Name Reactions-II PDF

CSIR-JRF (NET), GATE
DRDO, BARC, IISC…...

LONG COURSE For CSIR-NET (JRF)-June-2017
U R
CHEMISTRY BY H. GAUR
GA
ORGANIC CHEMISTRY
H.
BY
NAMED REACTIONS
RY
SHEET-2
IST
E M
ACHARYA INSTITUTE
CH
1-K-4, M.N. Ext. KOTA
Contact: +91-8946891920
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Contact: +91-8946891920 www.hgaurchemistry.com Page (1)
MANNICH REACTION:
* It Involve the condensation of a compound having active methylene group (active H-atom) with formaldehyde &
H-N< (H–N<  NH3 or, NH2R or NHR2 ,but not used NR3) in the presence of acid and formed amino methyl
derivative or substituted amino methyl derivative (Mannich base) is called Mannich Reaction.
| HCl |
G–––C–––H + O + H–N< G–––C––CH2–N<
| || –H2O |
H–C–H Mannich base or
Active H-atom Methanal NH3 or 10-amine Amino Methyl derivative
0
or 2 -amine or
R
0
(But not 3 amine) Substituted amino
methylderivative
U
O O
|| HCl ||
CH3–C–CH2–H + HCHO + R2NH CH3–C–CH2–CH2–NR2
GA
–H2O
Mannich base
Mechanism:
* It is acid catalysed as well as base catalysed.
+
O OH .. R .. R R
|| || R +
_+
H.
R2NH +
CH2–N CH2––N CH2–N
H–C–H + H+ H–C–H CH2–N |
| | R R –H2O R R
OH H OH
+ 2
More Stable
+
BY
O OH O–H
|| || |
H+ CH3–C=CH 2
CH3–C–CH3 CH3–C –CH2–H +
–H
Enol
.. +
OH R OH R O R
| + || || ..
CH3–C=CH2 + CH2 = N CH3–C–CH2–CH2–N CH3–C–CH2–CH2–N
RY
+
R R –H R
Mannich Base
Generally, mannich base, used for the synthesis of  ,   unsaturated carbonyls.
R
IST
.. R–X (1 equ.)
CH3 –C–CH2–CH2 –N CH3–C–CH=CH2
|| R /Ag 2 O ||
O O
Unsaturated carbonyl
M
* It is substrate of Michael addition

Examples of Mannich Reactons:
E
OH OH
..
H CH2–NR2
CH
(1) + HCHO + R2NH HCl
+
CH2 = NR2
As a E+
HCl
(2) + HCHO + R2NH
N H N CH2–NR2
| |
H H

O
|| H–CH2
H
H
+ RN + =O HCl NR =O
(3) H H H–CH2
|| Tropinone
O
* It is example of double mannich base reaction.
* This reaction takes place as;
O
|| +
H NHR CH2 CH3
H+/HNHR + H
+
R
C––O C O
H H |
|| || H–CH2 H CH3
O O
U
GA
NR O NHR O
In Same H
Manner H–CH2
O
H.
O CH3 O CH3
|| | H+ || |
(4) CH3–C–C–H + HCHO + HNMe2 CH3–C–C–CH2–NMe2
| |
CH3 CH3
BY
Major Product
This H-atom involve in enol formation B’coz of
in acidic medium more substituted enol is the formed.
H CH2–NMe2
(5) HCl
+ HCHO + Me2NH
RY
N N
| |
H H
O O
|| ||
IST
H CH2–NR2
(6) + HCHO + HNR2 HCl
+
M
+ HCHO + R2NH H
(7)
N CH2–H N CH2–CH2–NR2
.. ..
E
H CH2–NR2
OH OH
CH
(8) + HCHO + R2NH H+
+
+ HCHO + R2NH H
(9) H CH2–NR2
O O

ROBINSON ANNELATION REACTION:
* It involve two reaction in following order.
(A) Michael Addition followed by
(B) Intramolecular aldol condensation reaction.
* This reaction can be very usefull in the synthesis of polycylic molecules due to this rea son this reaction
is also called Robinson ring forming reaction.
Acidic H-atom
H –
OH– OH H2 O
+ Intramolecular
Michael O O
O CH3 O addition O CH2 O Aldol Condensation O
–
OH
R
| reaction Enolate ion
H Aldol
–H2O
U
GA
O
Examples of Robinson Annelation Reaction:
Acidic H-atom O
O || CH3
|| H
CH3 (i) OH–
(1)
H.
+
CH3 O (ii) O
O
Acidic H-atom O
O
|| ||
H
BY
(i) OH–
(2) + (ii)
O CH3 O O
Acidic H-atom
COOC2H5
H
COOC2H5
RY
(i) CH3OK/THF
(3) + (ii) K2CO3/MeOH/
CH3 O O
O
* In this reaction, the ester group can be removed by Hydrolysis followed by decarboxylation
COOEt COO–
IST
–
OH / (i)
(ii) H3O+
O O O
O
M
O ||
|| –
Q. CH2O + CH3–C–CH3 OH
? Ans:
(Excess)
E
O OH
||
CH
–
OH | CH2O OH
–
Sol. CH3–C–CH3 CH2=C–CH3 CH2–CH–C–CH3 CH2=CH–C–CH3
| | || –H2O || CH2–C–CH3
Enol OH H O O | ||
H O
O
O O 2||
||6 5 4 3 2 || 1 OH–/ 3 1
CH3–C–CH2 –CH2–CH2 –C–CH2 6
| Intramolecular 4
H Aldol condensation 5 CH3
it is also substrate for
Michael addition

