CHEM261: PRICIPLES OF ORGANIC CHEMISTRY SPRING … · 2020. 1. 27. · chem261: priciples of...
Transcript of CHEM261: PRICIPLES OF ORGANIC CHEMISTRY SPRING … · 2020. 1. 27. · chem261: priciples of...
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CHEM261: PRICIPLES OF ORGANIC
CHEMISTRY
SPRING 2019/2020
REFERENCES
MCMURRY JE. ORGANIC CHEMISTRY. MARY FINCH. 2012
L.G. WADE JR. ORGANIC CHEMISTRY. PEARSON. 2013
THOMAS L. LEMKE. REVIEW OF ORGANIC FUNCTIONAL GROUPS. 2012
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ALCOHOLS Learning outcomes
Identify and draw structures of alcohols
Predict physical-chemical properties
Predict reactions and metabolism
NOMENCLATURE OF ALCOHOLS • Alcohols classified as primary, secondary and tertiary according to the number of organic
groups attached to the carbon contain the hydroxyl
• In the common nomenclature, the word (alcohol) is used
• For IUPAC nomenclature, the longest chain is selected, but the suffix (-ol) is used
• The chain is numbered from the end nearer to the hydroxyl
• The number of substituents and the hydroxyl are indicated
• The -OH group if presents as a substituent in a molecule with high priority functional
group, it will be given the name hydroxy.
This figure taken from Lemke L G. Review of organic functional groups. 2012
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CH2OH
CH2
OH
Ethylene glycol
1,2-Ethanediol
OH
OH
OH
Glycerol1,2,3-Propanetriol
CH3
CCH2
CH2CH3
CH3OH
2-Methyl-2-pentanol2-Methylpentan-2-ol
CH2
CHCH2
OH
Allyl alcohol2-Propene-1-ol
OH
OH
H
H
Cis-1,4-CyclohexanediolCis-cyclohexane-1,4-diol
These structures are adapted from McMurry. Organic chemistry. 2012
PHYSIOCHEMICAL PROPERTIES
• The –OH group has permanent dipole due to the electronegative oxygen and
electropositive hydrogen
• The –OH group has high boiling point due to intermolecular hydrogen bonding
This figure taken from Lemke L G. Review of organic functional groups. 2012
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• It is soluble in water due to hydrogen bonding. The solubility in water depend on the size
of the hydrocarbon part. For alcohol that contain from one to three carbons, it is soluble
in water. As the number of carbons is increased the solubility is decreased.
• Also, the location and position of the –OH group can influence the solubility
This table taken from Lemke L G. Review of organic functional groups. 2012
• Relatively the –OH group is stable, however, from pharmaceutical point, it can react with
an oxidizing agent
This figure taken from Lemke L G. Review of organic functional groups. 2012
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• Alcohols are weak acids and bases
• Compounds with smaller Ka and larger pKa are less acidic, whereas compounds with
larger Ka and smaller pKa are more acidic
O
R
H
+ B: - R O
- + :BH
This table taken from McMurry. Organic chemistry. 2012
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Reactions of alcohols
DEHYDRATION OF ALCOHOLS
H
R
OH
R
R
RH3O
+
1. Tertiary alcohol
+ H2O
OHCH3
H3O+ , THF
50 C
CH3
+ H2O
Example: Taken from McMurry. Organic Chemistry. 2012
H
R
OH
R
R
R
1. Secondary and Tertiary alcohol
+ H2OPOCl3
Pyridine
OHCH3
CH3
+ H2O
Example: Taken from McMurry. Organic Chemistry. 2012
POCl3
Pyridine, 0 C
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OXIDATION OF ALCOHOLS Primary alcohols oxidized into aldehydes and carboxylic acid while secondary alcohols
oxidized to ketones. The reactions depend on type of reagents used.
Tertiary alcohols do not undergo oxidation due to unavailability of hydrogen attached to
the carbon next to the hydroxyl group.
