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CARBOXILIC ACIDS, The partial positive charge on the carbonyl carbon is…
CARBOXILIC ACIDS
Carbonyl Condensation Reactions
Intramolecular aldol reactions
Enolate donor and the electrophilic acceptor of an aldol reaction are contained in the same molecule
the small distance between the donor and acceptor leads to faster reaction rates for intramolecular condensations making intermolecular condensations less favorable
The claisen condensation reaction
Mixed claisen condensations
Claisen condensations between different ester reactants are called Crossed Claisen reactions
General reaction
Mechanism
1) Enolate formation
The mechanism starts with the alkoxide base removing an alpha-hydrogen from the ester to form a nucleophilic ester enolate ion.
2)Nucleophilic attack
The enolate nucleophile adds to carbonyl carbon of a different ester, forming a tetrahedral alkoxide intermediate.
3) Removal of leaving group
The alkoxide then reforms the carbonyl, eliminating the –OR leaving group to form a beta-ketoester.
4)Deprotonation
The acidity of beta-ketoesters is high enough to allow them to be completely deprotonated by alkoxide bases to form a second enolate.
5) Protonation
The enolate is protonated in an acid work-up to form the neutral beta-ketoester product.
Mixed aldol reactions
Mixed aldols in which both reactants can serve as donors and acceptors generally give complex mixtures of both dimeric
ACH2CHO + BCH2CHO + NaOH --> A–A + B–B + A–B + B–A Products of a Uncontrolled Mixed Aldol Reaction
Intramolecular claisen condensation- The dieckmann cyclization
transform Diesters into cyclic beta-keto esters
Mechanims
3)Removal of leaving group
4)Deprotonation
2)Nucleophilic attack
5)Protonation
1)Enolate formation
Conjugate carbonyl additions- The michael reaction
When enolate nucleophiles undergo conjugate addition with an α, β-unsaturated carbonyl the process is called a Michael Reaction.
Mechanisms
2)Nucleophilic attack on the carbon β to the carbonyl
The enolate nucleophile then adds to the electrophilic β-carbon of the α, β-unsaturated carbonyl.
3)Protonation
The alkoxide is protonated, forming an enol.
1)Deprotonation
The alkoxide base removes an alpha-hydrogen to from an enolate nucleophile.
4)Tautomerization
Tautomerization converts the enol back into a carbonyl forming the neutral conjugate addition product.
During a Michael reaction two sp2 hybridized carbons are both converted to sp3 hybridization.
Carbonyl condensations with enamines - The stork reaction
Mechanisms of Enamine Acylation
2) Nucleophilic attack
The enamine adds to the electrophilic carbonyl carbon of the acid halide to form an iminium bond with tetrahedral alkoxide as an intermediate
3)Leaving group removal
The alkoxide reforms the carbonyl bond and eliminate a halide anion as a leaving group.
1)Formation of the enamine
The mechanism starts with the formation of an enamine.
4)Reform the carbonyl by hydrolysis
The iminium bond is then hydrolyzed to reform the carbonyl to create a 1,3-dicarbonyl compound as the product of a nucleophilic acyl substitution.
Enamines can add to acid halides to form 1,3-diketones and α, β-unsaturated Michael acceptors to from 1,5-dicarbonyls.
Mechanisms of the Stork reaction
3)Protonation
4)Tautomerization
2)Nucleophilic attack on the carbon β to the carbonyl
5)Reform the carbonyl by hydrolysis
1)Formation of the enamine
The Robinson annulation reaction
Many times the product of a Michael addition produces a dicarbonyl which can then undergo an intramolecular aldol reaction. These two processes together in one reaction creates two new carbon-carbon bonds and also creates a ring. Ring- forming reactions are called annulations after the Latin work for ring annulus. The reaction is named after English chemist Sir Robert Robinson who developed it.
The nucleophilic enolate donor is typically an enolate ion or enamine of a cyclic ketone, β-keto ester or β-diketone. The electrophilic acceptor is usually an α, β-unsaturated ketone. In the example below, 2-methyl-1,3-cyclohexanedione is deprotonated to form an enolate which affects a Michael reaction addition on 3-buten-2-one forming a C-C bond. The product contains a 1,5-diketone fragment which can undergo an intramolecular aldol condensation
Biomolecules: Lipids
Waxes, Fats, and Oils
Waxes
mixtures of esters of long-chain carboxylic acids with long-chain
alcohols
It has often a role of coat protection in fruits, leaves even animals furs which are close in their structure
A well known is beewaxe
triacontyl
hexadecanoate
Fats
Chemically, fats are triglycerides which can be esterified by fatty acid
Trygliceride
Fatty acid branched doesn't need to be the same
Fatty acid
2 major type of fatty acid
saturated
Each carbon carries as many hydrogen as possible.
