leaving group (H- and R-) are too basic
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Aldehydes
The carbonyl carbon is bonded to a hydrogen and to an alkyl or aryl group
Special case: Formaldehyde - carbonyl carbon is bonded to two hydrogens
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Ketone
The carbonyl carbon is bonded to two alkyl or aryl groups.
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Acetone
carbonyl carbon is bonded to two methyl groups
- common name for smallest Ketone
- - Propanone
- Widely used as solvent
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Naming Aldehydes
Replace the "e" on the name of the parent hydrocarbon with "al"
Position of Carbonyl group is not desiginated, it is always on the end and always has the 1 position
Ex: Methanal, Ethanal
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Naming Ketones
Replace the "e" in the parent hydrocarbon with "one"
The Chain is numbered in the direction that gives the carbonyl carbon the smaller number
No number needed for cyclic ketones
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Relative Reactivities of class II carbonyl compounds
Formaldehyde > aldehyde > ketone
- 1. The Hydrogens in aldehydes are electron withdrawling when compared to alkyl groups
- 2. Less steric interaction in aldehydes (H group)
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Relative Reactivities of Ketones
ketones with smaller alkyl groups bonded to the carbonyl carbon are more reactive than ketones with large alkyl groups
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Relative Reactivities of Carbonyl Compounds (class I and II)
Acyl Chloride > Aldehyde > Ketone > Ester > Carboxylic Acid > Amide > Carboxylate Ion
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Class II carbonyl compound reaction with nucleophile
Leaving group is too basic to be expelled
Undergo nucleophilic addition reactions
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Grignard Reagents
The most widely used carbon nucleophiles
- Prepared by adding an alkyl halide to Mg shavings being stirred in diethyl either
- -Reaction insterts Mg between the C and halogen
- -React as if they were carbanions
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Gignard Reagents as Nucleophiles
- Mg is less electronegative than C
- -The carbon bonded to Mg has a negative charge
Such a strong base that it reacts immediately with any acid (even traces amounts of poor acids) in solution
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Aryl Group
refers to any functional group or substituent derived from a simple aromatic ring
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Mechanism: Aldehyde/ketone with grignard reagent
- 1. Nucleophilic attack by Grignard Reagent on carbonyl carbon
- -Forms an Alkoxide ion complexed with Mg+
- 2. Reaction with H3O+
- -Protonation of the alkoxide ion forms an alcohol
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Product of the Reaction of Grignard Reagent with Formaldehyde
Product is a primary alcohol
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Product of the Reaction of Grignard Reagent with Aldehyde other than Formaldehyde
The procuct is a secondary alcohol
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Product of a grignard reagent reacting with a ketone
The product is a tertiary alcohol
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Reactions of an ester or acyl chloride with the Grignard reagent (overview)
- Undergo two successive reactions
- 1. nucleophilic acyl substitution reaction
- an ester has a group that can be replaced
- - sp3 carbon attached to O and another E- atom
- 2. nucleophilic addition reaction
- The ketone formed in 1. reacts with 2R-MgBR and H3O+
Forms alcohol
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Product of the reaction of Acyl chloride or ester with two equivalents of grignard reagents
forms a tertiary alcohol, with two identical groups
- 1st equivalent replaces Cl in a nucleophilic acyl substituion reaction
- 2nd equivalent reacts in a nucleophilic addition reaction
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Reaction of Aldehydes and ketones with Hydride ion
Nucleophilic addition reaction (addition of H = reduction)
- 1.NaBH4 is the source of the hydride ion
- - H- attaches to carbonyl carbon forming an alkoxide ion
- 2.H3O+ is added after 1.
- - protonates carbonyl oxygen
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Reaction of Class 1 carbonyl compounds with hydride ion
- Undergoes two succesive reactions
- 1. Nucleophilic acyl substitution (with H-)
- 2. Nucleophilic addition reaction (with 2nd equivalent of H-)
Source of hydride ion: NaBH4 (if more reactive than a ketone) or LiAlH4 (if less reactive than a ketone)
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Product of an Ester reacting with LiAlH4
- 1. 2 successive reactions with H- (from LiAlH4)
- 2. H3O+
Produces two alcohols, one corresponding with the acyl portion of the ester and one corresponding the alkyl portion
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Procuct of the reaction of carboxylic acid with LiAlH4
- 1. 2 successive reactions with H- (from LiAlH4)
- 2. H3O+
forms a single primary alcohol
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Reaction of Amide with Hydride ion
- 1. 2 successive reactions with H- (from LiAlH4)
- 2. H2O
- - the product is an amine
- if H3O+ is used instead of h20 in 2.