O
||
–
Q. + CH2–CHO OH
| ?
O Cl
O O O O
|| || || ||
CH–OH
(A) (B) (C) (D) CHO
O
O O
Ans: (B)
R
O O
O O H || ||
|| || H H
H
U
–
C=O OH H2 O
Sol. + CH2–CHO OH–
| –
| O O O OH
O Cl O H
GA
–H2O
O
||
H.
BY
RY
IST
E M
CH

1,3-DITHIANES:
HS R S R S
R BF3/Et2O R S R
RLi E+ HgCl2
=O + – =O
H HS H S S Hydrolysis E
E S
1,2 Dithol 1,3-Dithiane
H
BF3/Et2O BuLi BuLi HgCl2
=O A B C D
HS
Q. H
HS Br Br
R
O
S H S S
H Br
U
Ans: H S S S
(A) (B) (C) (D)
GA
SH
R
SH (i) BuLi HgCl2/H2O
=O (A) (B) (C)
Q. H BF3/Et2O O
(ii)
H.
Ph
R S R S R
HO HO
| =O
BY
Ans: H S S Ph
Ph
(A) (B) (C)
SH SH O
H ||
BuLi, Cl–C–OEt H+, HgCl2
C=O (A) (B) (C)
RY
Q. BF3/Et 2O H2O
R
(i) BuLi, –CH2Br (i) BuLi, (i) BuLi,

(ii) H+, HgCl2, H2O O O
||
IST
||
CH2–C–OEt R–C–Cl
| +
(ii) H , HgCl2, H2O
Cl
(ii) H+, HgCl2, H2O
(D)
M
(E) (F)
H S R S
E
O O O O O O O
|| || || || || || ||
Ans: S EtO–C S R–C–C–OEt R–C–CH2– R–C–CH2–C–OEt R–C–C–R
R
CH
|| (D) (F)
(A) O (B) (C) (E)

LDA (LITHIUM DIISOPROPYLAMIDE):
* It is strong base but weak nucleophilile.
* It is Bulky base
* Abstract less sterically hindard acidic H-atom
* Since, it is a strong base so it can also abstract very less acidic H-atom.
+ –
Li N
LDA (Lithium Diisopropyl Amide)
R
O O
CH3 || H CH3 ||
LDA –
U
O O
GA
|| – LDA – || –
CH2–C–O CH2–C–O
|
H
– –
COO COO
Ha | Ha | –
CH2–Hb
H.
CH2
LDA
Important Questions:
BY
(i) LDA
(1) R–CH2–C–R ? R–CH–C–R
|| (ii) R–X | ||
O R O
– (i) LDA –
(2) R–CH2–COO ? R–CH–COO
(ii) R1–X |
RY
R1
R1
(i) LDA |
(3) Ph–C–CH–CH=CH2 ? Ph–C–C–CH=CH2
|| | (ii) R1–X || |
IST
O R O R
CH3
(i) LDA
(4) CH3–C–O–CH2–CH3 ? =CH–C–OCH2–CH3
|| (ii) =O CH3 ||
O + O
M
(iii) H3O/
O O
|| || CH3
E
(5) (i) LDA

?
(ii) CH3I
CH
Less Hindard
H CH3
(i) LDA
(6) ?
H (ii) CH3I H
||
O O

Less Hindard
D CH3
(i) LDA
(7) ?
H (ii) CH3I H (Acidity of H & D are alsmost same)
C2H5–S
(8) (i) LDA (i) LDA
CH2 ? (A) (B)
(ii) R–C–Cl (ii) CH3
C2H5–S ||
O
||
R
O
U
||
O C2H5–S C–R
C2H5–S ||
GA
CH–C–R C
C2H5–S C2H5–S CH2–CH2–C–CH3

(A) (B) ||
O
H.
N
N (i) LDA |
(9) ? Ans: O
| (ii) Ph–C–OEt N ||
N || || C
|| H O Ph
BY
O O O O
|| || || ||
(i) LDA N O
(10) | N O ? Ans:
H (ii) PhCH2I
Ph
RY
H
CH3 |
(11) Br 6 5 | CH2 LDA (i) LDA
2 (A) (B)
3 || 1 (ii) R–C–Cl
4 ||
O
IST
O O
O || ||
R–C
||
CH3
M
CH3
(A) (B)
E
Ph
CH
|
(i) LDA
(12) Ph–C=CH2 ? Ans:
| (i) cis–Ph–CH=CH–Ph
CH3 (iii) HA
Ph Ph
(cis)

Solution:
Ph
| Ph
C Ph
– |– |
CH2 CH2
HA
H H
C=C Ph Ph Ph Ph
Ph Ph (cis)
cis
This reaction takes place by the concerted mechanism so that symmetry of reactant maintain in the product (i.e., cis cis
& trans trans)
R
Ph
|
U
(i) LDA N–Ar
(13) Ph–C=N–Ar ? Ans:
| (ii) E–Ph–CH=CH–Ph
GA
CH3
(iii) HA Ph Ph
trans
COOEt EtOOC Me
(i) LDA
H.
(14) ? Ans:
(ii) CH3I
t–Bu t–Bu
BY
Solution:
–
O
| EtOOC Me
H C
| – |
OEt OEt OEt
LDA CH3–I
|| ||
O O
RY
t–Bu
CH3 –I Bulky Base, so equitorial attack takes place