Examples
Palmitic acid
Stearic acid
Long straight fatty acids with single bonds tend to pack tightly and are solid at room temperature
unsaturated
It is a fatty acid which has one or more carbon-carbon double bonds
Examples
Oleic acid
linoleic acid
cis/trans isomerization
It is caused by hydrogenation
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Properties differences
Saturated fatty acid have a hgiher melting poi,nt than unsaturated
The resaon why
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Because the more there are double bond the less the molecules can crystallize together
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It has been established that in general unsaturated are better for the health than saturated
Animals have more saturated fatty acid than plants
a fatty acid is an aliphatic chain carboxylic acid
Fat in animal and plant are mostly called lipids
The purpose of lipids in animals tissues is to have a storage role
Because these molecules are less likely to be oxydized than carbohydrates
These concentrates 6 times more the energy at equal weight than thuir carbohydrate counterpart
There is difference in the physic appearance of fat between animals and plant
fat in animal are solid
The reasons why
Animals fat are more composed of trans fat
fat in plant are most likely liquid
The reason why
Soap
How is it formed ?
Saponification of a glyceride
Hydrolysis of animal fat with alkali
Focus on what happen
What is it ?
the salt of a fatty substance and potassium or sodium
Phospholipids
What is it ?
esters of phosphoric acid
2 kind of Phospholipids
glycerophospholipids
The base of this compound is:
Phosphatidic acid
The phosphate esterified at C3 links with amino alcohol
bonding with a Serine
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Bonding with amine
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This is a glycerol esterified by a phosphoric acid and 2 fatty acid
These fatty acid are usually different
The one linked at C1 carbon of glycerol is saturated
The one linked at C2 carbon of glycerol is unsaturated
sphingomyelins
Backbone is Sphingosine
A sphingomyelin
It has non polar hydrocarbon tail linked to a polar head
This characteristic makes that we find it in plasmic membrane of cells as a lipid bilayer
Prostaglandins and Other Eicosanoids
eicosanoids
prostaglandins
It has been identified firtly by Ulf von Euler at the Karolinska Institute in Sweden in 1930
Then Bengt Samuelsson and Sune Bergström have worked on their structural and chemical characteristics
They al received the Nobel Price for their work
A dozen type are known
Prostaglandins are hormones involved in many body reactions
Actions on the digestive system, on the inflammatory system, on kidney and so on
thromboxanes
Thromboxane B2 (TXB2)
leukotrienes
Leukotriene E4 (LTE4)
all these compounds derivate from 5,8,11,14-eicosatetraenoic acid, or arachidonic
acid
Arachidonic acid
Conversion mechanism
These compounds are named according a system which differenciate their ring system (PG, TX, or LT)
prostaglandin (PG)
Then the next letter will change depending on the subsitution pattern
For instance It could be for the prostaglandin
PGE
Finally the number that will change depending on the number of double bond
PGI
PGA
thromboxane (TX)
leukotriene (LT)
Terpenoids (also called isoprenoids)
Most of these compounds have multicyclic structures which differ from each other not only in functional groups.
