CHEM261: PRICIPLES OF ORGANIC CHEMISTRY SPRING … · 2020. 1. 27. · chem261: priciples of organic chemistry spring 2019/2020 references mcmurry je. organic chemistry. mary finch

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

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

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


• 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


• 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

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

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

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


NOMENCLATURE OF PHENOLS • Phenol are compounds that have an –OH group attached to aromatic ring


OHCH3

m-Methylphenol

OH

NO2O2N

2,4-Dinitrophenol

Structures are taken from McMurry. Organic Chemistry. 2012

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


• 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


• 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


• 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


• 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.


Ethers and Thioethers

Learning Outcomes

Identify and draw structure of ethers and thioethers


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



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 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).


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.


Thioether • High boiling point (diethyl thioether, 92 ͦ C)

• Less water solubility

Aldehydes and Ketones

Learning Outcomes Identify and draw structures of aldehydes and ketones


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


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.


• 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

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?).


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

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-

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


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

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

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 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.


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

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



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.


• Esters in the presence of base and acid can undergo hydrolysis.


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

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




• 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

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


Nomenclature




Reactions

• Carbonate and carbamates are unstable to acid and base hydrolysis

• Ureas are more stable and consider relatively unreactive


Amidines and Guanidines



• Amidines and guanidines are highly basic


Sulfonic acid and sulphonamides • Sulfonic acid nomenclature


Physical-chemical properties • Sulfonic acids are strong acids with strong pKa



• 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.


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


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.


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


• 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


• 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


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


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.



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

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


Nitrate Group

• The group named as –nitrate

• Nitrate ester group consider as an unstable group as it is susceptible to metabolism by

esterases.


Nitrite group

• Named as –nitrite

• Present in a drug called amylnitrite

ONO

Amylnitrite

Oximes

• Oximes are neutral and stable

• Can exist as geometrical isomers

• Found mostly in a type of drugs called cephalosporin


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

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.



Three-membered ring • Oxygen containing rings is known as oxirane (epoxides)


• 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



• Rings that contain nitrogen are called aziridine

• Azridines are highly-strained and highly-reactive


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


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.


• 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.

• Nitrogen found in five-member ring are named pyrrole and pyrrolidine


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.


• 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..

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.


• Oxygen and nitrogen rings can be synthesized by reacting an aldehyde or ketone with

amine and alcohol to give mixed acetal or ketal


• Oxazole and isoxazole are aromatic compounds

• Both compounds are weak bases (pKa ˂ 6 for the protonated nitrogen)

• Oxazolidine can be hydrolysed with a strong acid.


2-oxazoline and oxazolidine are basic


Nitrogen and Nitrogen • Heterocycles with two nitrogens are imidazole and pyrazole.

• Analogues are imidazoline and 2-imidazoline


• 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


Imidazolidine can be hydrolyzed in the presence of an acid


Nitrogen and Sulfur

• 1, 3-Thiazole

• Aromatic ring

• The nitrogen is weak base (pKa 2.44)

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.


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.


• Oxazolidine-2-one similar to carbamates

• In the presence of an acid or a base it undergoes hydrolysis


Oxazolidine-2,4-dione and hydantoin can form water soluble salts in the presence of

strong base.


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.


Nitrogen and Nitrogen • Are aromatics and so consider as stable

• Compounds are basic with different pKas

• Consider water-soluble


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.


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.


Barbiturates in solid form can exist in the trioxo form, but in solution can exist as

dihydroxy form.


Barbiturate can react with strong base and form a salt that it is water soluble.


Saturated six-membered rings • Have the same physical-chemical properties as the related aliphatic functional groups


Seven & eight membered rings Both rings are secondary amines and so will have the same chemical properties of

secondary amines.


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.



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.


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



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).


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.



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.


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



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


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CHEM261: PRICIPLES OF ORGANIC CHEMISTRY SPRING … · 2020. 1. 27. · chem261: priciples of organic chemistry spring 2019/2020 references mcmurry je. organic chemistry. mary finch