D. A.

Evans Functional Group Classification Scheme for Polar Bond Constructions Chem 206

Papers of Historical Interest:

http://www.courses.fas.harvard.edu/~chem206/
"Arthur Lapworth: The Genesis of Reaction Mechanism."
M. Saltzman J. Chem. Ed. 1972, 49, 750. (Handout)

Chemistry 206 "A Theoretical Derivation of the Principle of Induced Alternate Polarities."
A. Lapworth J. Chem. Soc. 1922, 121, 416.

Advanced Organic Chemistry "The Electron Theory of Valence as Applied to Organic Compounds."
J. Steiglitz J. Am. Chem. Soc. 1922, 44, 1293.

Lecture Number 30 Monographs:

Hase, T. A. "Umpoled Synthons. A Survey of Sources and Uses in Synthesis".;
John Wiley & Sons, Inc.: New York, 1987.
Functional Group Classification Scheme
for Polar Bond Constructions Ho, T.-L. "Polarity Control for Synthesis"; John Wiley & Sons, Inc.: NY, 1991.

Ono, N., "The Nitro Group in Organic Synthesis", Wiley-VCH, 2001

! Historical Perspective
Several Interesting Problems O R
! Charge Affinity Patterns 1) HO – R
Provide a mechanism for the Nef reaction N H O
! Functional Group Classification Scheme O R 2) H3O +
R
! The Chemistry of the –NO2 Group
The von Richter reaction is illustrated in the accompanying equation. Please provide a
! The Chemistry of the –N2 Group plausible mechanism for this transformation taking into account the following observations.
(a) If 15N-labeled KCN is used, the N2 formed is half labeled; (b) 3-bromo-benzonitrile does
not form 3-bromo-benzoic acid under the reaction conditions.
Reading Assignment for this Week:
Br Br
"An Organizational Scheme for the Classification of Functional Groups.
Applications to the Construction of Difunctional Relationships." KCN
D. A. Evans Unpublished manuscript. (Handout) + N2
heat,
aqueous EtOH CO2H
"Methods of Reactivity Umpolung." NO2
D. Seebach Angew. Chem. Int. Ed. Engl. 1979, 18, 239. (Handout)
Stoltz and co-workers recently reported the interesting rearrangement illustrated below
"Nitroaliphatic Compounds–Ideal Intermediates in Organic Synthesis"' (JACS 2003, 125, 13624). Please provide a mechanism for the illustrated transformation.
Seebach, D. et. al, Chimia, 1979, 33, 1-18. (Handout) Your answer should include clear 3-D drawings where relevant. the answer may be found in
the database.

MeO O MeO O
N2 AgOBz, Et3N
95% yield
H THF, 45 °
Me
Monday Me
D. A. Evans December 5, 2005
D. A. Evans Ambiphilic Functional Groups Chem 206

Required Reading: Arthur Lapworth (1872–1941)

"An Organizational Scheme for the Classification of Functional Groups.
Applications to the Construction of Difunctional Relationships."
D. A. Evans Unpublished manuscript.
"Methods of Reactivity Umpolung."
D. Seebach Angew. Chem. Int. Ed. Engl. 1979, 18, 239.
"Nitroaliphatic Compounds–Ideal Intermediates in Organic Synthesis"'
Seebach, D. et. al, Chimia, 1979, 33, 1-18.
Papers of Historical Interest:
Lapworth was among the first to understand and conceptualize the effect
of heteroatomic substituents on the reactivity of individual carbon centers,
and how this effect is propagated through the carbon framework of
organic molecules.
Lapworth's Theory of Alternating Polarities:
"Latent Polarities of Atoms and Mechanism of Reaction, with Special
Reference to Carbonyl Compounds."
A. Lapworth Mem. Manchester. Lit. Phil. Soc. 1920, 64 (3), 1.

"Arthur Lapworth: The Genesis of Reaction Mechanism."

