Baldwins Rules for Ring Closure

Dr Fabienne Pradaux Wednesday 2nd February 2005

Baldwins Rules
Qualitative set of generalization on the probability of a ring closure (RC) Empirical rules formulated from observations and stereoelectronic reasoning Describe kinetic feasibility of ring closure Physical basis lie in stereochemical The rules do not apply to second row elements and to pericyclic reactions

Terminology/Classification (1)
Prefix exo when the breaking bond is exocyclic to the smallest ring formed.
exo XY X Y-

Prefix endo when the breaking bond is endocyclic to the smallest ring formed.

endo

Y-

Terminology/Classification (2)
Numerical prefix describe the size of formed ring. Sufixes Tet, Trig and Dig indicate the geometry of the carbon undergoing the RC. Tetrahedral for sp3 carbon Trigonal for sp2 carbon Digonal for sp carbon
3 2 1 4 3

5-exo-Tet

2 1

X-

Y-

Rules for Ring Closure (1)

Tetrahedral Systems
3 to 7-exo-Tet are all favoured processes 5 to 6-endo-Tet are disfavoured
3 2 2 3 3 2 4 5 3 2 1 4 5 6

X-

X-

3-exo-Tet
4 3 2 1 5 6

4-exo-Tet
4 3

Y 5-exo-Tet
4 3 2 5

X-

6-exo-Tet Y

Y X1

Y 7-exo-Tet

-7

5-endo-Tet

X 6-endo-Tet
1

Rules for Ring Closure (2)

Trigonal systems
3 to 7-exo-Trig are all favoured processes 3 to 5-endo-Trig are disfavoured; 6 to 7-endo-Trig are favoured
3 2 2 3 4 2 1 4 4 5 2 3 6 1 5 3 2 4 5

Y
3

X-

X-

3-exo-Trig
2

4-exo-Trig
2

5-exo-Trig
4 3

6-exo-Trig
4 3 5

Y 7-exo-Trig
4 5 3

1X 7

X1

Y
3

Y
4

Y
5 1

Y
1

Y
2 1

X-

3-endo-Trig

4-endo-Trig

5-endo-Trig

6-endo-Trig

7-endo-Trig

Rules for Ring Closure (3)

Digonal Systems
3 to 4-exo-Dig are disfavoured processes; 5 to 7-exoDig are favoured 3 to 7-endo-Dig are favoured

Y
5-Di

-Di

-Di

Y -Di

-Di

-Di

-Di

5-

-Di

-Di

-Di

Y
-

Other Than Nucleophilic Cases

Radical Processes (homolitic):
3- ri

- ri

Cationic Processes:
- ri

5-

- ri

Attack Trajectories
Favoured paths to transition states are:
Wald n inv rsi n Y
XE

E = 80

Y-

Tetrahedral Systems

Brgi-Dunitz Y

X
E

Trigonal Systems

E = 09

XE

X C C
E
E

E = 20

C C Y

igonal Systems

Favoured and Disfavoured

Favoured RC
will be those in which length and nature of linking chain enables terminal atoms to achieve required trajectory to form final ring bond

Disfavoured RC would require severe bond angle

and distances distortion, so the desired RC will be difficult (if available, alternative pathways will dominate)

Tetrahedral carbon (1)

All exo-Tet cyclisations are favoured

n
1

H2N

Br

Xl p ir Ov rl p wit C- W* l c Att ck t 180

3-exo-Tet

ccur

Tetrahedral carbon (2)

Why all endo-Tet cyclisations are disfavoured?
O O S O NaH S O O S O O S O O O O S O O O S O

O O S O 6t? S O O

6-

t Di fav ur

: R acti

clu iv l i t r

l cular

Trigonal Carbon (1)

Why all exo-Trig cyclisations are favoured?

n
2

4 5

Y X lo e pair Overlap wit C= T* Attack at 109 angl p

OH

O H
ibl

5-exo-Trig

Trigonal Carbon (2)

Example of disfavoured 5-endo-Trig
O
Base X 5-endo-Trig

O O

H H O OH

HO O

OH

5-e o-Trig

Trigonal Carbon (3)

5-endo-Trig versus 5-exo-Trig
O OMe OH O

Base X 5-endo- rig O

OMe

Disfavoured and not observed

O
3 2 1 4

O OMe OH Base
1 3 2 4

O
5

5-endo- rig OMe 0%

OMe
3
5

2 5 1

5-exo- rig 100%

Trigonal Carbon (4)

5-endo-Trig exceptions :
CO2Me SH -S Base 5-endo-Trig .43 ngstrm . 2 ngstrm S CO2Me Se ond ro element -S ond longer em ty or ital 3d of S may intera t ith - T or ital isfa o red t ossi le

R O R

(CH2OH)2

OH R HO H OH R H2 O R O R O

H - H2 O

OH R O R

5-endo-Trig isfa o red

R O
5-exo-Trig Fa o red

R O

Trigonal Carbon (5)