IST
E M
CH

ORGANOMETALLIC REACTION:
Organometallic Reactions
Reformatsky Grignard Regent RLi Metallation R2CuLi R2Cd

Reaction (RMgX)
* Organometallic reactions takes place in following order always

1. Acid-base Reaction
R
2. Addition Reaction [AASE]
3. Substitution Reaction
U
4. Elimination Reaction
GA
REFORMATSKY REACTION:
=O+ CH2 – COOEt

|
Carbonyl Br Bromo ester
–
OH Zn
H.
Darzen Reaction Reformatsky Reaction
Darzen Reaction:
BY
COOEt
O
–
O OH Major
|| H H
RY
|
+ CH – COOEt O
| ||
Br – CH2–COOEt
OH
Minor
IST
* Reformatsky Reaction take place with organozinc ester

BrZnCH2–COOEt
M
CH2–COOEt + Zn
| Organozinc ester
Br
E
O ZnBr + OH
O H2O/H
|| –
CH
+ CH2–COOEt OH CH2–COOEt
| CH2–COOEt
+ZnBr –Zn
Br -Hydroxy ester
Reactivity w.r.t. Reformatsky reaction.
CH2–COOEt CH2–COOEt CH2–COOEt
Reactivity: | | |
I Br Cl
* RMgX have nucleophilic as well as basic character so it react with acidic-H-atom & give acid-base reaction.

* Advantage of Zn:
Zn is implace of Mg because of organozinc compound are less reactive than the organomangesim compound of
 -Bromo ester. So it does not react with other ester molecules.
Br–CH2–COOEt
Mg Zn
BrMgCH2–COOEt BrZnCH2–COOEt
Highly reactive Less reactive
So react only with the more
R
React with React with ester group reactive carbonyl compound
(Not react with ester)
=O group Mg–CH2– COOEt
U
|
Br
Major Product
GA
Minor Product
(It is side reaction)
* On heating,   Hydroxy ester give  ,   unsaturated ester
H.
OH H
| |
R–C––CH–COOR R2C = CH – COOR
| –H2O
R -Unsaturated ester
* During the reformatsky reaction, zinc enolate formed as a Reformatsky reagent.
BY
O .. O–ZnBr O–Zn–Br O
|| Zn | | ||
Br–CH2–C–OC2H5 CH2=C–OC2 H5 CH2=C–OC2 H5 CH2–C–OC2H5
|
ZnBr
Zinc enolate Organozinc ester
RY
* During the reformatsky reaction, zinc (Zn) behave as two electron dondor
Example of Reformatsky reaction:

IST
(i) Zn
1. + BrCH2–COOR
CHO (ii) H3O+/ CH=CH–COOR
S S
+
N ZnBr H3 O O
M
|| (H2O/HCl) ||
2. R–C N + BrZnCH2COOR R–C–CH2 –COOR R–C–CH2–COOR + NH4 Cl
OH
–Zn
E
Br
CH3 CH3
CH
| (i) Zn/ether/ |
3. CH3–CHO + Br–C–COOEt CH3–CH–C–COOEt
| (ii) NH4Cl/HOH | |
CH3 OH CH3
CH3
| (i) Zn/C6H6/
4. Ph–CHO + Br–CH–COOEt Ph–CH=C–COOEt
(ii) H2O/H+/ |
CH3

O
(i) Zn/ether/ ||
5. CH3–C N + Br–CH2–COOEt CH3–C–CH2–COOEt
(ii) H2O/H+
O CH3 OH O CH3
|| (i) Zn/ether/C6H6/ | ||
6. CH3–CH2–CHO + Br–CH2–C–N CH3–CH2–CH–CH2–C–N
CH3 (ii) H2 O/NH4Cl
CH3
–
H2O/ OH/
O CH3
||
R
CH3–CH2–CH=CH–C–N
CH3
U
OH O CH3 – O
| || H2O/ OH/ ||
GA
CH3–CH2–CH–CH2–C–N CH3–CH2–CH=CH–C–N
CH3
H.
BY
RY
IST
E M
CH

GRIGNARD REAGENTS:
* It is very strong base
* It is give following reactions.
1. Acid-base reaction
2. Addition reaction
3. Substitution reaction
4. Elimination reaction
* It is organomatallic compound which have polar C-Mg bond.
Preparation:
R
Dry Ether
R–X + Mg RMgX
Grignard reagent
U
Mechanism:
GA
+ –
R–X R + X
R+ + Mg R– + Mg
+2
– +2 –
R + Mg + X RMgX
* Etheral solution of Grignard Reagent is used for the synthetic application because of it is highly reactive.
H.
R
O
R R
BY
Mg
R X
O
R
* Solvated form of RMgX is stable. It can not be isolate in individual form (i.e., pure form)
RY
* In the Grignard Reagent following equilibrium also exist. (Schlenk equilibrium)

Schlenk
2RMg X R 2 Mg + MgX 2
Equilibrium
* Grignard Reagent fis an umpolung reagent
IST
R––X RMgX
Electrophilic site Nucleophilic as well as basic site

M
* There is polar covalent bon in between C-Mg in Grignard Reagent

E
Hard
C–Na
C–Li
Above this hard
CH
C–Mg
C–Al Below this soft
C–Zn
C–Pb
C–Cd * Ionic bond in C-Na & C-Li
C–Sn * In all other, polar covalent bond
C–Cu
C–Hg
Soft

