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OC II (FS 2019) Review of Key Concepts Prof. J. W. Bode
1
Review of Key Concepts
1 Arrow Pushing Arrow pushing is a technique used to describe the progression of a mechanism. Arrows represent the movement of electrons during bond formation and/or cleavage. A full arrow represents the movement of an electron pair (e.g. heterolytic cleavage), whereas a half arrow represents the movement of an unpaired electron (e.g. homolytic cleavage). Full arrows usually start from a lone or bonding electron pair and point either to another atom or to the middle of another bond. Half arrows typically start from a bonding electron pair or an unpaired electron (radical) and point to another atom or combine with another unpaired electron to form a new bond. Since electrons are negatively charged their movement represents a charge transfer. Consequently, the atom or functional group, where electrons move to, becomes more negatively charged, while the atom or functional group, where electrons originate from, becomes more positively charged. At the same time the octet rule should not be violated. Generally, electron transfers occur from electronegative to electropositive functionalities. In all cases, the formal charge of the system does not change.
2 Functional Groups 2.1 Carbonyl
2.2 Carbonyl Derivatives
2.3 Other Important Functional Groups
A B
Heterolytic Cleavage Homolytic Bond Cleavage
A B
A B
A B
A B
A B
R Cl
O>
R H
O
R R
O
R OR
O
R OH
O> > >
R O
O O
R>
R SR
O> >
R NR2
O
Acyl halide Acid anhydride Aldehyde Ketone Thioester Ester Carboxylicacid
Amide
less electrophilic
Carbonyl compounds
Other carbonyl derivatives
RO OR
O
RO NR2
O
Carbonate CarbamateR R
NR
Imine
Other important groups
R RR
O
R R'
RO OR
Acetal
Alcohol
Me N
Alkene Alkyne Epoxide NitrileMe N C
isonitrileR
OO
H
Peroxide
R OH
R NH2
Ether
R OR
Primary Amine
R NHR
Secondaryamine
R NR2
Tertiaryamine
R
OR
Enolate
R
NR2R
Enamine
R
OHR
Enol
R NO2
Nitro
Other carbonyl derivatives
RO OR
O
RO NR2
O
Carbonate CarbamateR R
NR
Imine
Other important groups
R RR
O
R R'
RO OR
Acetal
Alcohol
Me N
Alkene Alkyne Epoxide NitrileMe N C
isonitrileR
OO
H
Peroxide
R OH
R NH2
Ether
R OR
Primary Amine
R NHR
Secondaryamine
R NR2
Tertiaryamine
R
OR
Enolate
R
NR2R
Enamine
R
OHR
Enol
R NO2
Nitro
Carboxylic Acid
Isonitrile
Types of Arrows
electron pair transfer
single electron transfer
equilibrium
resonance
OC II (FS 2019) Review of Key Concepts Prof. J. W. Bode
2
3 Oxidation and Reduction of Functional Groups Oxidation is a process in which a chemical species loses electrons. Reduction is a process in which a chemical species gains electrons.
4 Electronegativity
4.1 Electronegativity (χ) is the tendency of an atom to attract electrons e.g. in a covalent bond.
The most common scale to compare the electronegativity of atoms and functional groups in organic chemistry is the Pauling scale. The electronegativity values are dimensionless and range from 0.7 – 3.98.
H3C H H3C OH H2C O C OHO
HC OO
most reduced most oxidized
R
XR
Other functional groups with equivalent oxidation states
R
alkyl halide
NR N CR O
N CR N R
CO
NH
RR'
SRR
methane methanol formaldehyde formic acid carbon dioxide
alkene
thiol/thioether
terminal alkyneamide
nitrile isocyanate
ROR'
OR'OR'
orthoester
O CR Ncyanate
carbodiimide
C SScarbon disulfide
-IV -II 0 +II +IV
R R
alkane
-II -I +I +III +IV
O N
OR
R
R
carbamate
R OR
O
carboxylic acid/ester
R OR
OR
acetal
ORRalcohol/ether
NH2Ramine
R H
O
aldehyde
N R
Rimine
Li0.98
H2.2
Mg1.31
B2.04
Al1.61
C2.55
Si1.9
N3.04
P2.19
O3.44
S2.58
F3.98
Cl3.16
Br2.96
I2.66
CH3
CH2Cl
CHCl2
CCl3
CF3
CH=CH2
C CH
C N
NH2
NH3
NO2
OH
2.3
2.8
3
3
3.4
3
3
3.3
3.3
3.4
3.8
3.4
3.7
Ph
OC II (FS 2019) Review of Key Concepts Prof. J. W. Bode
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5 Bond Energies Bond energies describe the amount of energy required to cleave a chemical bond. It is important to have a rough idea of these energies in order to know which bonds are more likely to be cleaved or formed during a reaction process.