These figures taken from McMurry. Organic chemistry. 2012
Oxidation of primary alcohols to carboxylic acid
This figure taken from McMurry. Organic chemistry. 2012
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Oxidation of primary alcohol to aldehyde: primary alcohols are easily converted to carboxylic
acid using chromate reagents. To limit the reaction to aldehyde, another reagent can be used such
as pyridinium chlorochromate (PCC) in dichloromethane (CH2Cl2).
CH3 CH2 CH2 CH2CH2CH2 CH2 OHPCC
CH2Cl2
CH3 CH2 CH2 CH2CH2CH2 CH
O
Heptan-1-ol Heptanal
CH3
CH3
CH3 OHNa2Cr2O7
H2O, CH3COOH, HeatO
CH3
CH3
CH3
Oxidation of Secondary alcohols to ketones (taken fom McMurry. Organic Chemistry. 2012)
4-tertButylcyclohexanol 4-tertButylcyclohexanone (91 %)
PHENOLS
Learning outcomes Identify and draw structures of phenols
Predict physical-chemical properties
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NOMENCLATURE OF PHENOLS • Phenol are compounds that have an –OH group attached to aromatic ring
This table taken from Lemke L G. Review of organic functional groups. 2012
OHCH3
m-Methylphenol
OH
NO2O2N
2,4-Dinitrophenol
Structures are taken from McMurry. Organic Chemistry. 2012
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Physical-chemical properties
• It contains an –OH group which make it able to form a hydrogen bonding
• Have high boiling points and water solubility due to hydrogen bonding, ion-dipole
interaction and dipole-dipole interaction
• The solubility is affected by type of substituents present in the aromatic ring
This figure taken from Lemke L G. Review of organic functional groups. 2012
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• The acidity of phenol affected by the stability of the phenolate anion during dissociation,
which is affected by the ratio of K1 to K-1
• If the value of K1 ˃ K-1, then a strong acid exists.
• If the value of K1 ˂ K-1, then a weak acid exists.
• Phenolate anion can be stabilized by resonance
This figure taken from Lemke L G. Review of organic functional groups. 2012
• The acidity of phenols varies with the type and position of the substituents and this
affected by its ability to stabilize the phenolate ion
• Electron-donating groups decrease acidity
• Electron-withdrawing groups increases acidity
This table taken from Lemke L G. Review of organic functional groups. 2012
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• Phenols can react with strong bases to give phenolate salts
• Sodium and potassium salts will increase water solubility of phenol
• Heavy metal salts are less soluble in water
• Phenols can be reversed by the addition of an acid
• If salt formation results in precipitation of organic molecules, then this can be considered
as pharmaceutical incompatibility
This figure taken from Lemke L G. Review of organic functional groups. 2012
• Phenols in the presence of oxygen can be oxidized to p-quinone or o-quinone (yellow
coloration).
• This reaction occurs more with phenol salts and polyphenols.
• Therefore, phenols and their salts must be stored in closed, amber containers or by the
addition of an antioxidants.
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Ethers and Thioethers
Learning Outcomes
Identify and draw structure of ethers and thioethers
Predict physical-chemical properties
Nomenclature of Ethers • For simple ethers, the two organic groups are identified and then the word (-ether) is
added.
• For more complex molecules containing ethers, the term (-oxy) is used
These figures taken from McMurry. Organic chemistry. 2012
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This table taken from Lemke L G. Review of organic functional groups. 2012
Physical-chemical properties • Ethers have the same tetrahedral geometry as water but with angle of 110 °.
• Have low boiling points as the only interaction is through van der Waals.
• Low-membered ether molecules have partial solubility in water but as the hydrocarbon
portion increased, the solubility decreased.
This figure taken from Lemke L G. Review of organic functional groups. 2012
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This figure taken from Lemke L G. Review of organic functional groups. 2012
This table taken from McMurry. Organic Chemistry. 2012
• Ethers are non-reactive stable compounds.
• Exception for liquid ethers, can react with air and form peroxides (an antioxidant such as
copper metal is added to take up any oxygen that present and so prevent instability).
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Thioethers nomenclature
• Are alkyl or arylthio group or alkyl or arylmercaptans.
• For simple compounds, the organic groups are identified and the word (sulfide) is added
at the end.