* Reactivity Order w.r.t. Preparation of Grignard Reagent:
R––X
R––X
R–X
R––I > R–Br > R–Cl 1 > 20 > 30
0
X
X X
Due to leaving group ability of halide
> >
R
Due to stability of carbonion (RMgX)
U
Points about the preparation of Grignard Reagent:
GA
1. Compounds having acidic H-atom can not be used in preparation of Grignard Reagent.
Mg/Dry Ether
C––C––C––C No Grignard Reagent
| |
G X
G = Functional groups having active H-atom like: –NH2, –OH,–SH, –COOH etc.
H.
2. 1,2-dihaloalkanes (Vicinal) are not used for the preparation of Grignard Reagent.
Mg/Ether
C––C No Grignard Reagent but formed C = C + Mg X2
| |
BY
X X
Mg/Ether
3. C––C No Grignard Reagent but formed C = C
| |
X L
RY
* L = OTs, OBs, OAc, etc.

4. 1,3- Dihaloalkanes not used for the preparation of Grignard Reagent
CH2–X
Mg/Ether + X2
CH2
IST
CH2–X
5. 1,4- & higher dihalides may be used for the preparation of Grignard Reagent
X
|
M
6. m- & p- may be used for the preparation of Grignard Reagent but O-form is not used because of,
X
E
X
Mg/ Ether (Et2O)
CH
X
o-Dihalo benzene Benzyne Dimer
7. Generally allylic & benzylic halides are not used for the preparation of Grignard Reagent. (Also rarely used so
answer give according to option)
8. .. Mg/ Et2O
CH2=CH–Cl No Grignard reagent
In the reaction Grignard reagent is not formed, because of, during the reaction high temperature is required which
is greater than boiling point of Et2O but if THF is used then.

.. Mg/THF
9. CH2=CH–Cl CH2=CH–MgCl
Due to high boiling point of THF
But
Mg/Et2O
CH2=CH–MgBr
CH2=CH–Br
Mg/THF
CH2=CH–MgBr
Because of less double bond character in C-Br bond of CH2 = CH–Br

similarly:
R
Cl
U
|
GA
Br
Mg(1equ.)/ Mg(excess)/
Mg(excess)/ THF
1 equ. Mg/ Et2O THF
Et2O
MgCl
H.
Cl Cl
| | |
Cl
|
MgBr MgBr MgBr

BY
MgBr
Chemical Properties of the Grignard reagent:

RMgX
RY
Acid-Base Reaction * Nucleophilic addiction reaction

* Nucleophilic substitution reaction
IST
Bronstate basicity
:Lewis Besicity
Acid-Base Reaction:
M
It is required less amount of energy (activation energy) so allowed always first.

So that, Always first check acid-base reaction with RMgX. before the other reactions.
E
Z
– +
R Mg X + H–––Z R–H + Mg
CH
X
High Electronegative atom. Like
O, N, F, S or sp-hybrid-carbon
Above reaction takes place in

H–––OH H–––NH2
H–––OR H–––Indol
H–––OPh H–––Isoindol
H–––O–COR H–––Amide
H–––SR H–––C C–R
H–––NR2 H–––C C–H
H–––NH–Ph COCH3
H–––CH
H––– COCH3
Due to Aramaticity
RMgX
R
H––C C–CH 2–CH 2–O H Two equ. RMgX is used.
* The reactivity of the compounds w.r.t. RMgX would be high which have more acidic H-atom, so that
U
Acidity of H-atom ses reactivity w.r.t. Grignard reagent ses
GA
* During the acid base reaction Grignard reagent behave as the Bronstate base.
Nucleophilicity of RMgX (Lewis Basicity):

* Preparation of Alcohols:
H.
Alcohols
BY
0
0 2 -Alcohol 0
1 -Alcohol O2 3 -Alcohol
From O2 O2
O
O || O
|| R–C–H ||
H–C–H R–C–R
O
O || O
RY
H–C–Z ||
R–C–Z
Oxirane (Except-Amide)
(Except-Amide)
Reaction with O2 :
IST
H3O+
RMgX + ½O2 RO Mg X R–OH
0 0 0 0 0 0
1,2,3 1 , 2 , 3 -Alcohol
Nature of Alcohol is depends on the Alkyl groups in grignard reagent
M
R in G.R. R–OH
If then
E
0
Me–, 1 , 2 , 3
0 0
MeOH, , 10, 20, 30 -Alcohol
CH
Reaction with Carbonyl Compounds:

–
O Mg+X OH
– + H3O+
= O + R Mg X
R R
* It is nucleophilic Addiction reaction

* So nature of alcohol is independed on the nature of G.R. but depend the nature of carbonyl compound.