Bond Bond strength
[kcal/mol] Bond Bond strength [kcal/mol]
C–H 98 N–N 38 C–N 73 N–O 48 C–O 85 C=C 147 C–F 116 C=O 178 C–Cl 81 C=N 147 C–Br 67 P=O 110 C–I 58 S=O 94
6 Effect on Reactivity
The equilibrium between carbonyl compounds and their hydrated forms is described by Keq. The larger Keq, the more the equilibrium is shifted towards the hydrated form.
The acidity of acetic acid (AcOH) and its derivatives (RCH2COOH) increases with increasing electro-negativity of the R substituent.
7 pKa Values In the following table general pKa values are given (acidity in H2O, extrapolated with various methods). For a more comprehensive compilation see:
- Bordwell pKa table (acidity in DMSO): http://www.chem.wisc.edu/areas/reich/pkatable/index.htm - Evans pKa table (acidity in H2O): http://evans.rc.fas.harvard.edu/pdf/evans_pKa_table.pdf
Compound Class pKa
Conjugated Base Example of Base
Alkanes (Csp3)
Alkenes (Csp2)
Hydrides
≈ 50
n-Butyllithium (n-BuLi)
≈ 43
Phenyllithium (PhLi)
≈ 36 H– Sodium hydride (NaH)
Amines ≈ 35
Lithium diisopropylamide (LDA)
Alkynes (Csp) ≈ 25 –
Ketones/Aldehydes ≈ 20
–
Water ≈ 16 OH– Sodium hydroxide (NaOH)
Protonated Amines ≈ 10
Triethylamine (NEt3)
R R
O H2O
R R
HO OH
H3C CH3
O
F3C CF3
O
Keq
0.001
1'200'000
(R)
2.3
3.4
χ
Keq OH
OR
R pKa
H
NO2
CN
2.2
3.4
3.3
4.76
1.7
2.4
χ
RH
H
RNR
R
O
R R
NRR
R
OC II (FS 2019) Review of Key Concepts Prof. J. W. Bode
4
Carboxylic acids ≈ 5
Sodium acetate (NaOAc)
Protonated Alcohols ≈ -2 R–OH – Mineral Acids < 0 X– (X = Cl–, NO3
–, HSO4–…) –
8 Resonance Structures Resonance is a concept that describes the distribution of delocalized electrons in molecules, where the “real” bonding situation cannot be correctly described by one single Lewis formula. In contrast, multiple Lewis formulas, so called resonance structures, are used to describe the same molecule. In fact, the “real” bonding situation is a mixture of all possible resonance structures. Resonance structures are indicated by double-headed resonance arrows (↔), which must not be confused with arrows indicating chemical reactions (→) or equilibriums ( ).
Different resonance structures can be transformed into each other by “moving” electrons, at the same time the nuclear positions remain unchanged. It should be noted that tautomerism is not a form of resonance, as a hydrogen atom is moved during the process.
Generally, delocalization of electrons or positive charges is energetically favorable for a molecule and increases its stability (delocalization energy). As a rule of thumb: the more (reasonable) resonance structures a molecule has, the more energetically stabilized it is.
Resonance structures can be used to explain reactivities by indicating the different polarities within a molecule or a specific functional group. It is important to distinguish between reasonable and unreasonable resonance structures. For example, the carbon atom of a carbonyl group displays electrophilic rather than nucleophilic character (positive charge at carbon atom in the left resonance structure). This can be explained by the fact that carbon is less electronegative than oxygen and therefore the electrons are preferentially located on the oxygen. On the other hand, the resonance structure of an enolate indicates that some electron density is located on the α-carbon (negative charge at the carbon atom in the right resonance structure). This explains why enolates tend to react as nucleophiles in the presence of aldehydes.