• For complex molecules, if the thio group presents as substituent, then it will be given the
name thio or mercapto.
These figures taken from McMurry. Organic chemistry. 2012
Thioether • High boiling point (diethyl thioether, 92 ͦ C)
• Less water solubility
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Aldehydes and Ketones
Learning Outcomes Identify and draw structures of aldehydes and ketones
Predict physical-chemical properties
Nomenclature • The longest continuous chain containing aldehyde or ketone is selected and then
numbered to give the lowest number to aldehyde or ketone.
• The suffix (–al) in case of aldehyde and the suffix (-one) in case of ketone.
• For common nomenclature, the words aldehyde and ketone are used.
• Carbon attached to oxygen is called carbonyl, however it is not an organic functional
group as it is available in ketone, carboxylic acid and aldehyde
This figure taken from Lemke L G. Review of organic functional groups. 2012
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This figure taken from Lemke L G. Review of organic functional groups. 2012
These figures taken from McMurry. Organic chemistry. 2012
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Physical-chemical properties • These compounds are polar, as it contains polar carbonyl.
• Ketones may exist in equilibrium with the enol form.
• Aldehydes and ketones have higher boiling points compare to the non-polar
hydrocarbons.
This table taken from Lemke L G. Review of organic functional groups. 2012
• Ketones relatively are not reactive.
• Aldehydes are not stable and can be oxidized in the air
• Low-molecular aldehydes can undergo polymerization to cyclic trimers
• Aldehydes and ketones can react with alcohols to form hemiacetal or hemiketal, but
under aqueous conditions (without considering the pH) these can be converted into acetal
and ketal
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These figures taken from Lemke L G. Review of organic functional groups. 2012
Oxidation of aldehydes • Oxidation reactions: aldehydes are oxidized to carboxylic acids by an oxidizing agent
while ketones do not oxidation (why?).
This figure taken from McMurry. Organic chemistry. 2012
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H
O
OH
O
Ag2O
THF/H 2O
CH3
CH3 H
O Na2Cr2O7
dil H2SO4
CH3
CH3 OH
O
Hydration of aldehydes and ketones
Hydration of aldehydes and ketones occur by nucleophilic addition reaction in the
presence of acid or base to give geminal diol.
O O+
H
H
H
O+ H
O
O+
H
H HH2O
OH
OH
Acid-catalyzed hydration
1. Protonation 2. Addition of water 3. Deprotonation
O O-
OH
OH
OH
HO -
H OH
+- OH
1. Addition of hydroxide 2. Protonation
Base-catalyzed hydration
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Reduction reactions Reduction of ketones and aldehydes occur by sodium borohydride NaBH4. it reduces
ketones to secondary alcohols and aldehydes to primary alcohols.
ONa+
-BH4
O-
H
+ Na+
BH3
H OH OHH
+ HO-
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Carboxylic acid and derivatives Learning outcomes
• Identify and draw structures of carboxylic acids.
• Understand and predict acidity, solubility and stability of carboxylic acids and its
derivatives.
• Describe and predict reactions.
Biological Important Carboxylic acids
• It is carbonyl attached to an oxygen which is attached to hydrogen.
• It is an important functional group because it is involved in important industrial and
biological molecules.
• Are intermediates for the synthesis of cholesterol. Also, present in body as fatty acids
such as monosaturated fatty acids and polyunsaturated fatty acids
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Nomenclature of carboxylic acids
The longest chain of the hydrocarbon will be the base unit.
The suffix –oic will be used and then this will be followed by the word acid
This figures taken from McMurry. Organic chemistry. 2012
Structure Common name IUPAC name O
H OH
Formic acid Methanoic acid
O
CH3 OH
Acetic acid Ethanoic acid
O
OHCH3
Propionic acid Propanoic acid
O
OHCH3
Caproic acid Hexanoic acid
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Physical-chemical properties of carboxylic acids • Can do hydrogen bonding through the oxygen of the carbonyl group and the oxygen of
the –OH. Also, the hydrogen of –OH.
• So that mean that carboxylic acids due to the strength of hydrogen bonding will have
high boiling points and high solubility.
