Chapter 11 Reaction of Alcohols

Oxidation of alcohols

Alcohols can be oxidized to carbon-oxygen double bonds (carbonyl compounds)

Alcohols are at the same oxidation level as alkenes

Therefore alkenes can be converted to alcohols with acidic water

H3O+H2C

CH2 H3C OH H3C

O

HOX

H3C

O

OHOX

Primary alcohols will be converted to aldehydes under basic oxidation conditions

Primary alcohols will be converted to carboxylic acids under nonbasic oxidation conditions

PDC or PCC

CrO3, H2SO4

Alcohols as Nucleophiles

To make alcohols more nucleophilic, need to abstract the acidic hydrogen (remember pKa’s!)

With this method, can make nucleophilic oxygen that can react through any SN2 type reaction already studied

Neutral alcohols can react as nucleophiles (often observe this with carboxylic acid derivatives or inorganic analogs)

Alcohols as Electrophiles

OHH

HH

NUC

In these reactions the alcohol is the leaving group (the C-O bond is broken during the reaction)

NUCH

HHOH

Usually the hydroxide, or alkoxide, is a BAD leaving group, therefore we need to convert the alcohol into a GOOD leaving group

1) The tosylate, which was seen earlier, is commonly used as a way to make the alcoholic oxygen a good leaving group

OTsH

HH

NUCNUC

H

HHOTs

2) Another method we have already observed is protonation to form water as the leaving group

OH OH2 XH+

X

Conversion of Alcohols into Halides

The methods to convert alcohols into electrophiles are used to transform alcohols into alkyl halides

Can occur with either SN1 or SN2 conditions depending upon alcohol used

Stereochemistry, and possibility of rearrangements, depends on mechanism for each reaction

Type of alcohol chloride bromide iodide primary

secondary tertiary

SOCl2

SOCl2

HCl HBr HI

PBr3

PBr3

P/I2

P/I2

Best reagents for interconversions:

Chapter 12 Infrared Spectroscopy

IR is used for Functional Group Identification

Position of peaks can be used to differentiate all possible carbonyl compounds in addition to distinguishing common functional groups including nitriles, alkynes and aromatic rings

Factors to be considered for peaks: Position of Absorbance

(related to energy needed for absorbance)

C=C double bond CC triple bond

Factors to be considered for peaks: Intensity of Absorbance

(related to dipole of bond undergoing absorbance)

C=C intensity

C=O intensity

O

Shape of Absorbance (sharp or broad peaks related to type of bond)

OH

Chapter 12 Mass Spectrometry

In addition to determining the parent molecular weight for a sample, a MS can also be used to characterize what atoms are present and to differentiate isomers

Isotopic Patterns for natural abundance:

Fragmentation patterns can also be different for isomers

Predicted Mass Spectrometry Differences

Isotope Differences Used to Distinguish Halogen Substituents

I

m/z = 204no m+2 for iodinem+1 = 6.4% of m

Br

m/z = 156m+2 ~ equal to m

Cl

m/z = 112m+2 ~ 1/3 of m

F

m/z = 96no m+2 for fluorine

Fragmentation Pattern to Determine Structure OH e-beam OH

m/z 102OH OH

OH

87 45

CH3 OH!-cleavage

57

or or

OH

84

CH3

69

loss of water Remember:

Only charged forms are observed in a MS

Chapter 13 NMR Spectroscopy

Any nucleus with either an odd atomic number or odd mass has a “nuclear spin”

A charge species that is spinning creates a current loop, which in turn creates magnetic field lines

In solution, however, there are many hydrogens present and the spinning direction is random

In presence of large external magnetic field the spin directions are quantized

Shielding

Need to remember the structure of a compound (consider only an isolated C-H bond)

To reach the nucleus the magnetic field must past through the electron cloud surrounding the nucleus

The electrons surrounding the nucleus are charged species that can rotate in the presence of the external magnetic field

What this means is that the external magnetic field (B0) is effectively reduced by the time it reaches the nucleus (B0 minus the field of the electron cloud)

C HB0

Bnet = B0 - Belectron

In addition to the electron density surrounding the hydrogen causing shielding, each hydrogen acts like its own magnetic field

If one magnet is close to another, it will feel the effect of that magnetic field

This occurs in a 1H NMR a hydrogen will feel the effect of neighboring hydrogens

In the field of one additional hydrogen therefore we would observe two signals

N+1 rule: can predict the splitting that will be observed by counting the number of hydrogens on adjacent carbons (N) and adding one

Splitting

1H NMR Chemical Shift Scale

Bapplied

Bmolecular

Beffective

Applied Magnetic Field: Homogeneous for 1H NMR – therefore spin sample Molecular Magnetic Field: two effects will change the magnetic field experienced by nucleus

1)  Density of electron density around nucleus “shields” nucleus (range ~12 ppm for 1H NMR, ~200 ppm for 13C NMR)

2) Nearby magnetic nuclei (spin-spin splitting) The effective magnetic field at the nucleus is thus Bapplied-Bmolecular

Due to empirically observed effects, chemists can predict the position for functional groups,

and the predicted splitting pattern for each signal

01234567891011

ppm (!)