M. Saltzman J. Chem. Ed. 1972, 49, 750.
"A Theoretical Derivation of the Principle of Induced Alternate Polarities."
A. Lapworth J. Chem. Soc. 1922, 121, 416.
"The addition of electrolytes to the carbonyl compound invariably
proceeded as if the carbon were more positive than the oxygen atom,
and invariably selected the negative ion; for example:"

"The Electron Theory of Valence as Applied to Organic Compounds." C O

J. Steiglitz J. Am. Chem. Soc. 1922, 44, 1293. C O

NC H NC H
–––––––––––––––––––––
"The extension of the influence of the directing, or "key atom," over a
"Displacement of Aliphatic Nitro Groups by Carbon & Heteroatom long range seems to require for its fullest display the presence of double
Nucleophiles." R. Tamura, A. Kamimura, N. Ono Synthesis 1991, 423. bonds, and usually in conjugated positions...."
"Functionalized Nitroalkanes as Useful Reagents for Alkyl Anion
Synthons." G. Rosini, R. Ballini Synthesis 1988, 833. C C C O C C C O

"Conjugated Nitroalkenes: Versatile Intermediates in Organic NC H

Synthesis." NC H
A. G. M. Barrett, G. G. Graboski Chem. Rev. 1986, 86, 751.
The "key atom" is the one with the most
Monographs:
electronegative character, in this case the carbonyl
Hase, T. A. "Umpoled Synthons. A Survey of Sources and Uses in oxygen.
Synthesis".; John Wiley & Sons, Inc.: New York, 1987. anionoid/cationoid nucleophilic/electrophilic
Ho, T.-L. "Polarity Control for Synthesis"; John Wiley & Sons, Inc.: New
York, 1991. The Lapworth polarity designations can be used to form the basis
of a functional group classification scheme.
An electronic handout will be provided
D. A. Evans Reactivity Patterns of Functional Groups: Charge Affinity Patterns Chem 206

! Polar rxns form the basis set of bond constructions in synthesis ! The actual reaction associated with this transform is the addition of
organometals to carbonyl substrates.
! Generalizations on conferred site reactivity will therefore be important
O M OM
O CH3 CH CH3 CH3 CH CH3
Given this target and the desire to form this bond
R R
When one considers the polar resonance
The functional group =O "dictates" the following bond construction O– +M structure for the C=O group it is clear that an
O atom is very good at stabilizing an adjacent
CH3 CH – CH3
M + (+) charge through resonance.
O O O
M R
R R R R R ! Consider polar disconnections of the illustrated !-hydroxy ketone 1:

O O (–)
TA
R C CH3 CH2 O
! Conferred site reactivity of =O (–) O (–)
R (+) (+) R (+) (–) (+) (–)
R C CH2 CH2 OH
Charge Affinity Patterns (+) (–) (+) (–) TB O (–)
1 R C CH CH2 H2O
! Use the descriptors (+) and (–) to denote the polar disconnections shown. (–)
(+) (–) (+)
(–) (+)
A B A: – B+ It is evident that the heteroatom functional groups, =O and -OH, strongly bias
(–) (+) the indicated polar disconnections.
A B A: + B:–

! In the transforms illustrated above, symbols (+) & (–) are used to denote the
Charge Affinity Patterns of Common Functional Groups
particular polar transform illustrated.
In the present case there is NO INTRINSIC BIAS in favoring one transform (+)
over the other. Me CH2 CH2 Br C C C E1
Let's now add an OH functional group (FG) to propane at C-2 and see H
(–) (+)
whether one creates a bias in the favoring of one or the other transforms: Me CH2 C O C C C E2
OH OH (+) (+)
TA H2C CH CH2 OH C C C E3
CH3 CH CH3 CH3 CH: – + CH3
(–) (+) disfavored OR
(+) (–) (+)
OH OH H2C CH C O C C C E4
TB
CH3 CH CH3 CH3 CH + – : CH3 favored
(+) (–)
D. A. Evans Classification of Functional Groups Chem 206
Functional groups activate the carbon skeleton at the point of A-Functions:
attachment by either induction & resonance.
A 3rd hypothetical FG, designated as A, may be defined that has an
Induction (+) (+) (–) (–) unbiased charge affinity pattern as in 1. Such an idealized FG's activates all
C F1 C F2 C F3 C F4 sites to both nucleophilic and electrophilic reactions, and as such include
(+) (–) (+) (–) those functions classifies as either E– or G–. The importance of introducing
Resonance
this third class designation is that it includes those functional groups having
non-alternate charge affinity patterns such as 2–4.
(+) (±) (–)
Symbol C E C A C G (+) (+)
Hypothetical A-function C C A 2
E = electrophilic at the point of attachment
A = ambiphilic at the pont of attachment (+–) (+–) (+–) (–) (–)
G = nucleophilic at the point of attachment C C C A C C A 3
1 (+–)
For simplicity, we will designate three FG classes according to the
C A 4
designations provided above.
E & G-Functions:
FG-Classification Rules
To organize activating functions into common categories it is worthwhile to
define "hypothetical" functional groups E, and G, having the charge affinity In the proposed classification scheme the following rules followed in the
patterns denoted below. assignment of class designation of a given FG.

