1 Re-visiting Baldwin’s Rules: The Basics

Organic Division Friday Problem Set

01-21-2011 Moon Young Hur

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Baldwin’s Rules

•  “Baldwinʼs Rules” is a qualitative set of “guidelines” to be considered for the probability of successful ring closure reactions.

•  The reason to be referred to as “guidelines” is that there are exceptions to this “rule.”

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Who is Baldwin?

•  Sir John Evan (Jack) Baldwin, FRS •  Born London, 1938 •  Currently Emeritus Professor

at Oxford University, UK

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Baldwin’s Rules: What’s in it?

•  Rule 1: tetrahedral (sp3) systems – 3 to 7-exo-tet are favored – 5 to 6-endo-tet are disfavored

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Baldwin’s Rules: What’s in it?

•  Rule 2: trigonal (sp2) systems – 3 to 7-exo-trig are favored – 3 to 5-endo-trig are disfavored – 6 to 7-endo-trig are favored

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Baldwin’s Rules: What’s in it?

•  Rule 3: digonal (sp) systems – 3 to 4-exo-dig are disfavored – 5 to 7-exo-dig are favored – 3 to 7-endo-dig are favored

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Nomenclature: exo vs. endo •  exo: exo-cyclization mode refers to breaking the bond

being positioned exocyclic to the forming cycle.

•  endo: endo-cyclization mode refers to breaking the bond being positioned endocyclic to the forming circle.

X

exo

XY Y

X Y

endo

X Y

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Nomenclature: #’s and geometry

•  Numbers: the number refers to the size of the formed ring (includes the heteroatom that consists the ring)

•  Geometry: tet, trig, and dig refer to the hybridization state of the electrophilic component in the nucleophilic ring closures(tet = tetrahedral, trig = trigonal, dig = digonal)

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Understanding the “Rule”

•  It is important to understand how the “rule” is made, not to memorize.

•  The “rule” is based upon the approaching trajectory of the nucleophile on to the electrophile. –  Therefore, electrocyclic processes do not apply to

this rule. –  Non-first-row elements that participate in the

cyclization do not apply, due to extended bond lengths and larger atomic radii (geometrical constraints are relieved)

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Angle of approach •  When tet:

•  When trig:

•  When dig:

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Angle of approach •  When tet:

•  When trig:

•  When dig:

YX X Yα = 180 °

α α

Y

Xα = 109 °

YX

α α

α ≈ 120 °X

Y

X

Y

α

α

α α

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Tetrahedral Carbon

•  All exo cyclization modes (n-exo-tet, n ≥ 3) are allowed

X

exo

X CY Y

X YH H

X YH

H

CH2X + Y

Formation of 3-Membered Rings (3-exo-tet)

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Tetrahedral Carbon

•  Endo cyclization modes are disallowed (n-endo-tet, n = 3 ~ 9)

X YC

endo

X YC(sp3)

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Tetrahedral Carbon

•  Endo cyclization modes are disallowed (n-endo-tet, n = 3 ~ 9)

X YC

endo

X YC(sp3)

Only possible when X-C-Y bond angle is 180°.This is only possible when the endo cyclization ring size reaches 9 or more members.

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Problem 1 S

OCX3

O O

SO O

CY3

SOCX2I

O O

SO O

CY3

NaH

NaH

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Solution S

OCX3

O O

SO O

CY3

SOCX2I

O O

SO O

CY3

6-endo-tetdisfavored

6-exo-tetfavored

SO

O O

SO O

CY3

SO

O O

SO O

CY3

NaH

NaH

CX3

CX2

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Solution S

OCX3

O O

SO O

CY3

SOCX2I

O O

SO O

CY3

6-endo-tetdisfavored

6-exo-tetfavored

SO

O O

SO O

CY3

SO

O O

SO O

CY3

CX3

CX2

therefore another moleculeparticipates in the reaction,

making it an intermolecular reaction

SOCX3

O O

SO O

CY3

SOCX3

OO

S OO

CY3

SOCX2

O O

SO O

CY3

H

B

due to favored mode of cyclization, this process is intramolecular.

SO

O O

SO O

CY3

CX3

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Trigonal Carbon

•  Endo cyclizations 3 to 5-endo-trig are disallowed.

X YC

n-endo-trig

X YC

on the condition thatX = first-row element

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Trigonal Carbon

CO2Me

OH

CO2Me

SH

base

5-endo-trigDisfavored

base

O

S

CO2Me

CO2Me

second row atom relaxes the geometrical restriction

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Problem 2

CO2Me

NH2

MeO2C?

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Solution

CO2Me

NH2

MeO2C

HN

CO2MeMeO2C

HN

MeO2C

O

5-endo-trig0 %

5-exo-trig100 %

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Trigonal Carbon

•  Exocyclic enolate alkylation in essence is an exo-tet cyclization, but stereoelectronically exhibits endo-trig properties.

C C

exo

C CY YO C CO

MO

Br

OO

only observedproduct

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Problem 3

OCl MeO

- HCl

Favorskii Rearrangement

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Problem 3

OCl

CO2MeMeO

- HCl

Favorskii Rearrangement

OCl

OCl

OOMe

O OMeMeOH

CO2Me

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Exceptions •  Like any other rules, thereʼs always

exceptions.

N N N OOH

O

CH3CO2H 5-endo-trig

NCO2Me

R2

CO2Me

R1HCHN

CO2Me

CO2MeR2

R1

HN

CO2Me

R2

CO2Me

R1

3 : 1

KOtBu

5-endo-trig