OR
O
CH3 CH3
Two possible resonance structures of toluene
O
OMeH
H
O
OMeH
H
Two resonance structures of an enolate indicating that the negative chargeis delocalized over two carbon atoms and one oxgen atom.
O
OMeH
HH
OH
OMeH
H
No Resonance
Chemical equilibrium between two different molecules (no resonance forms), since not only electrons but also a hydrogen atom is moved.
ResonanceKeto-Enol Tautomerism
HH
H
Me
H
HH
H
H
HH
Me
H
HH
H
H
H HH
Me
H
HH
H
H
H HH
Me
H
HH
H
H
H HH
Me
H
HH
H
H
H
Homobenzylic Carbocation
Charge cannot be delocalized: Low stabilization
Benzylic Carbocation
Charge can be delocalized into aromatic system: High stabilization
OC II (FS 2019) Review of Key Concepts Prof. J. W. Bode
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9 Hybridization Hybridization is a chemical concept that describes the fusion of atomic orbitals to form newly hybridized molecular orbitals. Molecular orbitals are often used to describe molecular geometry and atomic bonding properties.
9.1 Construction of Polyene Molecular Orbitals (MOs) Rules:
1. The number of molecular orbitals (MOs) has to be equal to the number of atomic orbitals (AOs). e.g. in the case of ethylene: two 2p atomic orbitals form two molecular orbitals. 2. The molecular orbital with the lowest energy has no nodal plane. 3. The relative energy of the molecular orbitals increases with the number of nodal planes. 4. The molecular orbitals are occupied by max. two electrons, starting from the energetically lowest orbital. Example 1: ethylene
Ph
O
HPh
O
H Ph
O
H
A valid, but unreasonable resonance structure.
Oxygen is more electronegative than carbon. Howeverm, in this resonance structure the oxygen atom exhibits a positive charge, whereas the more eletropositive carbon atom exhibits a negative charge.
A valid and reasonable resonance structure.
The more electronegative oxygen atom has moreelectron density than the more electropositive carbon atom.
O
OMeH
H
O
OMeH
HO
OMe
O
PhH H
HPh
O
H
Nucleophilic attack of an enolate to the electrophilic carbon of an aldehyde
!
!
!
sp hybridization:
sp2 hybridization:
sp3 hybridization:
1s 1p = 2sp
1s 2p = 3 sp2
1s 3p = 4 sp3
i.e.H
180°
i.e.
i.e.
R R
R
120°
R
R RR
109.5°
ELUMO (π*)
HOMO (π)
2p2p
in-phase combinationHOMO lower in energythan carbon p-orbital
out-of-phase combinationLUMO higher in energy
than carbon p-orbitalnodal plane
anti-symmetrical
no nodal planesymmetrical
Ethene CC
OC II (FS 2019) Review of Key Concepts Prof. J. W. Bode
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Example 2: butadiene
10 Stereochemical Terminologies
Stereochemical terminology in organic chemistry can either refer to structure of a molecule or to properties of a physical sample of the molecule.
10.1 Chirality A molecule (or any object) is chiral if it is non-superimposable on its mirror imagine (its enantiomer).
achiral – a molecule or object that is superimposable on its mirror image. chiral – a chiral molecule is non-superimposable on its mirror image. meso – a molecule that is superimposable on its mirror image due to an internal plane of symmetry.
10.2 Diastereomers
Diastereomers are stereoisomers that are not enantiomers. Diastereomers have the same connectivity but differ in their spatial arrangements.
10.2.1 Relative Stereochemistry
The relationship between the configuration of different stereocenters within one molecule is known as relative stereochemistry.
E
HOMO (π2)
π
nodal plane anti-symmetrical
no nodal planesymmetrical
ππ1
π4
π* π*LUMO (π3)
three nodal planes anti-symmetrical
two nodal planessymmetrical
ButadieneEthene Ethene
O Me OH OH Me OHC Me
H
H
Cl
Me
Me
Me
MeMe
Me
OH
OH
achiral(no stereogenic center)
chiral(at least one stereogenic center)
meso(achiral due to symmetry)
OH
OH
OH
OH
trans(chiral)
cis(meso)
OH
OH
O
OMeH3C
OH
CH3
O
OMeH3C
OH
CH3
syn anti
OC II (FS 2019) Review of Key Concepts Prof. J. W. Bode
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10.2.2 Olefin geometry
Olefin isomers are described by cis/trans or (Z)/(E) respectively. Under normal circumstances (at room temperature, without any catalysts or reagents) olefins do not interconvert between geometric isomers.
