Professional Documents
Culture Documents
Chemistry
B R Thorat
Department of Chemistry,
Govt of Maharashtra,
Organometallic Chemistry
organopalladium
chlorophyll
Gilman reagent
Tetracarbonyl
nickel
ferrocene
Organo zinc
Organo
chromium
boron, silicon, arsenic, and selenium
Grignard
reagent
hemoglobin and
myoglobin
Vit B12
Chemical Reactivity
of Organometallic
compounds
Grignard Reagents
Discovered by Victor Grignard in
1900
Key factors are ethereal solvent and
water-free conditions
Organomagnesium Compounds
Grignards Reagent:
The organometallic compounds with the general molecular formula RMgX are
called as Grignards reagents [Nobel Prize winner 1912 in Chemistry]. This
reagent is highly reactive and widely used for the organic synthesis.
Synthesis
It can be obtained by carrying out the reaction of organic halide with magnesium in
dry ether.
+
R-X
dry ether
Mg
R-MgX
(CH3)2CH-Br
Cl
2.
3.
CH2=CH-CH2I
Mg
Mg
dry ether
MgCl
THF
Mg
(CH3)2CH-MgX
dry ether
CH2=CH-CH2-MgI
Organomagnesium Compounds
Grignards Reagent:
The R group should not contain a group bearing active hydrogen atom such as
COOH, -CCH, -OH, -NH2, etc.
The reactivity of alkyl halide is RI > RBr > RCl > RF whereas organomagnesium
fluoride are not known yet.
The Grignard reagent was exist in dimeric form which is in equilibrium with dialkyl
magnesium compound and magnesium dihalide.
The X-ray diffraction studies shows that the two ether molecules are also tightly
bonded to magnesium in RMgX.
OEt2
R
Mg
OEt2
Organomagnesium Compounds
Grignards Reagent: Reactivity
The RMgX is colorless and unstable solid hence it is freshly prepared when
required and used in ethereal solution. The C-Mg bond is highly polar in which
carbon bearing partial negative charge and magnesium bearing partial positive
charge because of large electronegativity difference between them. The Grignard
reagents are strong bases and are also used as powerful nucleophiles.
Reaction with water and alcohol:Grignard reagent behaves as a strong base and hence react with weak acids such as
water or alcohol forming corresponding hydrocarbon.
R-MgX +
H2O
R-H
R-MgX +
R'OH
R-H
MgX(OH)
MgX(OR')
The reagent similarly reacts with phenols and acids. These reaction is used for the
synthesis of deuterium containing hydrocarbons. E.g.
H3C
CH2MgX
H3C
dry ether
H3C
D2O
CH2-D
H3C
MgX(OD)
Organomagnesium Compounds
Grignards Reagent: Reactivity
Reaction with carbonyl compound and ethylene oxide:Grignard reagents are behaves as carbanion or nucleophile and they are added to
carbonyl group of various carbonyl compounds.
R-MgX
OMgX
R
alkoxide
OH2
or H3O+
OH
R
alcohol
Mechanism:By using appropriate carbonyl compounds, the reaction is useful for the preparation
of alcohols.
+
MgX
O
O Mg
X
Mg
Mg
X
-MgX2
X
OH2
OH
OMgX
O Mg
X
Mg
X
O Mg
MgX2
Organomagnesium Compounds
Grignards Reagent: Reactivity
By using appropriate carbonyl compounds, the reaction is useful for the preparation
of alcohols.
Primary alcohol:- Grignard reagent reacts with formaldehyde or ethylene epoxide
with subsequent hydrolysis.
H
H
R-MgX
OMgX
R-MgX
RCH2-CH2-OMgX
OH
or H3O+
H R
OH2
H R
OH2
R-CH2-CH2-OH
or H3O+
Ether
R'
OMgX
OH
or H3O+
H R
R'
OH2
H R
OMgX
R''
R''
R'
2 R-MgX +
O
HO
Ether
R'
OMgX
R R
or H3O+
OH2
or H3O+
OH
R''
R'
OH
R R
Organomagnesium Compounds
Grignards Reagent: Reactivity
Nature of the product depends on the nature of starting carbonyl compound. If R, R
and R are bulkier groups and atleast one group of this containing -hydrogen atom,
then tertiary alcohol undergoes dehydration forming alkene.