TMS (standard)

alkane CH-O, CH-X, CH-N C=C-H Aromatic-H RCHO RCO2H

RO-H

ROCH3

13C NMR Spectroscopy

Because a 13C atom has an odd mass, it also has inherent magnetic field lines and will display NMR spectroscopy in the presence of a large external magnetic field

The downfield shift is dependent upon the shielding caused by the electrons around the carbon, due to the extra electron density around carbon compared to hydrogen there is a

greater amount of shielding in a 13C NMR

Instead of ~11 ppm range for 1H NMR, 13C NMR is typically in a ~200 ppm range

Due to the low probability of having two 13C isotopes adjacent, there is no splitting observed from the possible spin states of adjacent carbons

Typically observe a spin decoupled 13C NMR spectrum which has only singlets for each carbon

Observe all carbons though, do not need to have a hydrogen attached as with a 1H NMR

020406080100120140160180200220

ppm (!)

01234567891011

ppm (!)

Amount of Downfield Shift is Comparable

1H NMR

13C NMR

alkanes

alkanes

alkyl halide

C X

ether

alkene

aromatic

aldehyde

carboxylicacid

C-O

alkene

aromatic

carbonyl carbons

alkyne

Chapter 14 Ethers

Ethers are generally synthesized through a nucleophilic method

Ethers are often used as solvents for organic reactions because the functional group is relatively unreactive

One of the few reactions that they can undergo is alkyl cleavage with HI or HBr

Very similar to alcohol reactions observed in chapter 11

HI > HBr >> HCl

OH+

OH

BrOH Br+

HBr

Br

Epoxides

One type of ethers that are reactive is a cyclic ether in a 3-membered ring called epoxides

Epoxides can be synthesized in one of two ways:

1) Reacting alkenes with a peracid

2) Reacting halohydrins with a weak base

Regiochemistry in Reaction of Epoxides

The base catalyzed opening of epoxides goes through a common SN2 mechanism, therefore the nucleophile attacks the least hindered carbon of the epoxide

OCH3MgBr

O

O H+ OH

In the acid catalyzed opening of epoxides, the reaction first protonates the oxygen This protonated oxygen can equilibrate to an open form that places more

partial positive charge on more substituted carbon, therefore the more substituted carbon is the preferred reaction site for the nucleophile

CH3OHHO OCH3

Chapter 15 Conjugated Systems

Conjugated systems occur anytime there are p orbitals on adjacent atoms in conjugation

Whenever there are p orbitals in conjugations, molecular orbitals result by the mixing of orbitals

The difference in energy is due to the number of nodes (different phases overlap), more nodes means higher in energy and electrons are filled in lowest energy orbitals first

=

4 p orbitals = 4 MOs

E

Addition to Conjugated Dienes

As we have already seen, alkenes can react with electrophiles to create a carbocation

With conjugated dienes this reaction will create an allylic carbocation

The nucleophile can then react with either resonance form in the second step

Kinetic versus Thermodynamic Control

What forms faster (kinetic product) and what is more stable (thermodynamic product) need not be the same

H+

H2O

Consider the addition to conjugated dienes

Generate allylic cation in first step Allylic cation can have water react at two sites

Reaction at 2˚ cation site has a more stable transition state

!+

!+H2O

H2O

!+

!+

Thus the kinetic product has water reacting at 2˚ site

OH

OH

Reaction a 1˚ site, though, generates more stable product

(more substituted double bond) The thermodynamic product has

water reacting at 1˚ site

E

Reaction at 2˚ site Reaction at 1˚ site

Diels-Alder Reaction

The reaction between butadiene and ethylene is called a Diels-Alder reaction

Obtain cyclohexene functional units after a Diels-Alder reaction

Always try to find the cyclohexene unit in the product, this will indicate what was the initial butadiene and ethylene parts

