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Aliphatic Ethers
Pharmacy Student
• Ethers have two alkyl groups bonded to an
oxygen atom.
´ CnH2n+2O
´
CnH2n+2O
Nomenclature of Ethers
• Simple ethers are usually assigned common names. To do so:
Name both alkyl groups bonded to the oxygen, arrange
these names alphabetically, and add the word ether.
For symmetrical ethers, name the alkyl group and add the
prefix “di-”.
• More complex ethers are named using the IUPAC system.
One alkyl group is named as a hydrocarbon chain, and the
other is named as part of a substituent bonded to that
chain:
Name the simpler alkyl group as an alkoxy substituent
by changing the –yl ending of the alkyl group to –oxy.
Name the remaining alkyl group as an alkane, with the
alkoxy group as a substituent bonded to this chain.
• The oxygen atom in alcohols, ethers and epoxides is sp3
hybridized. Alcohols and ethers have a bent shape like that
in H2O.
• The bond angle around the O atom in an alcohol or ether
is similar to the tetrahedral bond angle of 109.5°.
• Because the O atom is much more electronegative than
carbon or hydrogen, the C—O and O—H bonds are all
polar
Hydrogen bonding make ROH more
soluble and have higher b.p. than
ROR or RH .
Preparation of Alcohols, Ethers
• Alcohols and ethers are both common products of
nucleophilic substitution.
• The preparation of ethers by the method shown in the
last two equations is called the Williamson ether
synthesis.
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Methods of Preparetion:
1- Willianson’s continuous etherification
Primary alcohols can dehydrate to ethers
This reaction occurs at lower temperature than the
competing dehydration to an alkene.
Step 1
CH3CH2-OH
H+
CH3CH2-OH2
-H2O
CH3CH2
Step2
CH3CH2 + HO-CH2CH3
Step 3
CH3CH2-O-CH2CH3
H
CH3CH2-O-CH2CH3
H
- H+
CH3CH2-O-CH2CH3
HSO4diethyl ether
Williamson continuous etherification
1) The Williamson Ether Synthesis :
Reaction of an alkoxide with an alkyl halide or tosylate
to give an ether.
 Alkoxides are prepared by the reaction of an alcohol
with a strong base such as sodium hydride (NaH)
The Williamson ether synthesis is an SN2 reaction.
Synthesis of Ethers
O
H
Alcohol
(Lewis Base,
Nucleophile)
•
H
O
H
Protonated
Alcohol
SN2
Reaction
O
H
Protonated Ether
+ H2O
Utility of this Reaction is Limited in its Scope:
 Mixture of Ether/Alkenes with 2° Alkyl Groups
 Exclusively Alkenes with 3° Alkyl Groups
 Only Useful for Synthesis of Symmetric Ethers
 ROH + R’OH  ROR + R’OR + R’OR’
Williamson’s Synthesis
 1- Reaction with alkali metal (Na- K)
R
OH
 RONa
+
+
Na
R’X
C2H5ONa + CH3Cl
R
ONa + ½ H2
ROR’
+ NaX
C2H5 O CH3
Williamson Synthesis of Ethers
Unsymmetrical Ethers From RONa + Halide, Sulfonate, etc.
O
Na
LG
O
Asymmetric Ether
• Utility of this Reaction is Much Greater Than Condensation:
 Works with 1° and 2° Halides, Sulfonates, etc.
 Still Exclusively Alkenes with 3° Alkyl Groups
 Lower Temperatures Favor Substitution over Elimination
 SN2 Conditions Apply  Prefer Unhindered Substrate
Chemical Properties
 Ether linkage is quite stable towards bases, oxidizing
and reeducing agents.
 Cleavage takes place under quite vigorous conditions
as conc. Acids.
Reaction of Ethers with Strong Acid
• In order for ethers to undergo substitution or
elimination reactions, their poor leaving group must
first be converted into a good leaving group by
reaction with strong acids such as HBr and HI.
• HBr and HI are strong acids that are also sources of
good nucleophiles (Br¯ and I¯ respectively).
• When ethers react with HBr or HI, both C—O bonds
are cleaved and two alkyl halides are formed as
products.
• The mechanism of ether cleavage is SN1 or SN2,
depending on the identity of R.
• When 2° or 3° alkyl groups are bonded to the ether
oxygen, the C—O bond is cleaved by an SN1
mechanism involving a carbocation. With methyl or
1° R groups, the C—O bond is cleaved by an SN2
mechanism.
• The mechanism of ether cleavage is SN1 or SN2,
depending on the identity of R.
• When 2° or 3° alkyl groups are bonded to the ether
oxygen, the C—O bond is cleaved by an SN1
mechanism involving a carbocation. With methyl or
1° R groups, the C—O bond is cleaved by an SN2
mechanism.
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1-Action of HI
 R-O-R
HI/ Low temp
ROH + RI
HI / High temp
2RI + H2O
CH3-O-CH3
CH3OH + CH3I
2 CH3I + H2O
 This reaction can proceed by :
 1- SN1 or SN2.