O
|| then R–OH
If Carbonyl
0
H–CHO 1–Alcohol
* Formation of MeOH is not possible
R–CHO 0
2– Alcohol
0
R–C=O 3– Alcohol
|
R
Reaction with Acid Derivation:
R
– +
O – O Mg X O
|| + | ||
R Mg X
U
Y–C–L Y–C–L Y–C–R
| X
R –Mg Carbonyl compounds
L
GA
H or R
*
Acid halide,
Ester or Anhydride
* MeOH & 10 alcohol can not be formed by this reaction
– +
Y O Mg X
H.
O OH
|| RMgX H3 O
+ |
0
Y–C–R Y–C–R If Y = H = 2 alcohol
R R X | 0
–Mg R Y = R = 3 alcohol
BY
L
O
|| R OMgX
O R R
OMgX
RY
RMgX R
O + RMg X O
OMgX
|| OMgX
O O O ||
Succinic anthydride O
IST
+
H2O/H
R OH
R
M
OH
||
E
O
CH
O R OH
||
(i) RMgX R
O + ? Ans. OH
(ii) H2O/H
|| ||
O O
Phthalic anhydride

O R OH
||
(i) RMgX R
O ?
(ii) H2O/H+ OH
O2N || O2N ||
O O
–R & –I effect
Reaction with Epoxide Ring:
–
O Mg X
+
OH
+
O H3 O
R– Mg+ X +
R
R R
If Grignard reagent react with the unsmmetrical epoxide ring, then ring opening takes place from the less hindrad
U
site.
O – Mg +X OH
O H3O
+
GA
– +
R Mg X +
R R R R R
* Here: o-atom can be replaced by the other hetero atom like S, N etc.
* Prepared alcohol have two C-atom more than the R of Grignard reagent
But in case of carbonyl only one C-atom more than the R of G.R.
H.
if the case of
(i) O2 with RMgX = ROH of same C
(ii) =O with RMgX = ROH of more than one C.
BY
(iii)
O with RMgX = ROH of more than two C.
(i) RMgX
Q. R–C C–H
O
? R–C C–CH2–CH–OH
RY
|
(ii) R
R
(iii) H2O
D
IST
Q. Br MgBr
1 equ. Mg D2 O
(A) (B) Ans.
Et2O OD Cl
Cl Cl
–Mg (A) (B)
Br
M
* Preparation of Acid:
+
H3O
RMgX + O = C = O R–C–OMgX R–C–OH
E
|| ||
O O
CH
* Preparation of Cyanide:
RMgX + Cl–C N R–C N

X
–Mg
Cl

* Reaction with benzene carbonitrile:
C N CH3–C=NMgX O
||
N.A.R H 3O+ CH3 Because of RMgX finish
+ CH3MgX
(Excess) due to acidification
Acetophenone
* If is best method for preparation of acetophenone
CN O CH3 OH
||
Q.
(i) CH3MgX (i) CH3 MgBr CH3 CH3
+ (A) + (B) Ans.
(ii) H2O/H (ii) H2 O/H
R
(A) (B)
CN
U
CH3 OH
(i) CH3MgX
Q. ? CH3
GA
+
(ii) H2O/H
(iii) CH3MgBr
+
(iv) H2O/H
RMgX
Assuming both condition as excess
* or
H.
RMgX(excess)
* Reaction with ketene:
+
H3O
CH2=C=O + CH3MgBr CH2=C–O–Mg+Br CH2=C–O–H CH2–C=O
BY
| | | |
CH3 CH3 H CH3
H3O+
R–CH = C = O + R–Mg+X R–CH–C=O
+
| |
E H R
Nu– Nu–
E+
RY
* Reaction with Ortho Ester:
.. +
OEt OEt OEt OEt
RMgBr/MgBr2 + RMgX
H––C––OEt H––C––OEt H––C H––C
IST
+ OEt
OEt OEt OEt OEt
–Mg
Ortho ester Br
MgBr
M
OEt OH O
H2O/H
+
||
H––C H––C R–C–H
| | –H2O
E
R OEt R OH
CH
OEt
H––C––OEt + RMgX R – CHO
|
R OEt

CHO
|
?
Q.
Cyclohexane Cyclohexane carbeldehyde
Solution:
CHO
X MgX
X2/hv Mg (i) orthoester
Et2O (ii) H2O/H+
R
Cyclohexane
Q. CH2=C=O+Br2 CH3MgBr CH3MgBr

(A) (B) (C)
U
Solution:
GA
– +
O Mg Br OH
CH3MgBr CH3MgBr H2O/O+
CH2=C=O + Br2 CH2–C=O CH2–C=O CH2––C CH––C
| | | | | | CH3 | | CH
Br Br Br CH3 Br CH3 Br CH3 3
(B)
(A)
H.
O CH3
(C)
CH3
BY
* Reaction With Alkylhalide:
RMgX + R’––X R––R’

–MgX2
Higher alkanes
RY
Abnormal Behaviour of Grignard reagent:

MgBr
IST
MgBr
O
Q. + ?
MgBr
M
Solution:
BrMg
E
O BrMg O
|| O– Mg+Br OH
C + H3O+
CH
6-membered cyclic
* Allylic Grignard reagent react with the allylic shift.

CH3 O
||
CH3
RMgX
No reaction
CH3 CH3 Because of steric repulsion
O
|| RMgX
No reaction
* If the Grignard reagent has   H-atom then following reaction takes place.
R
O O– Mg+Br OH OH
|| H2O/H+
+ CH2–CH2–MgBr + Mg
| –CH2=CH2 Br
U
H H
GA
G.R. & Michael Addition:
Michael addition takes plcae only in acyclic  ,  unsaturated ketones with G.R. (in carbonyl compounds)
RMgX
O or Ar Michael
||
C6H5–CH=CH–C–CH3
H.
Unsaturated Ketone RLi
Direct
But in
O RMgX
Direct
BY
RLi
Direct
Unsaturated
cyclic ketone
RY
RMgX
O Direct
||
C6H5–CH=CH–C–H
Unsaturated RLi
Direct
aldehyde
IST
O R OH
||
R
Q. O (i) RMgX(excess)
+ ? Ans. OH
(ii) H2O/H
M
OH
(i) RMgX(excess) OH
Q. R–CH ? |
E
+
(ii) H 2O/H Ans. R–CH–R
OEt
CH
O
|| O
Q. RMgX + Cl–C–OEt ? ||
(1equ.) Ans. R–C–OEt
O OH
|| + |
H2O/H
Q. RMgX + Cl–C–OEt ? Ans. R––C––R
|
(excess) R

