Lecture 09 & 10
SN-1, E-1 (Monomolecular)
SN-2, E-2 (Bimolecular)
SE and SN on Aromatic
Radical Substitution
Addition on Not Activated Multiple
Bond
Carbocation
Carbocation is ion formed via heterolytic cleavage of
covalent (sigma) bond especially in alkylhalogenide
(R-X) compounds
Formation of Carbocation is reaction rate determining
step
Change of hybridization: from sp3 (tetrahedron) to
sp2 (planar): needs a lot of energy
Unstable and reactive
Planar geometry (SP2 hybridization) enables
nucleophilic attack from both side (top and bottom)
SN-1 Reaction
Reaction rate
determining Step
Fast
Fast
Geometry of Alkylhalogenide
Carbocation
Carbocation
Reactivity of Alkylhalogenide
The reactivity of halo compounds in biological
systems can be predicted to a significant extent on
the basis of their relevant chemical properties such
as alkylating potential and susceptibility to hydrolysis.
Bromo compounds are expected to be more reactive
than chloro compounds; SN1 and SN2
characteristics will determine the nature and the
extent of reactivity towards nucleophiles
Steric factors may also play a part in some cases
David J. Snodin, Genotoxic Impurities: From Structural Alerts to Qualification
Organic Process Research & Development 2010, 14, 960976,
Toxicity of Alkylhalogenide
TD = Tumorigenic Dose
nda = no data available
NP = No Positive Test
Carboanion
A carboanion is an anion in which carbon has an
unshared pair of electrons and bears a negative
charge usually with three substituents for a total of
eight valence electrons.
This ion has a trigonal pyramidal geometry
Formally, it is the conjugate base of a carbon acid.
A reactive intermediate and is encountered in organic
chemistry for instance in the E1cB elimination
reaction and in organometallic chemistry for instance
a Grignard reaction or in alkyl lithium chemistry
Carboanion
CH-Acidic Compounds
A series of CH-acidic compounds such aldehyd, keton,
carboxylic acid, and ester compounds (compounds with
a hydrogen in -position to carbonyl group, as well
as cyanide and acetylene) have the ability to release hydrogen (dissociation) to form Carboanion
E1cB Reaction
(Monomolecular)
Fast
Carbanion
Conjugated Base (cB)
Leaving Group
The cleavage of C-H bond occurs prior the C-Y bond cleavage
pKa
Substance
pKa
Methane
50
Malononitril
11.2
Ammonia
36
Piperidiniumion
11.1
Triphenylmethane
33
Ethyl acetate
10.8
Acetylene
26
Cyanoacetic acid-ethylester
10.5
Acetonitrile
25
Nitromethan
10.2
24
Phenol
10
Acetone
20
Cyanide
9,3
Ethanol
18
Ammonium ion
9.3
Methanol
16
Acetyl acetone
9.0
Water
15.7
Malon aldehyd
5.0
12.9
Acetic acid
4.8
Radical
Radical are atoms or molecule with one or more
unpaired electrons
They are formed in a homolytic cleavage of a Bond:
Radical
Polar solvent on the contrary promotes
the heterolytic bond cleavage
(solvatation of formed ions)
Production of Radical
Photochemical cleavage, Photolysis:
Irradiation with Light which is absorbed by the
compound. Ex. UV radiation or sun light
Production of Radical
Thermal cleavage, Thermolysis:
Compounds which is easy to be cleaved at low temperature
(<150 C):
Radical Starter
Initiator of radical-reaction
Activation at 80-100 C
Benzoylperoxide
Sandmeyer Reaction
Stability of Radicals I
Alkyl Radical
General
Formation Reaction
Stability order
Triphenylmethyl radical
The reason for the stability is however steric
shielding of radical function, not dimerization
to hexaphenylethane
Carbene
Carbenes are neutral species containing a
carbon atom with only six valence electrons:
two in each bond and two nonbonding
electrons
Carbenes are extremely reactive species.