R'
R-MgX +
Ether
R-MgX +
O
X
R'
OMgX
R OR''
R''O
R'
R'
Ether
R-MgX
O
R
R'
R-MgX
R X
OMgX
R R
R'
OMgX
R'
R'
OMgX
R R
R'
OH2
or H3O+
OH2
OH
R R
R'
or H3O+
OH
R R
The above reaction shows that, each mole of ester or acyl chloride can be reacted
with two moles of Grignard reagent. They are converted into tertiary alcohol through
ketone intermediate. The Grignard reagent is more reactive towards ketone than
ester and acyl chloride.
Reaction with cyanide or nitriles:It is useful synthesis for the ketones. Grignard reagents add to a nitrile group
followed by the hydrolysis of the resulting complex.
R
R-MgX + R'-CN
NMgX
R'
imine salt
OH2
or H3O+
R
NH
R'
R'
imine
2+
+
O + NH4 + Mg
Organomagnesium Compounds
Grignards Reagent: Reactivity
Acetylenic exchange:An acetylenic hydrogen atom is acidic in nature. Grignard reagent act as base and
reacts with it to give hydrocarbon and an alkynyl Grignard reagent. The resulting
reagent reacts with other organic compounds such as ketone forming alkynyl
alcohol.
R'
HC CH
+ R-MgX
HC CMgX +
R'
1. O
R-H
R''
R''
OH
+
OH2 or H3O
CO2
OH2
R
OMgX
+ MgX(OH)
OH
Grignard reagent shows same reaction with sulfur dioxide forming corresponding
sulfinic acids asO
R-MgX
SO2
R S
OH2
R S
OMgX
+ MgX(OH)
OH
Organomagnesium Compounds
R'''
+
R'''
R''
OMgX
R'' R'
R
(1,4- addition)
R'''
OMgX
R'
(1,2- addition)
The composition of the product can be varied with sterric bulk of R in the Grignard
reagent and R group in the carbonyl compound. As size of R- group increases, the
amount of 1,4-addition product increases, but ,-unsaturated aldehydes gives only 1,2addition product. Also as size of R- group of the Grignard reagent increases, the amount
of 1,4-addition product increases. The 1,4-addition of the Grignard reagent was proceeds
though six membered transition state, whereas the 1,2-addition reaction proceeds through
four membered transition state. In four membered transition state, the sterric hindrance
between RR increases the energy of intermediate than in six membered transition
state. Also as size of R and R increases the magnitude of RR or and RR
interaction also increases in the six membered transition state, and therefore decreases the
yield of 1,4-additon. The removal of byproduct MgX2 (Lewis acid) increases the yield of
1,4-addition product.
Also if electron withdrawing group attached to alkene moiety, increases the yield of 1,4addition product.
Organomagnesium Compounds
Grignards Reagent: Reactivity
X
R''
R'-MgX
R'
+
R'''
R''
R'''
Mg
R
O
H3O+
R'''
R'' R'
O
R
The cuprous salts (Cu2X2) was added to the Grignards reagents forming less
reactive product such as [R2MgCu or RCu) containing copper (I) which forming coordinate bond strongly with carbonyl oxygen atom in six membered transition state.
Grignard reagent shows 1,4-addition reaction with carbonyl compound except ,unsaturated aldehyde.
It is very reactive with oxygen and moisture, hence stored and reacts
in dry solvent.
Reactions with carbonyl compounds
HCOH
RLi
H2CR-OLi
aq. acid
R-CH2-OH
aq. acid
R'CHO
+ RLi
R'2CO
+ RLi
R-CHR'-OH
RCHR'-OLi
aq. acid
R'2CR-OLi
R'2CR-OH
H3C
SN2
OLi
aq. acid
OH
H3C
H3C
Wittig reaction
The ether undergoes rearrangement reaction in presence of strong base such as n-BuLi to
form alcohol. The ether must contain -hydrogen atom with respect to oxygen.
R-CH2-O-R'
Synthesis of Ketone
RLi
R'
R'
n-BuLi
R'
aq. acid
R'
R
OH
R
N-Li
R'
aq. acid
RLi excess
O
R'
aq. acid
R R
OH
R'
R'Li
R-COOH
R-COOLi
R'
R'Li
aq. acid
OLi
OLi
RLi
CH3Li
R-NH2
- 78 C
CO2
ether
R-COOLi
aq. acid
R-COOH
R-CO-R'
RLi
+ R'
+
N
ether
R'
+
N
Li
Li
N
R'
Isocyanide
RCO-COOH
CO2
aq. acid
R''COCl
Li
R'
O
aq. acid
aq. acid
aq. acid
R''CO-COR
R''X
R''-CO-R
R'' R''
COR
HO
CH3Li
2 (CH3)3CLi
CuI
ether
CuI.Ph3P
CH3Cu
ether
CH3Li
Li(CH3)2Cu
Li[(CH3)3C]2Cu.PPh3
1. n-C6H13-OTs
OH
H3C
H
2.
