Baldwin’s Rules

Nadia Fleary-Roberts02/05/12

•Proposed in 1976 by Sir Jack Baldwin

•Guidelines for ring closing reactions of 3- to 7-membered rings-

•empirical rules derived from experimental observations

J. Chem. Soc. Chem. Commum., 1976, 734-736Advanced organic chemistry, March p 212Clayden 1st Edn p 1140 2nd Edn p 810Dr. F. Pradaux, Sheffield University

Baldwin’s rules for ring closure

Nomenclature

3, 4,......7

Number Indicates the size of the ring being formed

1. Ring size

The bond broken as the ring is formed is outside the new ring

X-

exo

XY Y-

X-Y X Y-

endo

2. Bond

The bond broken as the ring is formed is inside the ring

Nomenclature

sp3 tetrahedral carbon tet

sp2 trigonal carbon trig

sp digonal carbon dig

3. Geometry

geometry of the carbon undergoing the ring closing can be describes as:

Nomenclature

Y

Y

Y

For example.....

1

3 4

2

OH

OH

OH

5

5-exo-trig

2

3

1H2N

Br

3-exo-tet

O56

12

3

4

O

6-endo-dig

Reactions can be favoured or disfavoured

•kinetic favourability of a reaction

• A disfavoured reaction does not mean that the reaction will not occur -just that it is more difficult

•Disfavoured cases require severe distortion of bond angles and distances

Ideal bond angles

•Favoured cyclisations enable terminal atoms to achieve proper geometries

O

Nu-

= 109°

Nu

OH

Trigonal carbons(Bürgi-Dunitz)

YX-

X Y- = 180°

C C

X-

= 120°C C

Y

X

Y

Tetrahedral carbons(Walden inversion)

Digonal carbons

Tetrahedral systems

-XY

X-

YX-

Y X- Y

X-

YX-

Y

X-

Y

5-exo-Tet3-exo-Tet 4-exo-Tet 6-exo-Tet

7-exo-Tet 5-endo-Tet 6-endo-Tet

12

351

23

5

6

7

1

2

3

1

2

3

1

2 3

4

4

4

5

6

4

1

2

3

45

6

1

2

3

4

all exo-tet cyclisations are favoured

Trigonal systems

-XY

X-Y

X-

Y X- Y X-

Y

X-

Y

X-

Y

5-exo-Trig3-exo-Trig 4-exo-Trig 6-exo-Trig 7-exo-Trig

5-endo-Trig 6-endo-Trig

-XY

-X Y

X-

Y

3-endo-Trig 4-endo-Trig 7-endo-Trig

12

3

51

23

5

6

71

2

3

1

2

3

1

2 3

4

445

6

4

1

2

3

4

5

6

1

2

3

4

1

2

3

12

3

4

5

71

2

3

45

6

All exo-trig cyclisatons are favourable

5-endo trig are disfavoured!

NH2

O

OEt 5-endo-trig

HN

OEt

O

NH2 OEtO

5-exo-trig

NH

O

Exo-tet

X

Y

n

X lone pair C-Y * overlapattack at 180° angle possible

X n

Y

X lone pair C=Y *overlapattack at 109° angle possible

Exo-trig

Favoured exo-tet and exo-trig

Disfavoured 5-Endo-trig

N

OOMeH

H

Bad alignment

N lone pair cannot reach * orbital Dünitz angle (109°) attack not possible

N

H H

O

OMe

Too far away

Disfavoured 5-Endo-trig...iodocyclisation

•Iodocyclisation forms the disfavoured “anti-Baldwin” endo-trig product•WHY?1)Overwhelming attraction between nucleophile and electrophile2)No kinetically favoured alternative pathways- 4-exo-tet would be too strained

HO

O

I

3 eq I2, NaHCO3

MeCN

HO

I

Knight et.al. Tetrahedron Lett. 1998, 39, 8909

however

TsHN OH

3 eq I2, K2CO3

MeCN

NTs

I

O

NHTs

I

5-endo-trig

5-exo-trig

OH

•5-exo-trig strongly favoured over the 5-endo-trig

Digonal systems

-X -XY

X-

YX- X-

X-

Y

X-

Y

5-exo-Dig3-exo-Dig 4-exo-Dig 6-exo-Dig 7-exo-Dig

5-endo-Dig 6-endo-Dig

-XY -X Y

X-

Y

3-endo-Dig 4-endo-Dig 7-endo-Dig

YY

Y

12

35

6

7

1

23

4

5

6

71

2

3

1

2

3

1

2 3

4

44

5

6

5

1

2

3

4

5

1

2

3

4

5

12

34

1

1

1

1

63 3

22

4

All endo-dig are favoured

Endo-dig rationale

O

O

Ar1

2

3

4 5

5-endo-Dig

O

O* inaccessible

Ovelap in the plane of the ring

Ar

•Alkyne has two π* orbitals-one in the plane of the ring

-X -XY

3-exo-Dig 4-exo-Dig

Y

12

3 1

2 3

4

x x

Disfavoured 3- and 4-exo-dig

•Nucleophile cannot attack at the required 120° angle

Exceptions to the Baldwin’s rules

•second row elements

Why?

•Long C-S bond•Sulfur has empty 3d orbitals

SH

OMe

Obase

S

OMe

O5-endo-trig

S

O

OMe

O

OH 5-endo-trig O O O OH

•cations

Summary

Size Exo Endo

Tet Trig Dig Tet Trig Dig

3 X X

4 X X

5 X X

6 X

7

Intramolecular endocyclic alkylation of ketone enolates

Baldwin, Kruse, JACS Chem Commun. 1977, 233

Nomenclature

enolexo or enolendo orientation of the enolate C-C bond

exo-tet or exo-trig with respect to the C-Y terminus

+ Y--O Y O

(Enolexo)-Exo-Tet

-O Y O

+ Y-(Enolendo)-Exo-Tet

6 to 7 Favoured3 to 5 Disfavoured

3 to 7 Favoured

OBr

O O

5-enolendo

not observed

(Compare with disfavoured 5-endo trig)

Oxygen alkylation vs. Carbon alkylation

O Br O O

6-enolendonot observed

(Compare with favoured 6-endo-trig)

O

Y

C alkylations

180° attack

O alkylations

OOO

MX X

M

•Oxygen alkylation -electrophile approaches in plane of the enolate

XOM

Carbon alkylation in 6-enolendo possible

•Perpendicular approach to the enolate

Oxygen alkylation vs. Carbon alkylation

-O Y O

(Enolendo)-Exo-Trig

Y-

-O Y O

(Enolexo)-Exo-Trig

Y-

disfavoured 3 to 5 favoured 6 to 7

Favoured 3 to 7

Intramolecular aldol condensations

Baldwin, Tetrahedron, 1982, 38, 2939

5-enolendo-exo-trig vs. 6-enolendo exo-trig

O

O

O O

O

O

O

O

O

+5-(Enolendo)-

exo-trig

6-(Enolendo)-

exo-trig

•6-enolendo-exo-trig exclusively formed.

Summary

Exo-Tet Exo-Trig

Size enolendo enolexo enolendo enolexo

3 X X

4 X X

5 X X

6

7

Just remember.....

1. Exo-tet and endo-trig favoured2. 5-endo trig disfavoured*

3. Endo-dig favoured

1. Enolexo endo-tet and trig are favoured

Endocyclic reactions

N

O

Ph

Ph2

51

4

3

5-endo-trig*

Other Than Nucleophilic Cases

• Radical Processes (homolitic):

• Cationic Processes:

3-exo-Trig

4-endo-Trig

6-endo-Trig

5-endo-Trig