• However, as the length of the hydrocarbon side chain increased, the solubility will
decrease.
• A mixture of ethanol-water can be used to increase the solubility carboxylic acids
This figures taken from Lemke L G. Review of organic functional groups. 2012
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Other property for carboxylic acids is acidity
• The acidity depends on the dissociation constant which in reverse depend on the
concentration of protons in solution.
• Also, it will depend on the nature of alkyl or aryl group attached to it and that’s mean it
depend on the stability of the carboxylate ion.
• The position and nature of the substituents in the aromatic ring can affect the acidity.
• General rules from this will be as follow:
• If the R group is an electron-donating group, then acidity will decrease.
• If the R group is an electron-withdrawing group, then acidity will increase.
This table taken from Lemke L G. Review of organic functional groups. 2012
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This table taken from McMurry. Organic chemistry. 2012
Can form salts with bases and metals
• If the carboxylic acid molecule reacts with bases such as (sodium, potassium and sodium
hydroxide) then the salts formed will be more soluble than the free carboxylic acid. Here
the ion-dipole bonding is stronger than dipole-dipole interactions
• If the carboxylic acid molecule reacts with metals such as (calcium, magnesium,
aluminium and zinc), then the salts formed will be less soluble than the free carboxylic
acid.
This table taken from Lemke L G. Review of organic functional groups. 2012
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Reactions of carboxylic acids
1. Condensation of acids • Carboxylic acids can react with alcohols to form ester compounds.
Mechanism of Condensation
OH
O
R OH
O+
R
H
OH
O
O+
R
H H
H
OH
OH
OR
RH
+
R OH
R OH
+ R+OH2
Acid-catalyzed addition of alcohol to the carbonyl
OH
OH
OR
R O+
OH
OR
R
H
H
R OR
O+ H
H+
+ H2O
ROH
R OR
O
+ R+OH2
Acid-catalyzed-dehydration
Question Write the full mechanism for the condensation of the following reaction:
O
OH
+ CH3OHH
+
-
2. Condensation of acids
• Carboxylic acids can react with amines to produce amides.
COOH
+ CH3 CH2 NH2NH
O
- H2O
Heat
3. Reduction of carboxylic acids Carboxylic acids reduced to primary alcohols using Lithium aluminum hydride.
For selective reduction of the carboxylic acid in the presence of another functional
group like ketone, borane and THF can be used.
O
CH3 OH
O 1. BH3. THF
2. H3O+
O
CH3
OH
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4. Alkylation of carboxylic acids Carboxylic acid group can be alkylated using two equivalents of organolithium reagent to
produce ketone.
Carboxylic acid derivatives Esters
• Ester functional group contain two portions, an alcohol and carboxylic acid.
• The name of alkyl group will be followed by the suffix –ate-
• Examples
This figure taken from Lemke L G. Review of organic functional groups. 2012
This figure taken from McMurry. Organic chemistry. 2012
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Physical-chemical properties of esters • Less solubility and boiling point than the carboxylic acids.
• The reason for that due to hydrogen bonding occur only between the hydrogen of water
molecule and the carbonyl of the ester.
This figure taken from Lemke L G. Review of organic functional groups. 2012
• Esters in the presence of base and acid can undergo hydrolysis.
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Hydrolysis of esters
Esters reacts with a base or with an acid to undergo hydrolysis to an acid and alcohol.
O
O+ NaOH
O
O-Na
+
OH+
Ethyl propanoate Sodium propanoate Ethanol
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Amides • Nomenclature of amides is by selecting the longest alkyl chain and then this will be
followed by the suffix –amide
• Amides can be primary, monosubstituted and disubstituted.
• Amides when undergoes intramolecular cyclization will form a ring called lactam
This figure taken from Lemke L G. Review of organic functional groups. 2012
This figure taken from McMurry. Organic chemistry. 2012
Physical-chemical properties
• Can undergoes hydrogen bonding and so consider as polar and water-soluble molecules
• Has high boiling points due to its ability for interactions
• Primary and monosubstituted can undergo hydrogen bonding
• Disubstituted can undergo dipole-dipole interactions and so are with less boiling points
• Amides are neutral and that due to unavailability of the unshared pair lone of electrons
for accepting a proton, as those protons involved in resonance with the carbonyl group
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This table taken from Lemke L G. Review of organic functional groups. 2012
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Hydrolysis of amides Hydrolysis of amide functional group can occur under basic and acidic hydrolysis.