O
||
Q. HO–CH2 –CH2–C–CH2–CH2–C–OEt How many equivalents of RMgX will be used
||
O
Ans. 4-equivalent of RMgX is used.
R
H 2O/H
+ |
Q. RMgX + Ethylcarbonate ? Ans. R––C––R
|
(excess) OH
Solution:
O R
|| |
RMgX + EtO–C–OEt R––C––R
|
R
Excess Ethyl carbonate OH
30- Alcohol
U
* Best Grignard reagent CH3MgI
* In Grignard reagent R Alkyl group, phenyl group, allylic group but not vinyl group.
GA
* Solvated form of RMgX is stable. It can not be isolated in individual (pure) form.
R
R O
R
Mg
H.
R X
O
Solvated form
R
* Solvents for RMgX Saturated ethers
BY
O
O O
THF 1,4-dioxane
RY
* Reaction with AAE:

O O OH O OMg X O
|| || | || RMgX | ||
CH3–C–CH2–C–OEt CH3–C=CH–C–OEt CH3––C=CH–––C–OEt + R–H
IST
Keto form Enol form
Similarly:
– +
M
O O OH O O Mg X O
|| || | || RMgX | ||
CH3–C–CH2–C–CH3 CH3–C=CH–C–CH3 CH3––C=CH–––C–CH3 + R – H
Acetylacetone
E
* Preparation of thiols, amines & ethers:

CH
H2O/H+
RMgX + S RS– Mg+X R–SH
X
Thiols
–Mg
OH
Cl
RMgX + Cl–NH2 R–NH2 + Mg
Amine X
R’–MgX + R–O–CH2X R–O–CH2R’ + MgX2
Ether
CH3
|
CH3–C–MgX
O |
|| (i) CH3
Q. CH –CH–C–CH ? No Reaction Due to Steric hindrance
3 3
| (ii) H2O/H
+
CH3
O CH3 OMgBr CH3

|| | |
C + CH2 –C–MgBr ? Ans. R––C––R + C = CH2
| | |
Q. R R H CH3 H CH3
(Because of steric hindrance)
U R
GA
H.
BY
RY
IST
E M
CH

ORGANOLITHIUM COMPOUNDS:
* ionic bond in between C–Li so hard species than RMgX
R––Li
Ionic bond
* Reaction with CO2 :
When CO2 in excess:
H3 O+
RLi + O = C = O R–C=O R–C=O
Excess | |
OLi OH
Carboxylic acid
R
* When RLi in excess:
U
R R O
– + RLi | H3O
+ | ||
– +
RLi + O = C = O R–C–O Li R–C–O Li R–C–OH R–C–R
|| |– + | –H2O
GA
Excess O Ketone
O Li OH
* Reaction with Carboxylic Acid:
O O O– Li+
|| || RLi | H3O+
R–C–OH + RLi R–C–O– Li+ R–C–O– Li+ R–C–R
| ||
H.
R O
Symmetric ketone
* Similarly:
BY
O O
|| (i) RLi ||
––––C–OH +
––––C–R
(ii) H2O/H
With reaction in configuration
O
||
RY
CH3 CO OH (i) CH3Li CH3 C

CH3
CH3 Et (ii) H2O/H+ CH3 Et
* Reaction with Acetal:
IST
O O
OH R H
H+ BuLi – Li+
+ O=C –H2O –BuH
R R O
OH O
E M
–+
+ R–C–OLi
||
CH
O
Cyclo hexene
* RLi has advantage over Grignard reaction when the Grignard reaction is fail to react with highly hindard carbonyl
group, the oganolithium react with such compound to give normal product.
O OH
|| –––Li |
–––C––– +
–––C–––
(ii) H2O/H |
Tritertiary butyl-carbinol

METALLATION REACTIONS:
Na/Liq.NH3 – +
R–C C–H R–C C Na
–
Work as a Nu
D2O R’–X
R–C C–D R–C C–R’

Higher Alkynes
Na/Liq.NH3 R–X Na/Liq.NH3

Q. H–C C–H (A) (B) (C)
D2O
R
(D)
U
Solution:
Na/Liq.NH3
GA
+ – – +
H–C C–H Na C C Na (A)
R–X D2O
R–C C–R D–C C–D
(B) (D)
Na/liq. NH3
H.
(Birch reduction)
R H
C=C
BY
H (C) R
Trans-Alkene
Lithation Reaction:
* It is addition of Lithium
RY
* Takes place of active H-atom
+ BuLi + BuH
*
N CH2–H N CH2 –Li+
IST
F F
H Li
* + BuLi
M
Behave as Nu–
BuLi & give substitution reaction
E
* Li
O O
CH
Behave as Nu–
BuLi
*
N N Li
* For Pyridine, first preority lithation (acid-base reaction) after then chichibabine reaction (second priority)
BuLi
O O Li

* Lithation reaction by Halogen Exchange:
X Li
* BuLi (X = Br, or Cl but not F)

N
OMe OMe
BuLi
*
Br Li
R
* R  C  C  H  BuLi 
 R  C  C  Li
U
* CH 2  C  CH 2  BuLi 
 CH 2  C  CHLi
* CH 2  CH  CH 3  BuLi 
 CH 2  CH  CH 2 Li
GA
*S + BuLi
S S S
Li
H.
BY
RY
IST
E M
CH

DIALKYL CADMIUM:
R
RMgX |
R–C–OH 30-Alcohol
O H2O/H+ |
|| R
R–C–Cl
O
+I –I R2Cd || R2Cd
R–C–R No reaction
(Dialkyl cadmium) +I +I
Reactivity towards the nucleophilic addition reaction.