Hypothetical E-function Hypothetical G-function ! Activating functions are to be considered as heteroatoms appended to or
included within the carbon skeleton.
(+) (–) (+) (–) (+) (–)
C C C E C C C G ! Activating functions are inspected and classified according to their
Given the appropriate oxidation state of the carbon skeleton, such functional observed polar site reactivities.
groups confer the indicated polar site reactivity patterns toward both
electrophiles and nucleophiles. ! Since proton removal and addition processes are frequently an integral
aspect of FG activation, the FG, its conjugate acid or base, and its proton
Any FG that conforms either to the ideal charge affinity parrern or a sub- tautomers are considered together in determining its class designation.
pattern thereof will thus be classified as either an E- or G-function.
! The oxidation state of the FG is deemphasized since this is a subordinate
strategic consideration.
Representative E-functions:
(+)
Me CH2 CH2 Br C C C E1 Common E-Functions: Symbol: (+) C E
H
(–) (+)
Me CH2 C O C C C E2 exception: O
(+) (–) (+) OR O
(+) (+) C C C E exception: N
H2C CH CH2 OH C C C E3 NR2 NR
OR
(+) (–) (+) X, X = halogen
H2C CH C O C C C E4
Also consider all combinations of of above FGs; e.g =O + OR
D. A. Evans Classification of Functional Groups Chem 206

Common G-Functions: Symbol: (–) C G H-tautomer conjugate base conjugate acid

Typical G-class functions are the Group I-IV metals whose reactivity patterns, O HO O HO
falls into a subset of the idealized G-FG 5. N CH2R N CHR N CHR N CHR
(–) O O O HO
(–) (–) (+) (–)
H2C CH CH2 Li C C C G
FG C (–) FG C (+)
(–)
5
CH3 CH2 MgBr
–O
The Reaction: + N CH–R
Common A-Functions: Symbol: (±) C A –O
O El(+) O R
base
A-functions are usually more structurally complex FGs composed of + N CH2R +N
polyatomic assemblages of nitrogen, oxygen and their heavier Group V and VI –O –O El
relatives (P, As, S, Se). pKa ~ 10 O –
!!

+ N CH–R
Typical A-functions, classified by inspection, are provided below O (–)
–O
+ N CH2–R
NO2 NOR NNR2 N(O)R N2 N The charge affinity pattern: –O
+
SR S(O)R SO2R SR2
+
PR2 P(O)R2 PR3 ! This reactivity pattern may be extended via conjugation:
O
! These FG's are capable of conferring both (+) and (–) at point of attachment. The Reaction: + N CH CH R
(+) –O O (–) (+)
Nu(–)
X: X: X: + N CH2 CH Nu
(–) N N N –O
–O R
X = OR, NR2 +
R (+) H R H R (–) H + N CH CH R
–O
Remarkably, the dual electronic properties of oximes were first discussed by O (–) (+)
Lapworth in 1924 before the modern concepts of valence bond resonance Charge affinity pattern: + N CH CH R
were developed. –O
Lapworth, A. Chemistry and Industry 1924, 43, 1294-1295.

" The resonance feature which has been exploited:

The Nitro Functional Group
(+)
As an example, the class designation of the nitro function is determined by X: X: X:
(–)N N !! N
an evaluation of the parent function, its nitronic acid tautomer, as well as X = OR, NR2
conjugate acid and base. R (+) H R H R (–) H
D. A. Evans Charge Affinity Patterns & the Nitro Functional Group Chem 206
The Nef Reaction
Some Reactions of the Nitro Functional Group
O OH O R R
1) HO –
R NO2 R3N ! Overall Transformation: +N H O
O R
(–) (+) (–) H (+) R EtOH R –O R 2) H3O +
+ N CH CH R R
NO2
–O
O O
! Mechanism O R
HO – –O R HO R
R NO2 R3N H+
+N H +N +N
(–) R
(+) EtOH –O R –O R –O R
NO2 nitronate anion nitronic acid
O O O2N O2N
R3N O H+
MeO Me (+) EtOH
Me HO R HO R H2O HO R
CO2Me N H +
O N +N
R - H+
O2N HO H R HO HO
O2N OH R
Et–NH2
EtOH
(+) Me N The charge affinity patterns represented
H
O R –O R HO R
HO – H+
Important Transformations of the –NO2 Functional Group +N H +N (±) +N (±)
–O R –O R –O R
O O
(–) nitronate anion nitronic acid
H2
rxn is quite facile O2N C(–)
! Reduction: H+
R Pd, Ni, Pt etc R