R NH2
O -OH
NH2
O-
OH
R R O
O
HR O
-
O
NH3
-NH2
Basic hydrolysis of an amide
N
O
+ NaOHH2O OH
O
+H N
CH2
CH2CH3
CH3
Acidic hydrolysis of amide
R NH2
O
+ H+
R NH2
O+ H
OH2
NH2
O
O+
R
H H
H
H2O
NH2
O
O
R
H
H
NH2
O
O
R
H
H
+ H+
NH3+
O
O
R
H
HO
+
R
H
O H
O+
R
H
O HNH4
-NH3
N
H
CH3
O
+ H2SO4H2O OH
O
NH2 CH3+
-
Carbamates and Ureas
• Carbonates are the ester derivatives of carbonic acid
• Carbamates are ester amides of carbonic acid
• Ureas are diamides derivatives of carbonic acid
This figure taken from Lemke L G. Review of organic functional groups. 2012
Nomenclature
This figure taken from Lemke L G. Review of organic functional groups. 2012
This figure taken from Lemke L G. Review of organic functional groups. 2012
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This figure taken from Lemke L G. Review of organic functional groups. 2012
Reactions
• Carbonate and carbamates are unstable to acid and base hydrolysis
• Ureas are more stable and consider relatively unreactive
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Amidines and Guanidines
This figure taken from Lemke L G. Review of organic functional groups. 2012
Physical-chemical properties
• Amidines and guanidines are highly basic
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Sulfonic acid and sulphonamides • Sulfonic acid nomenclature
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Physical-chemical properties • Sulfonic acids are strong acids with strong pKa
This figure taken from Lemke L G. Review of organic functional groups. 2012
Physical-chemical properties
• Sulfonamides has high melting point and poor solubility.
• Benzene sulfonamides are stable to hydrolysis by acid, base and enzymes due to the
ability of the SO2 of stabilizing the nitrogen anion through resonance.
• Can form salts in the presence of sodium and potassium.
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Amines
• Amines functional groups are important as it appear in a lot of biological molecules and
pharmaceutical drugs
• Amines molecules are named by choosing the longest alkyl or aryl chain and then adding
the suffix –amine to the end of name.
N
CH3
CH3 CH3
Trimethylamine
N
N
CH3
Nicotine
N
NN
N
CH3
CH3
O
O
CH3
Caffiene
Amines Nomenclature
This figure taken from Lemke L G. Review of organic functional groups. 2012
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NH2 CH2CH2CH2CH2NH2
Butan-1,4-diamine
CH3 CH2 CH CH3
NHCH3
N-methylbutan-2-amine
CH3
NH2
CH3
4,4-Dimethylcyclohexaneamine
CH3 CH2CH COOH
NH2
2-aminobutanoic acid
COOH
NH2
NH2
2,4-Diaminobenzoic acid
O
CH3 NH2
4-Amino-2-butanone
Physical-chemical properties of amines
• Water soluble: this due to unshared lone pair of electrons of the nitrogen. This will lead
to high electron density around the nitrogen which will promotes water solubility
between the hydrogen of water and the nitrogen
• RNH2 ˃˃ R2NH ˃ R3N
• Boiling point affected by type of amine or arylamine.
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Physical-chemical properties of amines • Are basic groups that can form salts
• The definition of base is to accept a proton from an acid
• Basicity strength is related to its ability to share the lone pair of electrons. The more
donated, the stronger the base
This figure taken from Lemke L G. Review of organic functional groups. 2012
• Steric hindrance can affect the basicity of amines
• Steric factor can affect tertiary amines, but with less importance for secondary and
primary amines
• For alkylamines R2NH ˃ R3N ˃ RNH2
This figure taken from Lemke L G. Review of organic functional groups. 2012
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• In case of aromatic rings, it will act as electron-withdrawing groups leading to decrease
in the basicity (lower pka).