Acid halide > Carbonyl
R
RMgX > R2Cd
O Rosenmund O
U
|| catalyst ||
R–C–Cl R–C–H
or
GA
* DIBAL
or
t-Bu3SnH
Reaction with Acid Anhydride:
H.
O
||
(CH3)2Cd CH3
O (A)
|| (Small)
COOH
BY
O CH3 CH3
* || (CH3)2Cd
O O (B)
(Excess)
||
O
RY
* But the above reaction in acyclic anhydrides is not particularly useful.

IST
E M
CH

GILMAN REAGENTS:
R2CuLi
In Solution In present of LiI
Dimer form Monomer form
4-methyl group attached R

to a tetrahedral cluster Cu– Li+
of Li & Cu-atom R
R
CH3 CH3
Cu
U
Li Li
Cu CH3
GA
CH3
* It is soft organocupper reagent.

* It is source of carbanions.
* It is a umpolung reagent.
H.
* It is very weak base so in the presence of Gilmann reagent present, halides does not give elimination reactions.
* It is replacement method of the wurtz reaction.
Dry ether
R–X + 2Na + X–R R––R
BY
Wurtz reaction
Higher alkanes
R2CuLi + R’–X R–R’
Corey-House
Reaction Higher alkane
* & by using this method we can also prepared alkanes having odd number of C-atom (corey-house method)
RY
Reagents:
R2CuLi or
RMgX / CuCl
or
IST
CuI
or
RLi / CuCl or CuI
or
R/Cu
M
* Gilman reagents give following type of reactions.

(i) SN-reaction (Nucleophilic substitution reactions)
E
(ii) Nucleophilic addition reactions.

CH
(iii) Michael addition.

(iv) Intramolecular cyclisation reactions.
Nucleophilic Substitution Reactions:

(i) In alkyl halides  R–X (But 30 alkyl halides are not used because of eleminated product will be formed)
(ii) In Aryl halides  Ar–X
|
(iii) In Vinyl halides  =C–X

| |
(iv) In Alylichalides  C=C–C–X
|
|
(v) In Proparglylic halides  –C C–C–X
|
|
(vi) In Benzyl halides  Ar–C–X
|
* Above all substrates give coupling reaction with R2CuLi
Z–X + R2CuLi Z–R
Alkyl, Aryl, Vinyl,
R
Allylic, Proparglylic,
Benzylic
U
1
* R–C–Cl + R 2CuLi R–C–R 1
|| ||
O O
GA
* In the case of Allylic & propargyl substrates, allylic shift will be takes place (Migration of n-bond or SN 2 ' mechanism)
always.
* Epoxides ring opening takes place from less hindard side (if possible alylic shift or SN 2 ' - mechanism takes place.)
H.
Nu–
O
* Epoxide ring opening take place always anti periplaner manner.
R 2CuLi
Q.1 CH3–(CH2)4 –CH2 –I ? Ans. CH3(CH 2)4CH2–R
BY
X R
| |
R2CuLi
Q.2 ? Ans.
R 2CuLi
Q.3 CH2=CH–X Ans. CH2=CH–R
RY
?
R2CuLi R–C–R
Q.4 R–C–Cl ? Ans. ||
|| O
O
Br
IST
H CH3
+ ? H CH3
C=C
Q.5 CH CuLi Ans. C=C
3 CH3
2 CH3
CH3
M
Here stereo-chemistry will be

mantain i.e.,Retension in configure.
E
R R
(CH3)2CuLi
Q.6 Ans. | CH3
CH
?
O OH
O=C–R
COCl
R2CuLi
Q.7 ? Ans.
NO2
NO2

Cl
R2CuLi
Q.8 ? Ans.
R
R2CuLi
?
Q.9 OAC Ans.
R
R2CuLi
Q.10 CH3O–C–CH2–CH2–C–Cl ? Ans. CH3O–C–CH2–CH2–C–R
|| || || ||
O O O O
R
(CH3)2CuLi
? OH
U
Q.11 H2O/H+ Ans.
O
CH3 5 6
GA
5 6 CH31 4
7
C=O
7
(CH3)2CuLi
4 ? 2 3 OH
3 O
Q.12 2 O Ans. or
CH3–CH2–CH=CH–CH2 –CH2–COOH
Hept- 4- enoic acid
H.
Michael Addition:
–
O O O–H O
H
H2 O
+ (CH3)2 CuLi CH3 CH3 CH3
BY
CH3
CH3 CH3 CH3
O
||
CH3 –C–Cl
O
COCH3
RY
CH3
CH3
CH3
IST
(CH3)2CuLi
Q.1 + ? Ans.
H2O/H
O O
M
O
||
E
R
CH
Q.2 R2CuLi RMgX RLi RMgX/CuI

