Structure and Reactivity: Prerequired Knowledge

!!! The concepts presented in this summary are required for lecture and examination!!!

1. Important Principles in Organic Chemistry

In general, structures which can stabilize electrons are favored.

1.1 Electronegativity and "Octet" Rule

The electronegativity describes the ability of atoms to attract electrons. The nearest to octet (closed shell)
the strongest the electronegativity. The electronegativity is weaker for larger atoms.
On chemical structures and during chemical reactions, the electrons go to the more
electronegative element.

example:acidity Me3CH Me2NH MeOH HF

pKa 53 > 36 > 16 > 3.2 The conjugate base is more stable
for more electronegative atoms!
electronegativity 2.5 3.0 3.4 4.0

Indirect effect: inductive effect

O O
Transfer of the influence of electronegative
F3C OH Me OH atoms through sigma bonds.
pKa 0.25 < 4.76

Effect of hybridization:
electron in orbitals with more s characters are more stabilized (more probability next to the nucleus)

example: acidity H H
Me3CH H H
H H
pKa 53 50 24
2
Hybridization SP3 SP SP

1.2 Stabilization through Delocalization: delocalized charges (electrons) are more stable

1.2.1 Delocalization onto 1 atom: large atoms are more able to stabilize charges (= polarizable)

HF HCl HBr HI
examples 1) acidity:
pKa 3.2 > -8 > -9 > -10
electronegativity 4.0 3.2 3.0 2.7

Delocalization is more important than electronegativity in this case!

2) leaving group ability in substitution reaction

R F < R Cl < R Br < R I

1.2.2 Delocalization on two atoms: the chemical bond
Important for organic chemistry:
1) bond is stronger than bond for C=C bond, but not for C=N and C=O
2) Delocalization is better between atoms of the same size (orbital overlap)
3) For strong polar bonds: ionic part can become important and compensate the
weaker covalent bonds: prediction is more difficult
examples:
size effects
bond: C-H C-C C-N C-O C-F C-F C-Cl C-I
energy in Kcal 99 83 70 86 117 117 81 52

-bonds C=C C=N C=O C=O C=S

energy in Kcal 64 77 92 92 49

Important practical consequence: in organic chemistry, losing C=C and making C=O is often favorable!

1.2.3 Delocalization on more than two atoms: resonance structures

Resonance structure = obtained by moving electron without changing position or connectivity of atoms

Resonance structures are essential to understand structure and reactivity in organic chemistry!

good resonance structure octet rule for 1.raw elements, no charges, charges on electronegative
atoms, more bonds, "better bonds", aromatic structures

stabilization through resonance (delocalization) is maximal if the resonance structures are identical

"reality" = weighted sums of the resonance structures

key examples:

O O O
O O
R R R
R R R R
best structure
best structure
reactivity of carbonyls conjugate reactivity

O O
O O
R O R O
R R
identical structures
-acidity of carbonyls and reactivity of enolates
acidity of carboxylic acid

O N N
O
N N N
N
R O R O
identical structures R R R R
best structure

structure of nitro and diazo compounds

 R R R R
O O

Stabilization of carbocations by neighbouring heteroatoms or bonds

Limitation of resonance structure: descripition of aromaticity

aromatic stabilization: cyclic conjugate -system with 4n+2 electrons (Hückel's rule)

identical structure identical structure?

destabilized!
stabilized

Higher level model is needed: orbital theory

Benzene Cyclobutadiene

Benzene: all electrons stabilized

in bonding orbitals
Cyclobutadiene: 2 electrons in
non-bonding orbitals, no
stabilization
LUMO

LUMO = Lowest Unoccupied

HOMO Molecule Orbital

HOMO = Highest Occupied

Molecule Orbital

In organic chemistry, many observations can be explained by FMO (Frontier Molecular Orbital, LUMO and HOMO)
considerations. This model is more powerful and precise than resonance/Lewis structure considerations, but need
more time to apply.

Test for part 1

Me
O O O O N O

Me OR Me NR2 Me Me Me H Me Me Me Cl

Classify this carbonyl compounds in order of increasing reactivity towards nucleophile addition.
2. Important Nucleophiles and Electrophiles in Bachelor Level Organic Chemistry
2.1 Nucleophiles
- - - - -
ROH RNH2 RSH PR3 R2N NH2
neutral
alcohols amines thiols phosphines hydrazines
Heteroatoms

RO RNH RS X charged
alcoholates amides thiolates halogen anions

- -
Hydrides (H-) sources NaBH4 LiAlH4
borohydrides aluminium hydrides
-
-
- - OM OM O
RMgBr RLi - M = Na, K, Li
R R - X
C Nucleophiles Grignard alkyl lithium enolates stabilized enolates
- -
NR2 ED
-
ED -
ED = Electron-donating group
1
CN - -
R
enamines cyanide electron-rich aromatic
compounds and alkenes

2.2 Electrophiles
+
O NR R R
H N EWG
RX EWG +
R + X +
M R X R + X + +

proton alkyl halogenide carbonyls imines iminiums electron-poor aromatic

metals compounds and alkenes
EWG = Electron-withdrawing group

2.3 Hard and Soft classification of Nucleophiles (Lewis Bases) and Electrophiles (Lewis Acids)

Hard charged, localized electrons, highly electronegative/positive, reaction under charge control
typical hard electrophiles: H+, Mg2+, RCl, ROTf
typical hard nucleophiles: RMgBr, RLi, RO-, RNH-, F-, O atom of enolates

Soft less charged, delocalized electrons, reaction under orbital (HOMO-LUMO) control
typical soft electrophiles: Pd2+, carbonyls, electron-poor double bonds and aromatic compounds
typical soft nucleophiles: C atom of enolates, stabilized enolates, electron-rich double bonds and
aromatic compounds, I-, RNH2, PR3

Principle: Hard-Hard and Soft-Soft interactions are favored!