5-endo-Trig versus 5-exo-Trig; Nitrogen analogue
MeO2C
1 3 2 4

CO2Me
5

MeO2C

CO2Me
5-endo-Trig %

NH2

HN
1

MeO2C

4 5

HN 1
ontrol ex eriment PhCH2NH2 CO2Me

5-exo-Trig %

O
H N CO2Me % O %

Ph

H N 1

Ph

Trigonal Carbon (6)

5-endo-Trig versus 5-exo-Trig; Nitrogen analogue (MO explanation)
Bad alignment Too far a ay

O H N H OMe

H N O OMe

N lone air an not rea h T* or ital of Mi hael a e tor nitz angle atta not ossi le

Digonal carbon
All endo-Dig cyclizations are favoured
T* ina O O Ar
1 2

essi le

O
3 4 5

Ar

ela ossi le in the lane of the ring

5-endo- ig

3- and 4-exo-Dig cyclisations are disfavoured

2 2 3 3 4

X x

Xx

3-exo- ig N le hile an not atta

4-exo- ig ith the req ired 2 angle

Intramolecular Alkylations of Ketone Enolates (1)

Endocyclic alkylations
(Enolendo)-Exo- et
-

+ O

6- to 7- membere RC Favoured 3- to 5- membere RC Disfa oure

Exoclyclic alkylations
(Enolexo)-Exo- et +
-

3- to 7- membere RC Favoured

Intramolecular Aldol Condensations (1)

Endocyclic reactions
(Enolendo)-Exo- rig
-

Y-

3- to 5- membered RC Disfavoured 6- to 7- membered RC Favoured

Exoclyclic reactions
(Enolexo)-Exo- rig
-

Y-

3- to 7- membered RC Favoured

RESTRICCIONES ESTEREOELECTRONICAS.
Intramolecular alkylations of ketone enolates Intramolecular aldol condensations

180 atta
C alkylatio s O

Y 109 atta C alkylatio s O

O alkylatio s

O alkylatio s

Intramolecular Alkylations of Ketone Enolates (1)

Why 5-(Enolendo)-exo-tet disfavoured?
Br O t-BuOM M O Br O O

> 70% 5-exo-Tet

0% 5-(enolendo) -exo-tet

X M O O M

X O

Intramolecular Alkylations of Ketone Enolates (2)

Why 6-(enolendo)-exo-tet favoured?
t-BuOM O Br M O Br O O

> 95% 6-(enolendo) -exo-tet

0% 6-exo-Tet

Possible because of extra bond lengt

Intramolecular Aldol Condensations (2)

6-(enolendo)-exo-trig versus 5-(enolendo)-exo-trig
O O + 5-( nolendo)exo-trig O O O O O 6-( nolendo)exo-trig O O

Statistics : 4 possibilities to form a 5 membered ring 2 possibilities to form a 6 membered ring Previsions : 6 membered ring would be predominant or exclusive

Intramolecular Aldol Condensations (3)

O KOH MeOH < 5 in 77% H2 O IR (observed) C=O C clohexanone 1707 c -1 C=O C clopentanone 1740-50 c O 1 O 6-(Enolendo)-exo-trig 100% 5-(Enolendo)-exo-trig 0% O

-1

Formation of cyclohexanone totally dominates over even statistically preferred cyclopentanones production.

Baldwin Rules in Harrity Group (1)

Formation of cyclohexanones :
RE RZ Lewis Acid R RE RZ Co2(CO)6

O R Co2(CO)6

LA

H RZ RE

Co2(CO)6 R

LA

H RZ RE

Co(CO)3 Co(CO)3 R

6-(enolendo)-exo-trig

Baldwin Rules in Harrity Group(2)

Formation

of cyclobutane ketones :
Co2(CO)6 R1 O

O R1 Co2(CO)6

R2

Le is

id

R2

6-exo- rig

LA

H O R2

Co2(CO)6 R1

LA

H O

Co(CO)3 Co(CO)3 R1

R2

4-(enolexo)-exo-trig

Conclusion
Only give information about whether processes are favoured or disfavoured and not allowed and forbidden. Nucleophilic RC feasibility strongly depends on ring size, geometry of reacting atom and exo or endo nature of reaction. Structural modification can dramatically affect the cyclization mode. If favoured trajectory of attack valid, then reaction will follow the Baldwins rules.

Summary (1)
Size Tet 3 4 5 6 7 Exo Trig Dig X X X X Tet Endo Trig X X X Dig

Summary (2)
Exo-Tet Size 3 4 5 6 7 Exo-Trig enolendo enolexo enolendo enolexo X X X X X X

References
J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734. J. E. Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman, R. C. Thomas, J. Chem. Soc., Chem. Commun. 1976, 736. J. E. Baldwin, R. C. Thomas, L. Kruse, L. Silberman, J. Org. Chem, 1977, 42, 3846. J. E. Baldwin, L. Kruse, J. Chem. Soc., Chem. Commun. 1977, 233. J. E. Baldwin, M. J. Lusch, Tetrahedron, 1982, 38, 2939. C. D. Johnson, Acc. Chem. Res. 1993, 26, 476. J. Clayden, N. Greeves, S. Warren, P. Wothers, Oxford, chapter 42, p 1140. D. A. Evans, internet course.