Application in the synthesis of alcohols,
cyclopropanes, insertion into CH bonds
Carbene
Clayden, J. Et al., Organic Chemistry, Oxford University
Press, New York, 2001, Chapter 40, page 1053-1077
Stable Carbene
Some very few examples show that certain
carbenes are stable compounds.
An X-ray crystal structure shows the bond
angle at the carbene carbon to be 102
Formation of Carbene
Carbenes from diazo compounds
Carbenes from tosylhydrazones
Carbene formation by elimination
Nitrenes
Nitrenes are the nitrogen analogues of carbenes
Nitrenes have two bonds fewer than a normal amine
and has two lone pairs making six electrons in all.
Nitrenes
Nitrenes are also reactive and electrophilic, and undergo
Wolff-style to give an isocyanate.
The substituent R migrates from carbon to the
electrondeficient nitrogen atom of the nitrene to form
isocyanates.
Isocyanates are in turn unstable to hydrolysis: attack by
water on the carbonyl group gives a carbamic acid which
decomposes to an amine.
SN-1 Reaction
Only the Halogen alkane, but not the
Nucleophil (here: H2O), takes part in the
reaction rate-determining step
1. Step: Dissociation to planar
Carbenium-Ion (Carbocation)
2. Step: nucleophilic Attack (here:
Formation of Alkyloxonium-Ions)
3. Step: Deprotonation
SN-1 Reaction
Reaction rate
determining Step
Fast
Fast
Activation
Energy, Ea
Reaction Coordinate
Stability of Carbocations
SN-2 Reaction
Transition State
Activation
Energy
Ea
Reaction Coordinate
Influence of Nucleophilicity on
the SN-2 Reaction
Increasing of base properties:
Slow
The cleavage of C-Y bond occurs prior the C-H bond cleavage
E1: Only one reaction partner determines the reaction rate
E1cB Reaction
(Monomolecular)
Fast
Carbanion
Conjugated Base (cB)
Leaving Group
The cleavage of C-H bond occurs prior the C-Y bond cleavage
SN vs E
Slow
Saytzev Product
Saytzev-Rule:
In Elimination reactions the -Proton will be
preferentially eliminated from the carbon
atom, which binds less hydrogen.
High substituted Alkene will be
produced!
Monomolecular Elimination gives mainly
Saytzev-Product.
The Saytzev-Product is thermodynamically
more stable
Hofmann Product
In Hofmann elimination, alkene with less number of alkyl group
on double bond will be produced.
Less substituted alkene will be produced
e.g. Hofmann degradation
E2 mechanism: degradation of quarterner Ammonium Salt
1,1-(,)-Elimination
In the case of 1,1-elimination, Carbene or Nitrene
will be produced. It is a short-life very reactive
intermediate
Reagent
Solvent
SN-1
SN-2
E-1
E-2
+
-
+
0
steric unhindered
++
steric hindered
++
++
Miscellaneous
Temperature
Stereochemistry of E2
Ingold-Rule: Bimolecular Eliminations (E2)
will smoothly run, if the Substituents to be
eliminated stand in staggered conformation
(anti-Elimination)
Stereochemistry of E2
Ingold-Rule for Cyclohexane:
Bimolecular Eliminations (E2) in
Cyclohexanes will only smoothly run, if
both Substituents to be eliminated
stand in the axial (a) position. If these
Substituents stand in the equatorial (e)
position (e,e-conformation), the Ring
can however easily turn into a,aconformation
Substitution on Aromatic
Electrophilic Substitution (SE)
Nucleophilic Substitution (SN)
What is an Aromatic ?
Hckel Rule:
Full conjugated, planar cyclopolyene
with (4n+2) -electrons, shows special
stabilities
Aromaticity
Aromaticity is special case of conjugation in olefine.
Conjugated systems are compounds with -bonds
(double bonds) in which each -bonds is separated
through -bond (single bond). In this case, the
interaction of -orbitals over -bond is possible
(delocalization), which leads to reducing of total
energy of molecule.