- -the acid would protonate the amine
- - the product would be an ammonium ion
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Imine (Hybridization and orbitals)
a compound with a carbon - nitrogen double bond
- Imine Nitrogen is sp2 hybridized
- 1 sp2 orbital - sigma bond with Imine carbon
- 1 sp2 orbital - sigma bond with a substituent
- last sp2 orbital contains a lone pair
- P orbital overlaps with imine carbon's p orbital
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Product of the reaction of an aldehyde or ketone with a primary amine
- Product is an imine
- - requires trace amounts of acid
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Product of the reaction of an aldehyde or ketone with a secondary amine
- product is an enamine
- - requires trace amounts of acid
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Enamine
- a tertiary amine with a double bond in the alpha, beta - position relative the nitrogen atom
- C=C--N (two R groups attached to N)
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Mechanism of Imine formation
- 1. The amine attacks the cabonyle carbon
- 2. the alkoxide ion is protonated
- 3. the Ammonium ion loses a Hydrogen by dissociation
- - forms a nuetral tetrahedral intermediate (a carbinolamine)
- 4. either nitrogen or oxygen can be protonated
- 5. elimination of H2O from the oxygen protonated intermediate forms a protonated imine
- 6. dissociation forms an imine
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acid-cataylzed hydrolysis of an imine
forms a carbonyl compound and a primary amine
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Acid catalyzed hydrolysis of an enamine
forms a carbonyl compound (ketone of aldehyde) and a secondary amine
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Reaction of a ketone or aldehyde with secondary amine
- forms an enamine
- - requires trace amounts of acid
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a Hydrate
a molecule with OH groups on the same carbon
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Procuct of the addition of water to a ketone or aldehyde
forms a hydrate in presence of acid catalyst
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Mechanism for Acid-catalyzed hydrate formation
- 1. the acid protonates the carbonyl oxygen, makes the carbonyl carbon more succeptible to nucleophilic attack
- 2. water attacks the carbonyl cation
- 3. loss of a proton from the protonated tetrahedral intermediate
- -produces a hydrate
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How substituents on carbonyl carbon affect the extent to which a ketone or aldehyde is hydrated
- 0.2% of acetone hydrated at equilibrium
- 99.9% of formaldehyde is hydrate at equilibrium
Bulky substituents and electron donating substituents decrease the percentage of hydrate present at equilibrium
small substuents increase it
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Product of one equivalent of alcohol and an aldehyde
and
Product of two equivalents of acohol and an aldehyde
a hemiacetal
an acetal
(both require acid catalyst b/c alcohols are poor nucleophiles)
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ketones react with aldehydes to form
1. hemiketals
- second equivalent of alcohol
- 2. ketals
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Mechanism for acid-catalyzed ketal and acetal formation
- 1. acid protonates the carbonyl oxygen
- 2. nucleophile attacks the carbonyl oxygen
- 3. proton dissociation
- - forms hemi - ketal or hemiacetal
- 4. either the OH or the OR' of the hemiketal/acetal group can be protonated
- 5. Loss of H2O from tetrahedral intermediate with protonated OH
- 6. nucleophile attacks the carbonyl carbon
- 7. proton dissociation
forms a ketal or acetal
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Nucleophilic addition to unsaturated carbonyl compounds
(alpha carbon double bonded to beta carbon and sigma bonded to carbonyl carbon)
- 1,2 addition or direct addition
- oxygen (1) gets the hydrogen
- carbonyl carbon (2) gets the nucleophile
- 1,4 addition or conjugate addition
- beta carbon (4) gets nucleophile
- oxygen (1) gets the hydrogen
- - Forms an enol which tautomerizes into a ketone
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Conjugate products are favored
by nucleophiles that are weak bases.
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Direct addition products are favored
By strong bases
ex: ethly alcohol in Grignard reagent
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Oxidation of primary alcohol
[aldehyde] ---> a carboxylic acid
Reagent is H2CrO4
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Oxidation of secondary alcohol
forms a ketone
H2CrO4 is reagent
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Primary alcohol and PCC
solvent (CH2Cl2)
stops the oxidation at the aldehyde intermediate
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Dehydration Reaction of Alcohol
H2SO4 and Heat
forms alkene and water
tertiary > secondary > primary
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