Br
H
Br
(C4H9)2CuLi
C10H22
ether, -75 C
H3C
3.
Li(CH3)2Cu
o
ether, -15 C
H3C
(sec-C4H9)2Cu(cn)Li2
o
THF, -78 C
I
4.
H
CH3
Cl
Br
OH
H
) Cu(CN)Li
2 o
2
THF, O C
Cl
(C4H9)2CuLi
CH3
C2H5
CH3
C6H5
ether-THF, reflux
But corresponding iodide gives a racemic product on reaction with lithium diphenylcuprate
which indicates that the reaction of cuprates with iodides at any rates takes place by a one
electron transfer and not by SN2 reaction.
Alkenyl halide reacts with organocuprates with retensation in configuration of the double
bond to give substituted alkene.
(C2H5)2CuLi
C6H5
Br
Li(CH3)2Cu
ether, 0oC
2 HC CH
C2H5
)2 CuLi
C6H5
H
H
CH3
I
HMPA
-30 to 25 oC
C2H5
(63%; 95% Z)
O
Cl
Li(CH3)2Cu
ether, 0 oC
CH3
R
C3H7
OH
(C3H7)2Cu(CN)Li2
o
THF, O C
86%
Li(CH3)2Cu
OH
ether, -10 C
CH3
OMe
Li(CH3)2Cu
o
ether, -10 C
O
O
(
) Cu(CN)Li
2
2
o
ether, -50 C
n-C4H9
(n-Bu)2CuLi, BF3
Diethyl ether, -70oC
O
O
53%
R''
O
+ Zn
R'
A carbonyl
compound
Dry C6H6
COOEt
Br
2-bromo ester
BrZnO
R
R'
R''
COOEt
OH2
HO
R''
R
R'
COOEt
3-hydroxy ester
Ph-CHO +
Zn
Ph
BrCH2COOEt
Ph
OH2
CH2COOEt
CH2COOEt
BrZnO
HO
H3O +
PhCH
COOEt
1. Zn, Ether
+ BrCH2COOEt
2.
COOEt
OH
COOH
+
2. H3O
COOH
1. Zn, Ether
3.
S
HOOCCH2
CHCOOEt
CHO + BrCH2COOEt
+
2. H3O
CH=CH-COOEt
The Reformatsky reaction is useful for the synthesis of various natural products such
as- geranic ester, citral, camphoronic acid, fenchane, cadalene (terpenoid), vitamin A, etc.
BrCH2COOEt
COOEt
COOEt
Zn, Ether
Ac2O
HO
1. H3O +
2. Distil Ca-salt
CHO
Natural
Products
Natural products
There are number of metabolism occurred in organisms for the synthesis of various natural
products, intermediates, etc. The intermediates and products formed by metabolism are
called as metabolites.
Terpenes
Primary
Metabolite
Alkaloids
Vitamins
Metabolite
Harmones
Steroids
Secondary
Metabolite
Primary
Metabolite
Secondary
Metabolite
Terpenes
The term terpene was given to the compounds isolated from terpentine, a volatile liquid
isolated from pine trees.
Terpenoids are the hydrocarbons of plant origin of the general formula (C5H8)n as well as
their oxygenated, hydrogenated and dehydrogenated derivatives are also found.
Terpenes
Classification: Most natural terpenoid hydrocarbon have the general formula (C5H8)n. They can
be classified on the basis of value of n or number of carbon atoms present in the structure.
Sr. No.
Value of n
Class
Example
10
Monoterpenoids(C10H16)
Citral
15
Sesquiterpenoinds(C15H24)
Farnesol
20
Diterpenoids(C20H32)
Retinol
25
Sesterpenoids(C25H40)
Geranyl farnesol
30
Triterpenoids(C30H48)
Squalene
40
Tetraterpenoids (C40H64)
Carotene
>40
>8
Polyterpenoids(C5H8)n
Rubber
Each class can be further subdivided into subclasses according to the number of rings present
in the structure.
i) Acyclic Terpenoids: They contain open structure.
ii) Monocyclic Terpenoids: They contain one ring in the structure.