Electronic Transition
Energy
Anti Bonding
MO
Bonding MO
MO
Ikatan
Colorless Compound
Absorbance
Absorbance
Retinol
Ergocalciferol
Endabsorption
211
265
325
350
300
250
Wave Length
Wavelength
200
(nm)
Colorful Compound
(-Carotene)
Absorbance
Absorbance
Absorbed
Reflected (Vis.
Perception)
0.8
0.6
0.4
0.2
300
400
Wavelength
500
nm
Colorful Compound
(-Carotene)
Absorbance
Absorbance
Absorbed
Reflected (Vis.
Perception)
0.8
0.6
0.4
0.2
300
400
Wavelength
500
nm
Aromaticity
The reducing of energy will be further more
favourable under special structural requirements
(aromatic system).
Hckel-Rule:
It should be a cyclic conjugated system, conjugated
-electrons should form a ring (It is the -electrons,
not the atoms)
The number of -electrons should follow the formula
"4n + 2" in which n = 0, 1, 2 ...
The whole aromatic system should be planar
Electrophilic Substitution
High electron density in aromatic
systems
The attacking agent is a positives ion
(cation) or a positively charged dipol
The leaving group must be cleaved
without electron pair. The most
available leaving group in the aromatic
electrophilic substitution is proton
(3) Re-aromatization
Stabilization of very reactive Intermediate,
either cleavage of Y or H
Aromatic system will be formed again
A fast reaction step
I and M Effects
The activating groups:
Alkyl
-OH -NH2 -NHR -NR2
-O-
Effects
+I
+M -I
+M; +I
-M;
-I
+M -I
-I
Nitration
Aromatic Hydrocarbon can be easily
nitrated
The substitution with nitro group can be
carried out using different reagent
Aromatic nitro compounds are
important products in organic chemistry
since they can be reduced to amines
Reaction Mechanism
Sulfonation
The Electrophilic agent: SO3, either free or bound to a
carrier
Possibilities: Oleum (SO3 in H2SO4)
Reaction Mechanism
Halogenation
1. Chlor and Brom:
ArH + Br2
ArBr + HBr
Halogenation
For active aromatics (ex. phenole,
aniline) no catalysator is needed
Aniline : always multi substitution
Phenol : Stopping the reaction after first
substitution is possible
Another Reagents: HOCl, HOBr, NChloramide, N-Bromamide (NBS),
always in the present of acid
Preparation of Agent
If Lewis acid is used as catalysator,
Br2/Cl2 is the attacking species which
was polarized by the catalyst:
Preparation of Agent
Friedel-Crafts-Acylation
The most important method for the
production of Arylketones
Reagents: Acid halogenide, Anhydride,
Ketene, Carboxylic acid
No rearrangement reaction
Due to deactivating Group, no multi
substitution
Preparation of Agent:
Reaction Mechanism:
In this reaction, activated aromatic, in the present of N,Ndisubstituted Formamide and Phosphoroxychloride, is
converted to an aromatic aldehyde
Nucleophilic aromatic
Substitution
Nucleophilic Substitutions in aromatic systems
are possible under following conditions:
1. Aromatic ring is activated by electron
withdrawing Group located in ortho or para
position to leaving group
2. Reactions are catalyzed by very strong
Base and undergo via Arin-Intermediate
4. Reactions, in which nitrogen of a
diazonium salt is substituted by a Nucleophile
Reaction Mechanism
Tschitschibabin Reaction
Schiemann Reaction
Reaction Mechanism:
Preparation:
Diazonium salt are normaly produced (nitrite and HCl). A cold aqueous
solution of NaBF4 or HBF4 or NH4BF4 are then added to the salt
The best way to produce aromatic fluoride
Radical Substitution
Radical
Radical are atoms or molecule with one or more
unpaired electrons
They are formed in a homolytic cleavage of a Bond:
Radical
Polar solvent on the contrary promotes
the heterolytic bond cleavage
(solvatation of formed ions)
Production of Radical
Photochemical cleavage, Photolysis:
Irradiation with Light which is absorbed by the
compound. Ex. UV radiation or sun light
Production of Radical
Thermal cleavage, Thermolysis:
Compounds which is easy to be cleaved at low temperature
(<150 C):
Radical Starter
Initiator of radical-reaction
Activation at 80-100 C
Benzoylperoxide
Sandmeyer Reaction
Stability of Radicals I
Triphenylmethyl radical
The reason for the stability is however steric
shielding of radical function, not dimerization
to hexaphenylethane
Reactions of Radical
Radical Substitution SR
Chain Reaction:
-Initiation Reaction:
-Propagation Reaction:
(Abstraction-Addition Mechanism)
Abstraction of one H atom
Addition of a Substituent
-Termination Reaction:
Recombination of two Radicals
SR Halogenation I
Differences in the reactivity of Halogen-Radicals
Ground: difference in the enthalpie of chain reactions
Fluor: both steps (Abstraction, Addition) strongly
exotherm (= -389 kJ/mol). consequence: Reaction start
without activation; often: Fragmentation of Molecule
(explosive-like Reaction)
Chlor: both steps are exotherm ( = -100 kJ/mol) Poor
selective; often multi chlorination.