Competition basicity-nucleophilicity: especially hard nucleophiles are usually also strong bases,
because proton is hard (hard-hard interaction)
3. Important Classical Reactions in Bachelor Organic Chemistry
3.1 Substitution Reactions

R1 R1 R1 R1
SN1 + -X + Nu
R2 3 R2 3 R2 racemization
R
X R2 R3 R
Nu Nu
R3

R1 R1
+ R1
SN2 2
R 3 + Nu Nu X -X
X R2 inversion
R R2 R3 Nu
R3

- El El
SEAr + El -H
H better for R electron-donating
R R in ortho-para
R

X Nu El
SNAr + Nu -X
X better for R electron-withdrawing
in ortho-para
R R
R

3.2 Elimination Reactions

H X -X H base
E1
+

base
base
E2 H X H
- +
X

base X -X
E1cb H X
-

3.3 Addition to double bonds

In principle: all mechanisms for elimination are possible in the reverse sense!

Special case: dibromination

Br2 Br Br

Br Br
bromonium ion
3.4 Chemistry of Carbonyls
3.4.1 Nucleophile Addition

Grignard
+ -
O - +
BrMgO R2 HO R2
2
H2O
R MgBr
R + R1 R R1 R R1

Hydride Reduction
Na BH3
-
O -
O H HO H
H2O
NaBH4 1
R + R1 R R R R1

O -

R + OR1 NaBH4 no reaction

Li AlH3
O - - O OH
O H LiAlH4
LiAlH4 Li R1OAlH3 H
R + OR1 R OR1 R + H then H2O R
H

Alcohols: acetal formation under acidic catalysis

H H
O O H R2
+H + R2OH HO O R2 H O O R 2 - H2O O
R + R1 R R1 2 1
-H - R OH R R R R1 + H2O R + R1
2 O
R H
- R2OH + R2OH
Equilibrium is on the side of the ketone
It is necessary to remove water to drive reaction! H
2 2 +H R2 O O R2
R O O R
R R1
R R1 -H
Acetal

Alcohols: ester formation under acidic catalysis

O H H R2 H
O 2 O O
+H + R OH HO O R2 HO O - H2O -H
R + OH H
R OH - R2OH R OH R O + H2O R OR2 R OR2
-H +H
O H
R2 H

Equilibrium is nearly 1:1

Use excess alcohol to drive reaction
 Ester Hydrolysis

O + OH O O O R2 - OR2 O O
+ OH
R + OR2 R OR2 R OH R OH -H2O R O
- OH + OR2
O
H
Stability of carboxylate completely on the side of product!

Amine addition and imine formation

H H H R2
O + R2NH2 O O N R2 H O N R2 - H2O N

R + 1
R - R2NH2 R R 1
R R 1
R R 1
+ H2O R R1

N H
R2 H
Water removal necessary for ketones, reaction easier with aldehyde

3.4.2 Enolate chemistry

Enolate alkylation R2
O
hard electrophile O- Alkylation
+ R
R2OTf R1
-
O O O
- base
H -
R R R
R1 R1 R1
+
soft nucleophile hard nucleophile R2I O
soft electrophile R2
R C-Alkylation
1
R
Aldol Reaction

O O O O H O HO H O
+
+H base
R R2 H R R2 R R2 R R2
1 1 1
or acid 1
R R R R
- H2O
Aldol product
Aldol Condensation

Claisen Condensation

O O O O R2 O O
+
R R2 OR3 R OR3 R R2
R1 R1 R1

Other related reactions: Knoevenagel condensation, Perkin condensation, Dieckmann condensation.

Wittig Olefination
O PPh3 O PPh3
B A
R1 R R1
R R1 R
R not
O cis-olefin stabilizing
+ A
1
R H

1) PPh3 B O PPh3 R
RX R PPh3 O PPh3 B
2) base
R1 R R1 R R1 R stabilizing
trans-olefin anion
betaine intermediates

For non-stabilized ylides (A), formation of the cis betaine is favored and irreversible, leading to cis olefin. For
stabilized ylides (B), an equilibrium lead to formation of the more stable trans betaine and finally to trans olefin.

3.5 Oxidation Reactions

Chrom(VI)
IV OH
R OH CrO3 R O VI OH R O + H2O R OH
Cr Cr
H2SO4
H O O HO O H - H2O H OH
Jones Reagents
CrO3

Second oxidation step possible only

in presence of water! IV OH R O R O VI OH
Cr Cr
HO
HO O OH H O O

In practice also often used PDC (pyridinium dichromate), PCC (pyridinium chlorochromate)

Moffat-Swern

R OH DMSO, (COCl)2 R O
base
H
Mechanism
O
+
Cl
O O O Cl
S Cl S O S CO2 CO
Me Me Cl Me Me Me Me
O Cl
Cl R O
H

- HCl
R R

O H base O H
S R O
Me Me S S
Me Me Me
H

In practice, there are many more methods!

Dihydroxylation, Ozonolysis and Epoxidation

mCPBA O
Epoxidation mCPBA = meta-chloroperbenzoic acid

OsO4 HO OH
Dihydroxylation

R 1) O3 O O
Ozonolysis
R 2) Me2S R H R H

These reactions will be rediscussed in more details in the lecture