Terpenes
The simpler mono and sesqui terpenes are chief constituent of the
essential oils obtained from sap and tissues of certain plant and trees
The di and tri terpenoids are not steam volatile. They are obtained from
plant and tree gums and resins
Terpenes
(Isoprene rule)
All terpenes on distillation gives isoprene as one of the product
(may be in some cases by thermal decomposition of terpene).
CH2 (Isoprene unit) Otto Wallach (1887) pointed out that carbon skeleton of terpenoids
H2C
can be built up from isoprene unit.
2-methylbuta-1,3-diene
Isoprene rule stats that the terpenoid molecules are constructed from
two or more isoprene unit.
CH3
Further Ingold suggested that isoprene units are joined in the terpenoid via head to tail
fashion. Special isoprene rule states that the terpenoid molecule are constructed of two or
more isoprene units joined in a head to tail fashion.
H3C
Head
Head
H2C
CH2
(Isoprene unit)
Tail
C
Tail
C
Head
Tail
C C
But this rule can only be used as guiding principle (for the skeleton of carbon) and not as a
fixed rule.
For example carotenoids are joined tail to tail at their central and there are also some
terpenoids whose carbon content is not a multiple of five
Terpenes (Examples)
CH3
2-(4-methylcyclohex-3-en-1-yl)propan-2-ol
Terpeniol
OH
H3C
CH3
CH3
(2Z)-3,7-dimethylocta-2,6-dienal
CHO
H3C
Citral
CH3
2,6,6-trimethylbicyclo[3.1.1]hept-2-ene
CH3
H3C
Pinene
CH3
O
H3C
CH3
1,7,7-trimethylbicyclo[2.2.1]heptan-2-one
Camphor
Alkaloids
Originally the name alkaloid was given to all organic bases isolated from plants.
Konigs (1880) suggested, alkaloids are naturally occurring organic bases which contain
pyridine ring.
Further Ladenburg modified this definition and said alkaloids have atleast one nitrogen
atom in heterocyclic ring.
Generally, alkaloids have basic properties, physiological action and are of plant origin.
Classification: Alkaloids are classified on the basis of nature of the chemical nucleus
containing nitrogen (pyridine, pyrrol, quinoline, tropane, etc) present in the molecule
Sr. No.
Example
Purrolidine group
Hygrine
Pyridine group
Recinine
Pyrrolidine-pyridine group
Nicotine
Quinoline group
Quinine
Isoquinoline group
Papaverine
Phenanthrene group
Morphine
Tropane group
Atropine
Alkaloids (Examples)
Nicotine: Contains pyrrolidine-pyridine rings. It
is also called as tobacco alkaloid as it is isolated
from tobacco leaf.
It is toxic and addictive component of a tobacco.
It is a substance of abuse.
It is used in insecticide and in the synthesis of
nicotinic acid.
3-(1-methylpyrrolidin-2-yl)pyridine
N
Nicotine
CH3
N
8-methyl-8-azabicyclo[3.2.1]oct-3-yl
3-hydroxy-2-phenylpropanoate
C 6H 5
CH 2OH
Atropine
Vitamins
Vitamins are the substances that are required for the proper growth, maintenance and well
being of all animals organism. E.g. vit. A, vit. B, vit. K, vit. D, etc.
They are required in very minute quantities.
Vitamins are not produced by the body (with exception of vit. D and vit. K) and hence
must be taken from daily foods.
There are about thirteen essential vitamins, broadly classified into fat soluble and water
soluble vitamins.
HOH2C
H3C
CH3
CH3
CH3
Vitamin A
CH 2OH
Retinol
Vitamin C
Ascorbic acid
HO
HO
OH
CH3
Hormones
Harmones are secreted by ductless endocrine glands of animal body. Only minute
amount of harmones are necessary to carried out various physiological reactions in the
body.
Harmones are classified as
Non-steroidal Harmones
Steroidal Harmones
OH
OH
HO
Thyroxine
Adrenaline
I
NH
HO
COOH
CH3
H
NH2
Molecular formula
Nature of oxygen atom present
Unsaturation
Dehydrogenation
Oxidative degradation
Ozonolysis in terpenoids
Hofmann exhaustive methylation and degradation in alkaloids
Synthesis
Molecular formula
Nature of oxygen
atom present