+
..
 R-O-R’
..


H
H
R-O-R’
+
I
-
SN2

SN1

RI + R’-OH
(R is 10 or 2o )
R+ + ROH
I
RI ( R 3o)
Action of PCl5:
 R-O-R + PCl5
 C2H5-O-C2H5 + PCl5
2R-Cl + POCl3
2CH3CH2Cl + POCl3

Thio Alcohols
(Mercptants) R-SH
Thiols (R–S–H) is sulfur analogs of alcohols and

ethers, respectively Sulfur replaces oxygen
Thiols

Thiols (RSH), also known as mercaptans, are sulfur analogs
of alcohols


They are named with the suffix –thiol
SH group is called “mercapto group” (“capturer of
mercury”)
Methods of preparations :
 Thiols are prepared from alkyl halides by SN2 with NaSH
 displacement with a sulfur nucleophile such as SH
–
The alkylthiol product can undergo further reaction with
–
the alkyl halide to give a symmetrical sulfide, giving a
–
poorer yield of the thiol
2- Heating of Alcohols with P2S5

R-OH + P2S5
 CH3-OH + P2S5
R-SH + P2O5
CH3-SH + P2O5
 3- Heating of Alcohols
H2S at high temperature
pressure, and catalyst:
 R-OH + H2S
R-SH + H2O
Chemical Properties:
 1- With alkali metals:
 2R-SH + 2 Na
2 R-SNa + H2
 2 C2H5 – SH + 2 Na
2 C2H5 –SNa + H2

sod. Ethyl mercaptide
 2- with Aldehyde :

 CH3CHO + 2C2H5SH

S-C2H5
HCl
CH3CH
+ H2O
mercaptal S-C2H5
N: 1s22s22px12py12pz1
Amines
Structures of amines
C N
N: 1s22s22px12py12pz1
sp3-hybrid
C－N：
sp3-sp3 hybridized
orbitals overlap
N－H：
sp3hybridized -1s
orbitals overlap
Pyramid
Tertiary amines with 3 different groups:
R'
R'' N
R'''
Interconversion of amine enantiomers
H
R'
N R''
R'''
Structure and Classification of Amines
Amines are derivatives of ammonia NH3.
 Contain N attached to one or more alkyl (Aliphatic
amine) or aromatic groups (Aromatic amine).
• The shape around the nitrogen is pyrimidal and there
is a lone pair of electrons on the nitrogen
-NH2 amino group+
CH3-NH2
NH
CH2 CH
2
3
CH3-NH-CH3
Ethylbenzene
Structure and Classification of Amines
 Amines can be classified as 1º, 2º or 3º, just like carbons,
based on how many alkyl groups are attached to the
nitrogen
H
N
H
H
Ammonia
NH2
Primary Amine
H
N
N
Secondary Amine
Tertiary Amine
Amines
Amines are classified into three groups:
depending on the number of carbon groups bonded to
nitrogen.
CH3—NH2
CH3