• The spreading of electrons over a greater area decrease its ability to donate the electrons
and so basicity decrease
This figure taken from Lemke L G. Review of organic functional groups. 2012
Also basicity of arylamines affected by type and position of substituents
EWG at the para or meta position will decrease the basicity
EDG at the para or meta position will increase the basicity
Substituents that are the ortho position are not predictable because of the ability to form an
intramolecular interaction
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This figure taken from Lemke L G. Review of organic functional groups. 2012
Amines can form salts if they reacted with strong acid. The type of salt formed, whether
it is water soluble or water insoluble depends on type of acid.
This figure taken from Lemke L G. Review of organic functional groups. 2012
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This figure taken from Lemke L G. Review of organic functional groups. 2012
Reaction with acid chloride Amines can react with acid chlorides to form amides
Cl
O
CH3 NH2+N
N
O
H
CH3
Formation of sulfonamides
Sulfonamides are type of drugs that are used as antibacterial agents, can be synthesized
by reacting acetanilide with chlorosulfonic acid.
-
NH
CH3
O
S OH
O
O
Cl
NH
CH3
O
SO O
Cl
NH3
H2O
NH
CH3
O
SO O
NH2
dil HCl
heat
NH2
SO O
NH2Acetanilide
Sulfanilamide
Oxidation of amines Amines can be oxidized using oxidizing agents as H2O2, permanganates and peroxyacids.
Depending on the type of amines, they will give different products.
Figures are taken from Wade L G. Organic Chemistry. 2013
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Nitrogen Functional Groups Learning Outcomes Identify and draw structures of nitro, nitrate, nitrite, oxime and hydrazines
Describe acid/base properties of nitro, nitrate, nitrite, oxime and hydrazines
Describe and understand stability and solubility of nitro, nitrate, nitrite, oxime and
hydrazines
Nitro group • Present as functional group in many drugs
• Appear as the name –nitro in the nomenclature of molecules
• It is neutral due to resonance structure and have electron-withdrawing properties
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Nitrate Group
• The group named as –nitrate
• Nitrate ester group consider as an unstable group as it is susceptible to metabolism by
esterases.
This figure taken from Lemke L G. Review of organic functional groups. 2012
Nitrite group
• Named as –nitrite
• Present in a drug called amylnitrite
ONO
Amylnitrite
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Oximes
• Oximes are neutral and stable
• Can exist as geometrical isomers
• Found mostly in a type of drugs called cephalosporin
This figure taken from Lemke L G. Review of organic functional groups. 2012
Hydrazone/Hydrazine/Hydrazide
• Hydrazone –C=N-NH2 is unstable functional group and can be hydrolysed by an acid
• The imine and the amine groups are basic
• Hydrazine –C-NH-NH2 is stable to acid hydrolysis with basic properties
• Hydrazide –C=O-NH-NH2, the amine group is basic while the –NH- group act as neutral
amide
-
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Heterocycles rings Learning Outcomes
• Identify and draw structures of three-eight ring
• Predict their physical-chemical properties
Three-eight membered ring heterocycles Heterocyclic rings are rings that contain one or more different atoms than carbon in their
base skeleton.
This figure taken from Lemke L G. Review of organic functional groups. 2012
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Three-membered ring • Oxygen containing rings is known as oxirane (epoxides)
Physical-chemical properties
• Have bond angle of 60° which make the ring strained and can be opened in the presence
of an acid or base
• Drugs contain epoxides rings can react in-vitro with a nucleophile in the presence of an
acid or a base to give open-chain compounds
• Also, can react in-vivo with biopolymers which may destruct the cell
This figure taken from Lemke L G. Review of organic functional groups. 2012
This figure taken from Lemke L G. Review of organic functional groups. 2012
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• Rings that contain nitrogen are called aziridine
• Azridines are highly-strained and highly-reactive
This figure taken from Lemke L G. Review of organic functional groups. 2012
Four-membered ring heterocycles • It is called β-lactam ring
• Available in drugs such penicillins, cephalosporins
• It is highly strained and so can be hydrolysed in the presence of an acid
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Five-membered rings
• Five-member rings containing oxygen are called furan and tetrahydrofuran
• Numbering of the ring start with oxygen atom and then proceed to the next substituent
• Tetrahydrofuran does not exist as pure form but mostly as ribose-containing drugs.