35,000 different terpenoids are known
These compounds are very diverse but they all are following the same rule
They all result, head to tail, from the binding of 5-carbon isoprene units
Classification
Diterpenoids
4 Isoprene unit
20 carbons
Sesterterpenoids
5 Isoprene unit
25 carbons
Sesquiterpenoids
3 Isoprene unit
15 carbons
Triterpenoids
6 Isoprene unit
30 carbons
Monoterpenoids
2 Isoprene units
10 carbons
Tetraterpenoids
_ Isoprene unit
40 carbons
Hemiterpenoids
1 Isoprene unit
5 carbons
Polyterpenoid
8 Isoprene unit
40 carbons
The Mevalonate Pathway to Isopentenyl Diphosphate which is the terpenoid precursor
Conversion of Isopentenyl Diphosphate to Terpenoids
which is a monoterpenoid
Steroids
They are derived from the triterpenoid lanosterol
The pathway from Lanosterol leads to Cholesterol which is a precursor to all the steroids
This is a biosynthesis that involves many enzymes
Based on tetracyclic rings system
2 fusions possibels between 2 cyclohexane. A-B rings can be linked in cys or trans state
Found in liver bile
The most common
B-C and C-D have trans fusion
In human body, these behave as hormones. They deliver "messages" to the organs and cells of the organism through the bloodstream
Sex hormones
Examples
Adrenocortical Hormones
Synthetic hormones
Nitriles
Naming
nitrile functional group
nitrile attached to a ring
molecule with carboxylic acid and nitrile: nitrile as cyano- substituent
Properties
nitriles : analogous to carbonyl groups : have pi bonds, strongly polarized, have electrophilic carbons
Preparation of Nitriles
from Aldehyde / Ketone
addition of a cyanide to aldehyde/ketone to form a cyanohydrin
from a 1° Amide
primary amides converted to nitriles by dehydration with thionyl chloride or other dehydrating agents
mechanism
: 1- nucleophilic attack on thionyl chloride 2- leaving group removal to reform the thionyl bond 3- deprotonation, 4- E2-like reaction to form a nitrile
Reactions of Nitriles
Hydrolysis of Nitriles to form Carboxylic Acids :
acid catalysed hydrolysis
1- Protonation
2- Nucleophilic additon of water
3- Proton transfer
4- Resonance to form a protonated amide
5- Deprotonation to form an amide
6- Amide hydrolysisi to form a carboxylic acid
base catalysed hydrolysis
1) Nucleophilic addition of hydroxide
2) Protonation by wtaer to form hydroxyimine & hydroxide
3) tautomerisation
4) Amide hydrolysis to form a carboxylic acid
Reduction of Nitriles to 1°amines with LiAlH4
1) nucleophilic attack by the hybride
2) second nucleophilic attack byb the hybride
3) protonation by addition of wtaer to give a primary amine
Conversion of Nitriles to Aldehydes with DIBALH
1)formation of a Lewis acid-base complex.
2) nucleophilic addition of hybride forms imine anion
3) imine anion hydrolysis with acidic aqueous work up, forms an aldehyde
Conversion of Nitriles to Ketones with organometalic reagents
1) nucleophilic attack by Grignard reagent to form imine anion
2) protonation to form an imine
3) Protonation to form an iminium ion
4) Nucleophilic attack by water
5) Proton transfer
6) Removal of NH3 as a leaving group to form a ketonium ion
7) deprotonation to form a ketone
general reaction
triple bond reacts with negatively charged nucleophiles : forms an imine anion intermediate
the anion have a pi bond & an electrophilic carbon -> additional nucleophilic additions can occurs -> form ketones/aldehydes/amines...
Carboxylic Acids
Structure and properties
Naming
carboxyl group
suffix: -oic acid
carboxyl group added to a ring: suffix -carboxylic acid
carboxyl on benzene ring
carboxylates (salts of carboxylic acids)
-ic acid ending replaced by -ate suffix
craboxylic acids with other functional groups
carboxil acid with alcohol group
alcohol named as hydroxyl substituent
carboxyl group with aldehyde/ketone
amine = "amino" substituent
carboxyl acid with amine group
carbonyl = "oxo" substituent
dicarboxylic acids
Structure of the carboxyl acid group
Carbon & oxygen in carbonyl both sp2 hydridized : trigonal planar shape of the carboxyl aicd
acidity of carboxylic acids
act as Bronsted-Lowry acid in aqueous solution
partial dissociation of a carboxylic acid to produce corresponding carboxylate ion
extent of this dissociation described by the Ka of the carboxylic acid
Physical properties of some carboxylic acids
higher boilign points thaht ether/alcohols/aldehydes/ketone with same molecular weight
2 carboxylic acids can form 2 hydrogen bonds with each other. This create a CYCLIC DIMER
2 hydrogens bonds -> stronger intermolecular forces -> higher boiling points
Preparing carboxylic acids
Through Oxidations
oxidation of 1° alcohols
oxidation of aldehydes
oxidation of alkyl arene side-chains
oxidative cleavage of alkenes
Carboxylation of Grignard Reagents
Nitriles Hydrolysis
Reactions of Carboxylic acids
salt formation
nucleophilic acyl substitution
substitution of the wholehydroxyl group
reduction
alpha substitution
proton on the alpha Carbon of carbonyl group is not acidic -> proton can be removed -> substitution at the alpha position
Hydroxyl hydrogen substitution
Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions
Carboxylic acid derivatives
They include:
Carboxylic acid derivative have two sides.
One side is the acyl group, which is the carbonyl
The other side is tha attached alkyl (R) group
Reactivity
Nucleophilic acyl substitution reactions
Mechanism for the reaction
the tetrahedral intermediate collapses and the acyl X group is expelled, usually accepting a proton from an enzymatic acid in the process
A nucleophilic acyl substitution reaction starts with nucleophilic attack at the carbonyl
Applications
3-monochloropropanediol (3-MCPD) in refined oils
What are the concern about this compound ?