NO2 NH2 R HO R R
O + H2O HO
O (+) N (+)
R +N
R3SnH H R - H+
HO HO R
Ono, N.; Kaji, A. OH
! R Synthesis 1986, 693.
O2N C(+)
" The resonance features which have been exploited:
O O
! Nef Reaction: (+)
HO – X: X: X:
(–)N !! N !! N
R H3O + R X = OR, NR2
R (+) H R H R (–) H
NO2 O Pinnick,
Org. Reactions 1990, 38, 655 O2N C(+) O2N C(–)
D. A. Evans Charge Affinity Patterns & the Nitro Functional Group Chem 206

Other Nonalternate Behavior of –NO2 FG (–) (–)

–
Representative examples: O2N C C
H !!

O CH2R –O CHR –O CH2

base base Bn
+N +N +N –O Ph
O Ph PhCH2Br O Ph
–O –O H –O H 2 LDA
+N +N +N
–O –O
–O
40% yield
base
Bn
–O CH2R –O CH2
CO2Et –O CO2Et PhCH2Br
O CO2Et
N O 2 LDA
nitronate dianion +N nitronate dianion +N +N
!!
–O H +N
–O – –O –O
–O
Seebach et. al. Tetrahedron Lett. 1977, 1161-1164 80% yield
2(–) (–) (–)
O2N C C O2N C C
Reactivity Patterns –NO2 As a Leaving Group
Review: Tamura et. al. Synthesis 1991, 423-434.
Seebach et. al. Tetrahedron Lett. 1977, 1161-1164 "Nitroaliphatic Compounds–Ideal Intermediates in Organic
Synthesis"' Seebach, D. etal, Chimia, 1979, 33, 1-18

2(–) Representative examples: O2N C(+)

Representative examples: O2N C C

O R R
Nu(–)
O CH2Me +N CH Nu CH + NO2–
O CH2Me 2 BuLi –O Et PhCH2Br
+N +N +N –O R R
!!

–O –O – –O Bn
51% yield
SnCl4
Ph
74%

O Ph –O Ph O Ph NO2 Ph
2 BuLi Et–I
+N +N !!
+N
–O –O – –O Et SiMe3
NO2
80% yield
Me Me
Me TiCl4 Me
SPh 65% SPh
D. A. Evans The Nitro Function as a Leaving Group Chem 206

–NO2 As a Leaving Group O O

CO2Et
Representative examples: O2N C (+) N N CO2Et
(+)
+ (+)
O2N C C
NO2
O R NO2
R
Nu(–)
+N CH Nu CH + NO2–
–O R R H3O+

O CO2Et O CO2Et
(+) R2NH
SnCl4 (+)
Ph
O2N C C
–NO2–
74% NO2

NO2 Ph (+) (+)

McMurry etal. Chem Comm. 1971 488-489. O2N C C
NO2 SiMe3

Me Me
Me TiCl4 Me O O O
SPh 65% SPh R3N R2NH

(+) (–) CO2Et CO2Et CO2Et

NO2 N(CH2)5 NO2 NO2
(–)
Pd(PPh3)3 O2N C C
Bakuzis etal. Tetrahedron Lett. 1978 2371.
(+)
N
H
CH(CO2Me)2 CO2Et (+) NO
2
Pd(PPh3)3 + (+)
NaCH(CO2Me)2
MeO NO2 MeO CO2Et

SO2Ph DBU –NO2–

(+) (+)
NaO2SPh
Pd(PPh3)3 O2N C C
Danishefsky etal. JACS 1978, 100, 2918.
MeO CO2Et
D. A. Evans Nonalternate Reactivity Patterns of Diazo Functional Groups Chem 206

The Diazo Functional Group Acid Catalyzed Reactions of Diazo Compounds

H H H Review: Smith, Tet. 1981 2407
– + – +
+C N N C N N –C N N
R R R O O
H+
CH3 CH3 N2 C R
! Both (+) and (–) reactivity patterns suggested by resonance structures H3C H3C
(–)
N N
N N
! Rxns with acids: Diazocarbonyl Diazonium
H +H H
+ X–
H X –C N N H C N N H C X N N Common acids include BF3•OEt2, HBF4, TFA, etc.
R R R
Mechanism of activation is unclear for both Lewis and protic acids;
activation may occur by protonation on C or O

