Baldwin’s Rules For Ring Closer

The presence of cyclic structures in the basic framework of many complex and biologically
interesting molecules has made their formation a fundamental process in organic synthesis.
Therefore, ring-forming processes have garnered the attention of synthetic chemists for
many years. A series of guidelines that describe the propensity of various systems to
participate in ring forming reactions was put forth by J. E.Baldwin in the 1970's. This set of
guidelines, which describe the relative ease of ring formations, has become known as
Baldwin’s rules of ring closure and has proved a useful tool in evaluating the feasibility of
ring forming reactions. Baldwin described his rules in terms of three features of the reaction
nomenclature:
1. The ring size being formed (indicated through a numerical prefix)
3 membered rings = 3
4 membered rings = 4
etc.
2. The hybridized state of the carbon atom (Y) undergoing the ring closing reaction
if Y= Sp3 center; then Tet (tetrahedral)
if Y= Sp2 center; then Trig (trigonal)
if Y= Sp center; then Dig (digonal)
Z

3. Indicate where displaced electrons end up

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 Z

Y Y
exo
+ Z
X X

- if the displaced electron pair ends up within the ring being formed; then Endo

4. Ring forming reaction is designated as Favored or Disfavored.

Example

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Rules (Suggestions) for Ring Closure

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Summary

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 1. Reaction at saturated carbons (substitution reaction SN2 mechanism)
Cyclization of halide alkyl amine (intramolecular reaction)
Note: All exo-Tet cyclization are favored
Example 1

H
N
Br
+ Br
H2N

Mechansim

H
N
Br
+ Br
H2N

3-exo-tet

Example 2

NH
+I
H2N I

Mechansim

NH
+I
H2N I

4-exo-tet

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Example 3

Mechanism

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 2. Reaction at unsaturated carbon

The groups of unsaturated:

C=C, C=O, C=N

C=O and C=N the polarity of oxygen and nitrogen are higher than that of carbon, so the
attack occurs on the carbon atom. The cyclization reaction takes place exo.

a. Reaction of carbonyl compounds

R Z

Z Compound Mechanism of reaction

H Aldehyde Addition
R Ketone

OH Carboxylic acid

OR Ester
Substitution
Cl, Br Acyl halide

NH2,NHR, NR2 Amides

OC(O)R Anhydride

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Example1 (Addition Reactions)
O OH

CH3
CH3
O
OH

mechanism

O
H3C

O
CH3
O
H
O H

OH

CH3

5-exo-trig

Example2 (Substitution Reactions)

Cl NH
- Cl
H2N

Mechanism
O

Cl
- Cl NH
H2N

O
5- exo - trig

b. Reactions of C=C
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The reaction of α, β-unsaturated aldehyde (chalcone) with phenyl hydrazine to form
hydrazones as intermediates. These hydrazone intermediates on treatment with glacial acetic
acid in ethanol isomerizes to pyrazolines the probable mechanism for the formation of
pyrazoline

H2 H
R1
C
O R
R1 CH=CH - C - R + NHNH2
N N

a, ß-unsaturated aldehyde or ketone (chalcone) phenyl hydrazine

R = H or alkyl

c. Reaction of C=N (imine group)

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 Synthesis of β-lactam:

O H R
O
R
NH N
R1 NH N + HSCH2COOH R1
H
S
O

Mechanism

O H R
O O O
R
-H2O
NH N
SH CH2 R1 NH N H R1
R1 NH
N OH S
HO C S O
H
O
H R

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Example
CH2
- OCH3
O 5-exo-trig
1 f avour
O
O

base CH3
HO CH3 4-exo-trig
O
O 2 O f avour
CH3
CH2
O
O
x3 5-endo-trig
CH3
O disf avour
O

mechanism
O
O
HO CH3
O base O CH3
O
CH2
CH2

CH2
- OCH3
O 5-exo-trig
1 f avour
O

2 CH3
1 CH3 O 4-exo-trig
O 2 O f avour
3 2
CH3
O CH2 O
3 O
1 x3 5-endo-trig
CH3
O disf avour
O

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 3. Cyclization of triple bonds

There are three types of triple bonds

alkyne nitrile isonitrole

The ring closer occurs for all types on the carbon atom.

a. Reaction of alkyne

Example1

N
CH H
Cu2Cl2

CH2
NH2

X NH

Mechanism
CH
Proton
transf er

N N
NH2 H
H
H
5-endo-dig
f avored

CH CH CH2

Proton
transf er
x H
N NH
NH2 H

4-exo-dig
disf avored

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Example2

O R
C 5-exo-dig
H
f avored

base
HO R
O
R 6-endo-dig
f avored

b. Reaction of nitrile

Example

CN CN O R

NaSH
R Cl R SH NH2
-NaCl S
O O

Mechanism
O
H
O R O R O R
R
H Proton
H
transf er
C
N NH NH2
HS C
S S
S
N
H

HO R

NH2
S

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