Aliphatic Ethers

Pharmacy Student

• Ethers have two alkyl groups bonded to an oxygen atom.

Ethers R-O-R or R-O-R´ CnH2n+2O

Ethers R-O-R or R-O-R´ CnH2n+2O

• 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-”.

Nomenclature of Ethers

• 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 .

8

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.

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 CH3CH2-O-CH2CH3 H

Step 3CH3CH2-O-CH2CH3 H+ CH3CH2-O-CH2CH3

H HSO4- diethyl 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

H

ProtonatedAlcohol

SN2Reaction + H2O

O

HAlcohol

(Lewis Base,Nucleophile)

O

HProtonated Ether

We’ve Already Seen Ether Synthesis by Alcohol Dehydration:

• 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 Synthesis1- Reaction with alkali metal (Na- K)R OH + Na R ONa + ½ H2

RONa + R’X ROR’ + NaX

C2H5ONa + CH3Cl C2H5 O CH3

Williamson Synthesis of Ethers

Unsymmetrical Ethers From RONa + Halide, Sulfonate, etc.

• 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

ONa LG O

Asymmetric Ether

Chemical PropertiesEther 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.

20

1-Action of HIR-O-R

HI/ Low temp

ROH + RIHI / High temp

2RI + H2O

CH3-O-CH3

CH3OH + CH3I

2 CH3I + H2O

This reaction can proceed by :1- SN1 or SN2.

.. H

+ H

R-O-R’ R-O-R’

.. + I-

SN2 RI + R’-OH

(R is 10 or 2o )

SN1

R+ + ROH

I-

RI ( R 3o)

Action of PCl5:R-O-R + PCl5 2R-Cl + POCl3

C2H5-O-C2H5 + PCl5 2CH3CH2Cl + POCl3

Thiols (R–S–H) is sulfur analogs of alcohols and

ethers, respectively Sulfur replaces oxygen

Thio Alcohols (Mercptants) R-SH

Thiols

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”)

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

Methods of preparations :

2 -Heating of Alcohols with P2S5

R-OH + P2S5 R-SH + P2O5

CH3-OH + P2S5 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 : S-C2H5

CH3CHO + 2C2H5SH HCl CH3CH + H2O

mercaptal S-C2H5

Amines

N: 1s22s22px12py

12pz1N: 1s22s22px

12py12pz

1

Structures of amines

sp3-hybrid

sp3-sp3 hybridized orbitals overlapC － N ：

N － H ： sp3hybridized -1s orbitals overlap

N

R'R''

R'''

NR'

R''

R'''

Tertiary amines with 3 different groups:

Interconversion of amine enantiomers

NCH

N: 1s22s22px12py

12pz1N: 1s22s22px

12py12pz

1

Pyramid

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

CH3-NH2 CH3-NH-CH3

Structure and Classification of Amines

-NH2 amino group+CH2CH3 CH3 CH=CH2

TolueneEthylbenzene Styrene

NH2

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

NH2

HN N

HN

H

H

Ammonia Primary Amine Secondary Amine Tertiary Amine

Amines are classified into three groups:

depending on the number of carbon groups bonded to nitrogen.

CH3 CH3

CH3—NH2 CH3—NH CH3—N—CH3

Amines

Primary 1° Secondary 2° Tertiary 3°

Naming 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.

IUPAC name – 1° amines

CH3CHCH3

NH2

NH2

H2NNH2

1,6-HexanediamineCyclohexanamine2-Propanamine

CH3-CH-CH3

NH2

2-propanamine

CH3-CH-CH-CH3

NH2

Cl

3-chloro-2-butanamine 1,6-hexanediamine

123 1 2 3 4

123456

Naming 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”.

IUPAC name – 2° and 3° amines

NCH3

CH3

NHCH3

N,N-Dimethyl- cyclopentanamine

N-Methylaniline

NCH3

CH3

NHCH3

N,N-Dimethyl- cyclopentanamine

N-Methylaniline

aniline

CH3-N-CH2-CH3

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                                                                               

R-C=N1)LiAl H4 / ether

2)H3O+R-CH2-NH2

2) Catalytic reduction of Alkyl cyanides ( nitriles)

CH3CN

H2/Ni CH3CH2NH2 (ethyl amine)

3) Hoffmann degradation reaction Of Amide

RCH2-C-NH2

O Br2/ NaOH

or NaOBrR-CH2NH2

CH3C-NH2

OBr2 / NaOH

or KOH / Br2CH3-NH2 +NaCO3+NaBr+ H2O

(methyl amine)acetamide

4-The Gabriel synthesis of primary amines

R X R NH2Reagent:

C

CN

O

O

K

Potassium salt of Phthalimide

C

CN

O

O

HKOH C

CN

O

O

KR X C

CN

O

O

RDMF

Imide

Primary alkyl halide, SN2Primary alkyl halide, SN2

C

CN

O

O

HKOH C

CN

O

O

KR X C

CN

O

O

RDMF

CO2Na

CO2Na

CO2H

CO2H

NaOH/H2OHCl /H2O

+ R-NH2+ R-NH3Cl-

5- Reductive amination:

CR

(R')H O + NH3(or R''NH2)

-H2O CR

(R')H NH(R'')

Imine

H2, NiCH

R

(R')H

NH2(R'')

C O

H

+ NH3H2, Ni90 atm

40 ~ 70¡æ

CH2NH2(89%)

(CH3)2C O + H2NCH2CH2OHH2, Ni, EtOH

95£¥(CH3)2CNHCH2CH2OH

1o Amine

23

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 electron donating-C6H5 groups-R-H-X-CHO, -COR-SO3H electron withdrawing-COOH, -COOR groups-CN-NR3

+

-NO2

1-Basicity:CH3CH2NH2 + HCl CH3CH2NH3+Cl-

ethyl amine ethylamine hydrochloride

2- Alkylation: H R RR-NH2 RX R-N-R RX R-N-R R-N+-R

-

R

3- Acylation: With acid chloride

O O

RNH2 + R’CCl RNHCR’ + HCl

CH3NH2 + CH3COCl CH3NHCOCH3

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

4- Reaction with Nitrous Acid (To differentiation1,2,3 Amine

A-Primary Amines:RNH2 + HNO2 ROH + N2 g + H2OC2H5NH2 + HNO2

(NaNO2/HCl)C2H5OH + N2 g. + H2O

B-Secondary Amin N= O

R-NH-R’ + HNO2 (NaNO2/HCl)

R-N-R’ + H2O

N= O

CH3-NH-CH3 + HNO2 (NaNO2/HCl)

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.

1 amine: N-alkylbenzene sulphonamide is formed, which is soluble in alkali

RNH2 + SO2Cl → SO2 NHR + HClKOH SO2-NK-R soluble salt.

• HINSBERG’STEST :(Action of benzene sulphonyl chloride)

-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