CH3—NH
Primary 1°
Secondary 2°
CH3

CH3—N—CH3
Tertiary 3°
Naming Amines
IUPAC name – 1° amines
The same method as we did for alcohols.
-Drop the final “-e” of the parent alkane and replace it by
-amine”.
- Use a number to locate the amino group (-NH2) on the
parent chain.
NH2 NH2
NH2
NH2
CH3-CH-CH-CH3
CH3-CH-CH3
CH3 CHCH3
3
2
1
3
Cl 4
2 1
2-Propanamine Cyclohexanamine
2-propanamine
3-chloro-2-butanamine
H2 N
5 4 32 1
NH2
6
1,6-Hexan ediamine
1,6-hexanediamine
Naming Amines
IUPAC name – 2° and 3° amines
– Take the largest group bonded to nitrogen as the parent
amine.
– Name the smaller group(s) bonded to nitrogen, and show
their locations on nitrogen by using the prefix “N”.
CH3
NHCH3
N-Methylanilin e
N
CH3
N,N-Dimethyl-aniline
cyclopentan amine
CH3
CH3-N-CH2-CH3
N,N-Dimethylethanamine
Methods of Preparations
1-Alkylation of ammonia
The reaction of ammonia with an alkyl halide
leads to the formation of a primary amine .
•The primary amine that is formed can also react
with the alkyl halide, which leads to a
disubstituted amine that can further react to
form a trisubstituted amine. Therefore, the
alkylation of ammonia leads to a mixture of
products
2) Catalytic reduction of Alkyl cyanides ( nitriles)
1)LiAl H4 / ether
2)H3O+
R-C=N
CH3CN
H2/Ni
R-CH2-NH2
CH3CH2NH2 (ethyl amine)
3) Hoffmann degradation reaction Of Amide
O
Br2/ NaOH
RCH2-C-NH2
or NaOBr
O
CH3C-NH2
acetamide
Br2 / NaOH
or KOH / Br2
R-CH2NH2
CH3-NH2 +NaCO3+NaBr+ H2O
(methyl amine)
4-The Gabriel synthesis of primary amines
Primary alkyl halide, SN2
R X
O
R NH2
C
Reagent:
C
N K
Potassium salt of
Phthalimide
O
O
O
C
C
C
O
N H
KOH
C
O
O
NK
R X
C
DMF
C
Imide
O
N R
O
O
C
C
C
N H
KOH
C
O
NK
O
O
R X
C
DMF
C
N R
O
NaOH/H2O
HCl /H2O
CO2H
CO2H
+ R-NH3Cl-
CO2Na
CO2N
a
+ R-NH2
5- Reductive amination:
R
(R')H
C O + NH3(or R''NH2)
-H2O
R
(R')H
C NH(R'')
Imine
R
H2, Ni
CH NH2(R'')
1o Amine
(R')H
H
C O + NH3
H2, Ni
90 atm
40 ~ 70¡æ
(CH3)2C O + H2NCH2CH2OH
3
H2, Ni, EtOH
95£¥
CH2NH2
(89%)
(CH3)2CNHCH2CH2OH
2
Physical properties of Amines
1. They have unpleasant odors (rotting fish like ammonia).
2. Amines solutions are basic (ammonia or died fish odor)
3. They are polar compounds; Difference in electronegativity
between N - H (3.0 – 2.1 = 0.9)
4- 1° and 2° amines have hydrogen bonds (N-H).
Weaker than alcohols (O-H).
3° amines do not form hydrogen bonds (no H atom).
Physical properties:
5- 1 , 2 amine can form H bond So their MP >
alkane of similar M.Wt
(B.P Amine >
Alkane)
6-Boiling points: Hydrocarbons< Amines < Alcohols
7- Almost soluble in water (hydrogen bonding).
Chemical Reactions of Amines
Basicity of amines:
1-Amines basic because N has non bonded pair of
electrons which can be donated to an acid to form
ammonium salt.
2- base strength depend on the degree of substitution on N.
- More basic CH3-NH-CH3 > NH2-CH3 > NH3
3-Activating groups. Increase basic properties.-- RNH2 > ArNH2 aliphatic more basic than aromatic
- Amine > RCONH2 (Amide) less basic from amine
Why are aliphatic amines more basic than ammonia?
NH3 + H2O  NH4+ + OH-
R-NH2 + H2O  R-NH3+ + OH-
The alkyl group, -R, is an electron donating
group. The donation of electrons helps to stabilize the
ammonium ion by decreasing the positive charge,
lowering the ΔH, shifting the ionization farther to the
right and increasing the basicity.
Common substituent groups:
-NH2, -NHR, -NR2
-OH
-OR
-NHCOCH3
-C6H5
-R
-H
-X
-CHO, -COR
-SO3H
-COOH, -COOR
-CN
-NR3+
-NO2
electron donating
groups
electron withdrawing
groups
1-Basicity:
CH3CH2NH3+Cl-
 CH3CH2NH2 + HCl
 ethyl amine
 2- Alkylation:
 R-NH2
RX
H
R-N-R
ethylamine hydrochloride
RX
R
R-N-R

3- Acylation: With acid chloride
O
O
RNH2 + R’CCl
RNHCR’ + HCl
CH3NH2 + CH3COCl
CH3NHCOCH3
R
+
R-N -R
R
4- Reaction with Nitrous Acid (To differentiation1,2,3 Amine
1°-Amines + HONO
(cold acidic solution)
Nitrogen Gas Evolution from a Clear
Solution
2°-Amines + HONO
(cold acidic solution)
An Insoluble Oil (N-Nitrosamine)
3°-Amines + HONO
(cold acidic solution)
A Clear Solution (Ammonium Salt
Formation)
4- Reaction with Nitrous Acid (To differentiation1,2,3 Amine
 A-Primary Amines:
 RNH2 + HNO2
ROH + N2 g + H2O
(NaNO2/HCl)
 C2H5NH2 + HNO2
C2H5OH + N2 g. + H2O
 B-Secondary Amin
N= O
(NaNO2/HCl)
R-NH-R’ + HNO2
R-N-R’ + H2O
N= O
(NaNO2/HCl)
CH3-NH-CH3 + HNO2
CH3-N-CH3 + H2O
N-nitrosodimethyl amine
C- Tertiary Amines doesn’t react with nitrous acid
Hinsberg Test:
unknown amine + benzenesulfonyl chloride, KOH (aq)
Reacts to produce a clear solution and then:
a- gives a ppt upon acidification  primary
amine.
b-Reacts to produce a ppt  secondary amine.
c- Doesn’t react  tertiary amine.
HINSBERG’STEST :(Action of benzene sulphonyl
chloride)
•
 1 amine: N-alkylbenzene sulphonamide is formed,
which is soluble in alkali
 RNH2 +
 KOH
SO2Cl →

SO2-NK-R soluble salt.
SO2 NHR + HCl
-2
amine: N,N-dialkyl benzene sulphonamide is
formed, which is insoluble in alkali
R2NH +
SO2Cl
SO2NR2
KOH
insoluble salt
3 Amine doesn’t react with benzenesuphonyl chloride
S