review of key concepts 1 arrow pushing - eth z · 1 arrow pushing arrow pushing is a technique used...

OC II (FS 2019) Review of Key Concepts Prof. J. W. Bode

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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


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


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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


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


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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


6

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


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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%


8

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


9

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


10

TBAF

tetra-butylammonium fluoride

Bu4N+F-

THP

2-tetrahydropyranyl

TIPS

triisopropylsilyl

Ts para-toluenesulfonyl

O

SiiPr

iPriPr

Me

SO

O

review of key concepts 1 arrow pushing - eth z · 1 arrow pushing arrow pushing is a technique used...

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