This figure taken from Lemke L G. Review of organic functional groups. 2012
• Furan has an aromatic property, as it contain four π electrons from the double bonds and
two pairs of sp2 electrons from oxygen.
• Tetrahydrofuran are cyclic ether, but are water-soluble as the unshared pair of electrons
of the oxygen can hydrogen bond with water molecule
• Tetrahydrofuran can react with oxygen to produce a peroxide
This figure taken from Lemke L G. Review of organic functional groups. 2012.
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• Nitrogen found in five-member ring are named pyrrole and pyrrolidine
This figure taken from Lemke L G. Review of organic functional groups. 2012
Pyrrole considered an aromatic and as weak base. This may due to the pair of electrons
which are included in the aromatic system
Pyrrolidine is a strong base have a pKa of 11. Also, it is water soluble.
This figure taken from Lemke L G. Review of organic functional groups. 2012
• Five-membered rings contain a sulfur atom
are called thiophene and
tetrahydrothiophene.
• Less water-soluble and more stable.
This figure taken from Lemke L G. Review of organic functional groups. 2012..
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Five-membered ring with two or more heteroatoms
Oxygen + Nitrogen
• Named as oxazole and isoxazole. The numbering start from oxygen atom and proceed to
nitrogen.
This figure taken from Lemke L G. Review of organic functional groups. 2012
• Oxygen and nitrogen rings can be synthesized by reacting an aldehyde or ketone with
amine and alcohol to give mixed acetal or ketal
This figure taken from Lemke L G. Review of organic functional groups. 2012
• Oxazole and isoxazole are aromatic compounds
• Both compounds are weak bases (pKa ˂ 6 for the protonated nitrogen)
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• Oxazolidine can be hydrolysed with a strong acid.
This figure taken from Lemke L G. Review of organic functional groups. 2012
2-oxazoline and oxazolidine are basic
This figure taken from Lemke L G. Review of organic functional groups. 2012
Nitrogen and Nitrogen • Heterocycles with two nitrogens are imidazole and pyrazole.
• Analogues are imidazoline and 2-imidazoline
This figure taken from Lemke L G. Review of organic functional groups. 2012
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• Imidazole and pyrazole both are aromatic that contain one basic nitrogen and one neutral
nitrogen.
• 2-Imidazoline has one basic nitrogen and the other is neutral.
• Imidazolidine has both nitrogens are basic
This figure taken from Lemke L G. Review of organic functional groups. 2012
Imidazolidine can be hydrolyzed in the presence of an acid
This figure taken from Lemke L G. Review of organic functional groups. 2012
Nitrogen and Sulfur
• 1, 3-Thiazole
• Aromatic ring
• The nitrogen is weak base (pKa 2.44)
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Complex five-membered rings
Five membered rings that contain more than two nitrogen in the ring.
Tetrazole can be used as a bioisostere instead of carboxylic acid due to the acidic proton.
This figure taken from Lemke L G. Review of organic functional groups. 2012
Complex five-membered rings • Oxazolidine-2,4-dione has an imide functional group.
• It has acidic property due to hydrogen that is attached to the nitrogen. The two EWGs
will withdraw electrons from nitrogen which will increase the possibility that hydrogen
will be donated.
• Hydantoin is a cyclic urea with an imide functional group. It is with an acidic property.
This figure taken from Lemke L G. Review of organic functional groups. 2012
• Oxazolidine-2-one similar to carbamates
• In the presence of an acid or a base it undergoes hydrolysis
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Oxazolidine-2,4-dione and hydantoin can form water soluble salts in the presence of
strong base.
This figure taken from Lemke L G. Review of organic functional groups. 2012
Six-membered ring heterocycles • Pyridine is quite water-soluble due to the unshared pair of electrons
• Pyridine is basic as the pyridinium ion has a pKa of 5.36.