N2 C R N2 C R
(–) (+)
! Initiating reactivity is (–); subsequent reactivity is (+) Acid-Catalyzed Reactions
! Ring expansion reactions: O O O N2 C R
N2 (–)
CH2N2
TFA, -20°C O
EtOH
(96%)

O N2 C R
+ HO
N2 C R HO CH2–N2 N2 C R Mander, Chem. Comm. 1971 773 (+)
(–) (+) Tet., 1991 134

"Having become familiar with the peculiarities of diazoketone chemistry while

preparing [other compounds] (and, I might add, inured to handling uncomfortably
large quantites of diazomethane), it occurred to us that we might be able to
Restriction: Starting ketone must be more reactive than product ketone substitute a diazo group for bromine."
Lewis Mander
(–) O
! Precursors to Carbenes: Cl3COCO OCOCCl3
N2 C N2
(+) empty (+) TFA O
H + H
– ! -25°C, 2 min
C N N C: H Gibberrellic Acid
R –N N R C filled (–) (82%)
R OMe O Mander, JACS 1980 6626
H E –E,G H
(+, –) C C:
R G R
D. A. Evans Nonalternate Reactivity Patterns of Diazo Functional Groups Chem 206

Diazo–Carbonyl Insertations:
Web Problem 150. Provide a concise mechanism for the indicated reaction in the space
below. Key descriptor for answer, "Carbene".
O
N2
O N2
OO BF3•OEt2 N2 –N2 O
CF3COOH
OBF3 O
R A C (–) R
R
A C (+) O O
MeO
Mander, Aust. J. Chem. 1979 1975
Wolff Rearrangements
The Answer
Web Problem 332. Stoltz and co-workers recently reported the interesting
N2 N2
rearrangement illustrated below (JACS 2003, 125, 13624).
O O O
MeO O MeO O
N2 AgOBz, Et3N +H+
95% yield –N2
H Me
Me THF, 45 °
MeO MeO MeO
AgOBz, Et3N –N2 Cope Rearr A C (–) A C (+)
O
O
C
H H Me
Wolff Rearr O O
Me H H
H [1,2]
H O equivalent
H to:
Diazo-mediated Ring Construction: MeO
MeO MeO
Evans, Mitch, JACS 1980, 102, 5956
Morphine alkaloid
Ph skeleton
1. HClO4
CH2 30% yield [1,2]
N 2. CH2N2
Me N
Me
O O O
A C (–) HClO4 –N2
A C (+) MeO O O
Ph Me
N Me –OTFA
CH2N2
H
N H
Me CH2–N2
H

A
D. A. Evans Nonalternate Reactivity Patterns of Diazo Functional Groups Chem 206

Dipolar Cycloadditions: Carbonyl Ylides Web Problem 109. The following is a general reaction for the formation of pyrroles.
In this condensation, any of the three reaction constituents may be widely varied.
Me Me
OAc Me (Ono, "The Nitro Group in Organic Synthesis" Wiley-VCH, 2001. Chapter 10, pp 326-
Me Me AcO
H AcO Me 328). Siince it is not clear what the "inorganic" reaction product is, provide us with
H H anything that is mechanistically sound using the reagents illustrated. Key descriptor
H (86%) H
O H for answer, "Nitro".
N2 Rh2(OAc)4 H H O
O O O Me Ph
CO2Et O
H NO2
O CO2Et Ph NH3
H H CO2Et Me Me
O O Me
N
H
Dauben, JOC 1993 7635 Tigilane Skeleton
In the space below provide a plausible mechanism for this transformation.

O
O
Me O OM O Me Ph
+NH3 Me Ph
N O MeO2C O O O–
MeO2C Me
N N+
N Me O –H2O Me
O N2 OMe O Me Me Me NH2
(93%) O2N O–
Rh2(pfb)4 H NH2 +
H
N A C C (+)
Bz
N tautomerization
N
Padwa, JOC 1995 2704 Bz
Bz
Lysergic Acid Skeleton O
O O
Me Ph
Me Ph Me Ph
H
O–
O–
O– Me N N+
O O O Me N N+ Me
O N NH2
H O– O–
N CO2Me H OH A C (+)
Me N N
Et N O
2

N O Et
Rh2(OAc)4 O
N O O
(95%) Me Ph Me Ph
O Et Me CO2Me
H O– H O–
Padwa, JOC 1995 6258 N O N N
Vindoline Skeleton
Me Me OH
Me CO2Me +N OH N
H H

(+) (+)
Overall reactivity pattern: A C C