Above the tolerable daily intake ( 4 µg/kg body weight) established by The Scientific Committee on Food (SCF), this compound :
It is suspected to be carcinogenic in humans
It has been classified by the International Agency for Research on Cancer as Group-2B which means that this compound is possibly carcinogenic
It can affects the kidney with a chronic oral intake
It can cause nephropathy, tubular hyperplasia and adenomas
What is it ?
It has 2 functional acohol groups and one chloride
Formula:
water, acetone, diethyl ether, alcohol soluble
It's a colorless liquid but can turn to straw yellow
These compounds are close to the 3-monochloropropanediol (3-MCPD)
Where can we find it ?
It has been found in asian sauce as oyster and soy sauce, bread, margarine, fine bakery, canned meats, vegetable oils, instant soups, bouillon cubes, savory snacks, ready-to-eat meals, instant noodles,
It's a by side product of acid-hydrolyzed vegetable protein at a high temperature. The oil is heated to a very high temperature to remove unwanted odors, colors and tastes
This technique is used to obtain soy sauce quickly (in matter of days) without fermentation
Soy sauce obtained by fermentation doesn't involve high temperature but last months
How is it formed ?
The formation occurs at high temperature with the presence of chloride ions and lipids
From Glycerol
Acid hydrolysis is used to produce soy sauce without fermentation
Flavonoids – biosynthesis, occurrence, and potential health benefits
For pharmaceutical purposes cost-effective bulk production of different types of flavonoids has been made possible with the help of microbial biotechnology
Flavonoids consist of a large group of polyphenolic compounds having a benzo-γ-pyrone structure and are ubiquitously present in plants. They are synthesized by phenylpropanoid pathway
Many flavonoids are shown to have antioxidative activity, free radical scavenging capacity, coronary heart disease prevention, hepatoprotective, anti-inflammatory, and anticancer activities, while some flavonoids exhibit potential antiviral activities. In plant systems, flavonoids help in combating oxidative stress and act as growth regulators
Flavonoids have beneficial anti-inflammatory effects and they protect your cells from oxidative damage that can lead to disease. These dietary antioxidants can prevent the development of cardiovascular disease, diabetes, cancer, and cognitive diseases like Alzheimer’s and dementia.
Metabolism of Flavonoids in Humans
The flavonoid can be absorbed from the small intestine or has to go to the colon before absorption. It may depend upon structure of flavonoid, that is, whether it is glycoside or aglycone. After absorption, the flavonoids are conjugated in the liver by glucuronidation, sulfation, or methylation or metabolized to smaller phenolic compounds
Some aromatic polyketides such as dietary flavonoids have gained reputation as miraculous molecules with preeminent beneficial effects on human health, for example, as antioxidants. However, there is little conclusive evidence that dietary flavonoids provide significant leads for developing more effective drugs, as the majority appears to be of negligible medicinal importance.
For the biosynthesis of phloroglucinol the simplest polyketide three molecules of malonyl coenzyme are required
Decarboxylation of the COOH group of the priming malonyl coenzyme would lead to the formation of 3,5-diketohexanoate (Fig. 14.4), an intermediate for triacetic acid lactone while the retention of the said COOH group would form 3,5-diketoheptane dionate, an intermediate for phloroglucinol
Carbonyl Alpha-Substitution Reactions
These reactions proceed through the formation of the enol form of the carbonyl compound.
Alpha-substitution reactions occur at the position next to the carbonyl group—the alpha position—and result in the substitution of an alpha hydrogen atom by an electrophile (E) through either an enol or enolate ion intermedia
The partial positive charge on the carbonyl carbon is stabilized by electron donation from nonbonding electrons on the adjacent heteroatom, which decreases electrophilicity
.
Carboxylate < Amides < Carboxylic esters < Carboylics acids < Thioesters < Acyl phosphates
An electron pair from the enol oxygen attacks an electrophile (E+), forming a new bond and leaving a cation intermediate that is stabilized by resonance between two forms
Loss of a proton from oxygen yields the neutral alpha-substitution product as a new C=O bond is formed.
linoleic acid
Elaidic acid
Acyl phosphate
Amide
Carboxylate
Acyl-AMP
Carboxylic acid
Thioester
Ester
ion
A carbonyl compound
A carbonyl compund
One of the atoms adjacent to the carbonyl carbon in carboxylic acid derivatives is an electronegative heteroatom
1 step
2 step
In this product, the nucleophile becomes the new acyl group
(Red colour)
(Blue colour)