• Piperidine is more basic as the piperidinium ion has a pKa of 11.3
• Both compounds are reactive towards strong acids.
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Nitrogen and Nitrogen • Are aromatics and so consider as stable
• Compounds are basic with different pKas
• Consider water-soluble
This figure taken from Lemke L G. Review of organic functional groups. 2012
Pyrimidines-I
• Uracil contains neutral urea
• Thymine contains acidic imide
• Both compounds exist in either keto or enol form
• Enol form have acidic and basic properties
• As both compounds favour keto form, then can be considered as weak acids. They are
less water soluble in water which may account to enol form which have acidic and basic
properties.
• Cytosine consider as weak base.
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Figures taken from Lemke L G. Review of organic functional groups. 2012
Pyrimidines-II • Barbituric acid is exist in four forms
• Barbituric acid is a strong acid with a pka 4.12
• 5,5-disubstituted barbiturates have a pKa values of 7.1-8.1and exist mostly in the trioxo
form.
• The 5,5-disubstituted barbiturates can react with sodium hydroxide to form a salt.
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Barbiturates in solid form can exist in the trioxo form, but in solution can exist as
dihydroxy form.
This figure taken from Lemke L G. Review of organic functional groups. 2012
Barbiturate can react with strong base and form a salt that it is water soluble.
This figure taken from Lemke L G. Review of organic functional groups. 2012
Saturated six-membered rings • Have the same physical-chemical properties as the related aliphatic functional groups
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Seven & eight membered rings Both rings are secondary amines and so will have the same chemical properties of
secondary amines.
This figure taken from Lemke L G. Review of organic functional groups. 2012
Five-membered ring plus six-membered ring with one heteroatom
• Indole is aromatic and weak base and so can be consider as neutral
• It can be oxidized by contact of air. So, better to be stored under nitrogen.
This figure taken from Lemke L G. Review of organic functional groups. 2012
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Five-membered ring plus six-membered ring with two heteroatoms
• Are aromatic with weak basic nitrogen
• Less water-soluble as there are four additional carbon atoms compare to imidazole,
oxazole and thiazole.
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Five-membered ring plus six-membered ring with four heteroatoms
• Purines are aromatic with four basic nitrogens
• Are highly water-soluble
• Adenine, guanine and xanthine are less water-soluble due to intramolecular interactions
• Xanthine has basic and acidic properties
This figure taken from Lemke L G. Review of organic functional groups. 2012
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Six-membered ring plus six-membered ring with one heteroatom
• Quinoline and isoquinoline are weak bases
• Can react with a strong acid to form a water-soluble salt (pKa 5.0).
This figure taken from Lemke L G. Review of organic functional groups. 2012
Six-membered ring plus six-membered ring with one heteroatom
• Coumarin contains an intramolecular ester known as lactone
• Lactone can be hydrolysed by an acid or base to give carboxylic acid and phenol.
This figure taken from Lemke L G. Review of organic functional groups. 2012
This figure taken from Lemke L G. Review of organic functional groups. 2012
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Six-membered ring plus six-membered ring with two or more
heteroatoms
• Quinazoline and pteridine are aromatic with basic nitrogens
• Are weak bases and so can form salts with strong acid.
This figure taken from Lemke L G. Review of organic functional groups. 2012
Six-membered ring plus six-membered ring with two or more
heteroatoms
• Benzothiadiazine contains a basic nitrogen and a cyclic sulphonamide
• If the nitrogen of the sulphonamide is unsubstituted, then the group is acidic and if it is
substituted, then it is neutral
This figure taken from Lemke L G. Review of organic functional groups. 2012
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This figure taken from Lemke L G. Review of organic functional groups. 2012
Six-membered ring plus seven-membered-ring
Example for this type are benzodiazepines
• The nitrogen at the 4 position is weak base (cannot form salt form as the pKa of the
protonated compound is 3.4).
• The nitrogen at position 1 can be a weak base or neutral
This figure taken from Lemke L G. Review of organic functional groups. 2012