+ + +
H2O/H
+ H2O/H H2O/H H2 O/H
? ? ? ?
O OH OH O
|| R R R
R
R
R R R
Via michael R
Via direct Via direct Via michael
addition addition addition addition

O Br O– O
Q.3 || ||
(CH3)2CuLi
(A) (B) Ans:
Ether
CH3 CH3
(A) (B)
COOEt
O COOEt COOEt
||
(CH3)2 CuLi R–C–Cl CH3
Q.4 (A) (B) Ans.
O Et2O
– CH3
O O
COR
(A) (B)
R
Cyclisation Reaction:
–
O O O
U
|| ||
(CH3)2CuLi
GA
Br Br
CH3 CH3
Questions:
H CH3
H Br
(CH 3)2CuLi C=C
Q.1 C=C ? Ans. Et
H.
H
Et H E-Alkene
H H H
(CH3) 2CuLi H
Q.2 C=C ? Ans. C=C
Ph
BY
Br Ph CH3
Z-Alkene
(CH3)2CuLi
?
Q.3 Via SN2 Ans. CH3
RY
OTs Mechanism
Inversion in configuration
O O
|| (CH 3) 2CuLi ||
Q.4 Ph–C–CH2–CH2–OTs ? Ans. Ph–C–CH2–CH2–CH3
IST
CH3 CH3
| (CH3)2CuLi |
Q.5 CH2=C–CH
|
–CH3
Via SN2
? Ans. CH3–CH2–C=CH–CH3
OCOCH3 Mechanism
M
CH3 CH3
O
|| (CH3)2 CuLi
E
Q.6 O–C–CH3 ? Ans.

Via SN2
Mechanism CH3
CH
CH3
| CH3
(CH3)2CuLi
Q.7 CH C–C–OCOCH3 2 ? Ans. CH3–CH=C=C
| Via SN CH3
CH3 Mechanism
CH3
(i) (CH3 )2CuLi
Q.8 O + ? Ans. + Enantiomer
(ii) H2O/H
2 OH
* SN Mechanism

O H
(i) (CH3)2CuLi HO
H ? Ph
H (ii) H2O/H+
Q.9 Ans. H
Ph Ph Ph CH3
C CH
(i) (CH3)2CuLi C=CH–CH3
O ?
Q.10 Via SN2 Ans.
Mechanism OH
* Michael addition takes place at less substituted C–C double bond.
* In biocylic  ,   unsaturated ketones always only cis product will be formed.
* In chiral centre containing  ,   unsaturated ketones, give two diastereomeric product.
R
O O CH3
|| CH3 (i) (CH3)2CuLi ||
U
Q.1 Ph–CH=CH–C–CH=C ? Ans. Ph–CH–CH
|
2 –C–CH=C
CH3 (ii) H2O/O+ CH3 CH3
GA
O O
O
|| ||
||
(i) (CH3)2CuLi +
+
? CH3 CH3
Q.2 (ii) H2O/H Ans. 10%
*| CH3 90% CH3
H.
CH3
Trans + enantiomer Cis + Enantiomer
CH3 CH3
(i) (CH3)2CuLi
BY
Q.3 O ? Ans. O
(ii) H2O/H+ 100%
CH3
cis-product
RY
IST
E M
CH

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CSIR-JRF (NET), GATE

DRDO, BARC, IISC…...

1-K-4, M.N. Ext. KOTA

* It is substrate of Michael addition

(1) + HCHO + R2NH HCl

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(8) + HCHO + R2NH H+

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Contact: +91-8946891920 www.hgaurchemistry.com Page (4)

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(i) BuLi, –CH2Br (i) BuLi, (i) BuLi,

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LDA (Lithium Diisopropyl Amide)

(5) (i) LDA

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C2H5–S C2H5–S CH2–CH2–C–CH3

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CH3 –I Bulky Base, so equitorial attack takes place

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Reformatsky Grignard Regent RLi Metallation R2CuLi R2Cd

* Organometallic reactions takes place in following order always

=O+ CH2 – COOEt

* Reformatsky Reaction take place with organozinc ester

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So react only with the more

* On heating,   Hydroxy ester give  ,   unsaturated ester

Example of Reformatsky reaction:

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* In the Grignard Reagent following equilibrium also exist. (Schlenk equilibrium)

Electrophilic site Nucleophilic as well as basic site

* There is polar covalent bon in between C-Mg in Grignard Reagent

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* L = OTs, OBs, OAc, etc.

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Because of less double bond character in C-Br bond of CH2 = CH–Br

MgBr MgBr MgBr

Chemical Properties of the Grignard reagent:

Acid-Base Reaction * Nucleophilic addiction reaction

It is required less amount of energy (activation energy) so allowed always first.

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Nucleophilicity of RMgX (Lewis Basicity):

Reaction with Carbonyl Compounds:

* It is nucleophilic Addiction reaction

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Reaction with Acid Derivation:

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RMgX + Cl–C N R–C N

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* Reaction with Ortho Ester:

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Q. CH2=C=O+Br2 CH3MgBr CH3MgBr

RMgX + R’––X R––R’

Abnormal Behaviour of Grignard reagent:

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* Reaction with AAE:

Keto form Enol form

* Preparation of thiols, amines & ethers:

O CH3 OMgBr CH3

(Because of steric hindrance)

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CH3 CO OH (i) CH3Li CH3 C