11 Stereochemistry of Reactions
11.1 Stereospecific Reactions vs. Stereoselective Reactions
In stereospecific reactions, the stereochemistry of the starting material determines the stereochemistry of the product. For a reaction to be stereospecific, the stereochemical transfer must be quantitative. If this is not the case and one enantiomer is preferentially formed over the other during the reaction process, it is a stereoselective reaction.
11.1.1 Inversion
Example: SN2 reactions
11.1.2 Retention
Double inversion = Retention
11.1.3 Stereospecific Reaction
Many reactions of alkenes are stereospecific and yield the products as a single diastereomer.
11.1.4 Diastereoselective Reactions
Endo/exo selectivity e.g. in Diels-Alder reactions
Me
Ph Ph EtO2C
PhMe
Me
EtO2C Ph
(E) (Z) (E) (Z)
Me
IMe
C6H11H
(R)
NaI*
acetone*I
MeC6H11
H
(S)
OTs
Me H
Me H
-OTs-MeH
Me H
AcOHOAc
Me H
Me H
Ph
Ph
CF3CO2ZnCH2I
Ph
Ph
cis
CO2Me
CH2Cl2
CO2MeH
HCO2Me
endo exoMeO2C H
endo TS
H CO2Me
exo TS
0oC
80% 20%
OC II (FS 2019) Review of Key Concepts Prof. J. W. Bode
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12 Other Important Selectivity Terminology
12.1 Regioselectivity
“A regioselective reaction is a reaction, in which one direction of bond making or breaking occurs preferentially over all other possible directions.” (http://www.iupac.org/goldbook/R05243.pdf)
12.2 Chemoselectivity
“Chemoselectivity is the preferential reaction of a chemical reagent/reactant with one of two or more different functional groups.” (http://www.iupac.org/goldbook/C01051.pdf)
13 Most Common Abbreviations (that are used in this class)
Abbreviation Name Structure
9-BBN
9-borabicyclo[3.3.1]nonane
Ac
acetyl
Ar
generic aryl group (rarely argon)
–
Bn
benzyl
Boc
t-butoxycarbonyl
BOM
Benzyloxymethyl
Bz
benzoyl
Cbz (Z)
benzyloxycarbonyl
O
O
Me
MeOMe
BF3.OEt2O
O
Me
MeO
Me
H
O
O
Me
MeO H Me
SnCl4
OCO2Me
Me
MeO
NaBH4O
CO2Me
Me
MeO
NaBH4CeCl3
HOCO2Me
Me
MeO
BH BH
Me
O
O
OMe
Me
Me
O
O
O
O
OC II (FS 2019) Review of Key Concepts Prof. J. W. Bode
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Cp
cyclopentadienyl
Cy
cyclohexyl
Dba dibenzylidene-acetone
DBU
1,8-diazabicyclo[5.4.0]undec-7-ene
DCC
N,N-dicyclohexylcarbodiimide
DHP
3,4-dihydro-2H-pyran
DIBAL diisobutylaluminium hydride
DIPEA,
(Hünig’s base)
N,N-diisopropylethylamine
Fmoc
9-fluorenylmethoxycarbonyl
LAH
lithium aluminum hydride
LiAlH4
LDA
lithium diisopropylamide
m-CPBA
meta-chloroperbenzoic acid
MOM
Methoxymethyl
Ms
Mesyl
NBS
N-bromosuccinimide
PG
generic protecting group
–
TBS
tert-butyldimethylsilyl
O
N
N
NCN
O
Me
MeAl
Me
MeH
NiPriPr
Et
HO
O
N Me
Me
Me
MeLi
OOH
OCl
MeO
SMeO
O
N Br
O
O
SiMe
MeMe
MeMe
OC II (FS 2019) Review of Key Concepts Prof. J. W. Bode
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TBAF
tetra-butylammonium fluoride
Bu4N+F-
THP
2-tetrahydropyranyl
TIPS
triisopropylsilyl
Ts para-toluenesulfonyl
O
SiiPr
iPriPr
Me
SO
O