Ex.: Chlorination of methan. Only if Methan-excess =>
CH3Cl as main product. Normally, because of the decrease
in the C-H bond strength (CH2Cl2 => CHCl3 => CCl4), the
next substitution will be easier
SR Halogenation
Brom: only the second step (addition) is
exotherm ( = -25 kJ/mol). More selective on
going: (prim. <) sec. < tert. < Allyl < Benzyl
With N-Brom-Succinimid (NBS) as Brom
supplier (Wohl-Ziegler-Reaktion), selective
Substitution in Allyl position is possible
SR Halogenation
Rule for aromatic hyrocarbon:
Ex. Of a Chlorination
Ex. Of chain
reactions (next
products are
possible)
2. Chain propagation:
Polymerisation: by products
3. Chain stop:
Through Recombination of Radicals or/and
Disproportionation
Chain growth
Disproportionation
In the absence of other species with which a
radical can react, their life is terminated
largely by dimerisation or disproportionation:
NO 2
N
H
H3C
H
O
CH
3
O
O CH
H3C
Disproportionation
H
H3C
H3C
H
CH3
O
O H
O
NO2
H3C
CH3
H3C
CH3
O
O
NO
CH3
Planar
Properties of Alkene
-Orbital posses richer energy than -Orbital and
hence less stable
Tendency: -Bonds formation
-Bond is easily polarizable
-Orbital is easily accessible
Negative partial charge between C-Atoms (LewisBasicity)
C-atoms are shielded from nucleophilic attack
Increasing of reactivity due to substituents with +Mand +I-effects
Cl-CH=CH2 < H2C=CH2 < R-CH=CH < R-CH=CH-R
Type of Reactions
Nucleophilic Addition AN
Only if DB due to electron attracting
substituents is for AN activated or with strong
Nucleophile
Radical Addition AR
Gas phase or non polar solvents
Light influence
high Temperature
Electrophilic Addition AE
polar solvents
low Temperature
Cycloaddition
Nucleophilic Addition
Radical Addition
Electrophilic Addition
Halogenation
Regioselectivity
Chloronation
Of Propene
Hydrohalogenation
Regiospecific
Regioselective
Markovnikov Rule
In the case of electrophilic addition of hydrohalogenic
acid on asymmetric substituted alkene, the hydrogen
atom will be bound to carbon atom which already
binds the most hydrogen atoms
but:
Anti Markovnikov
Product
(under influences of
Light or Peroxides)
Stereo specificity
2
1
Racemic 2,3-Dibromobutane
Stereo specificity
Hyroboronation
Diboran
Stereoselectivity of Hydroboronation
Epoxidation, trans-Hydroxylation
Cis-Hydroxylation
Advantages:
Selective, high yield
Disadvantages:
Toxic, volatile, expensive
With KMnO4:
Less selective, over
oxidation
Catalytic Hydrogenation
1,3-Dipole addition
From diazocompound, azide,
nitriloxide, ozon to different
heterocyclic compounds
endo-Rule of Diels-Alder-Reaction
exo-Product
Thermodinamically more stable
endo-Product,
Kinetic reaction control
is needed