Stereochemistry of Addition

Products on previous page did not indicate stereochemistry, but Diels-Alder reaction typically only yields one diastereomer preferentially

(does not differentiate enantiomers)

Whenever there is a p orbital on the atom attached to the dienophile, the endo product is favored due to orbital interaction between p orbital on dienophile and p orbitals on diene

NC H

Endo position

Exo position CN

Interaction of p orbitals

In exo orientation this interaction is not present In endo position, orbitals on alkene substituents can interact with p orbitals of butadiene

Regiochemistry of Unsymmetrically Substituted Diels-Alder Products

When a monosubstituted butadiene and a monosubstituted alkene react, different regioproducts can be obtained

Can predict favored product by understanding location of charge in molecules

OCH3 OCH3 OCH3

Consider resonance forms Negative charge is located on C2 and C4

OCH3NO2 !

OCH3NO2

OCH3

NO2

or

123

4

NO

O

Consider resonance forms

NO

O

Positive charge located on C2

12

The negative charge will react preferentially with the positive charge to obtain one regioproduct

Using this analysis we can predict regioproducts

A Diels-Alder reaction can therefore control both regio- and stereochemistry

Ultraviolet-Visible (UV-Vis) Spectroscopy

Instead of causing molecular vibrations, UV-VIS light causes electronic excitations

An electron is excited from the HOMO to the LUMO

E h!

Ethylene HOMO

Ethylene LUMO

If the correct amount of energy is applied (i.e. the correct wavelength of light), the excitation of one electron from the HOMO to the LUMO will occur

As the amount of conjugation increases, the energy gap between the HOMO and LUMO decreases

With a lower energy gap, the λmax shifts to a longer wavelength of light to cause excitations

Chapter 16 Aromatic Systems

When p orbitals are in conjugation in a ring, stability is sometimes much greater than acyclic

= =

Cyclic systems are thus different than acyclic as seen by how electrons can resonate, -is this difference always better?

Depends also on the placement of molecular orbitals (not only due to cyclic)

Hückels rule: 4n+2 electrons in conjugation = aromatic (more stable) 4n electrons in conjugation = antiaromatic (less stable)

Aromatic Ions

If p orbitals are in full conjugation in a cyclic system and the number of electrons in conjugation is equal to 4n+2, the compound is more stable regardless of whether the

compound is neutral, negatively charged or positively charged

=After rehybridization, system has 6 electrons in conjugation in a ring, therefore aromatic

pKa is ~16

Cyclopentadiene anion is very stable

Cyclopentadiene cation is very unstable (will not form)

With all cyclic ions, see if p orbitals are conjugated in a ring and then count the number of electrons in conjugation, if 4n+2 then stable, if 4n then unstable

Chapter 17 Aromatic Reactions

Electrophilic Aromatic Substitution

Aromatic compounds react through a unique substitution type reaction

Initially an electrophile reacts with the aromatic compound to generate an arenium ion (also called sigma complex)

The arenium ion has lost aromatic stabilization (one of the carbons of the ring no longer has a conjugated p orbital)

In a second step, the arenium ion loses a proton to regenerate the aromatic stabilization The product is thus a substitution

(the electrophile has substituted for a hydrogen) and is called an Electrophilic Aromatic Substitution

A Variety of Electrophiles Can Be Used

The key is generating an electrophilic reagent that can react with the aromatic ring

Br Br FeBr3!+ !-

Br

CH3

Cl2AlCl3

ortho/para director

CH3

Cl

NO2

HNO3

H2SO4

meta director

NO2O2N

CH3

O

ClAlCl3

OElectrophile:

Br2FeBr3

!+ !-Cl Cl AlCl3 NO2

O

Reactions on Aromatic Substituents

A variety of reactions can be performed on the aromatic substituents

NO2 NH2Sn, Fe, or ZnHCl

deactivating activating

AlCl3

O

Cl

OCl

AlCl3

Friedel-Crafts acylation

Friedel-Crafts alkylation

NH2NH2KOH

Wolf-Kishner

ZnHCl

Clemmensen

CO2H

KMnO4KOH

Br

NBSh!

Carbon side chains:

Nucleophilic Aromatic Substitution

Mechanism

Cl

O2N

NO2

NaCN

NO2

O2N

ClCN

NO2

O2N

ClCN

NO2

O2N

ClCN

The anion is stabilized by electron withdrawing groups ortho/para to leaving group

To regain aromatic stabilization, the chloride leaves to give the substituted product

NO2

O2N

ClCN

NO2

O2N

CN

1)  Must have EWG’s ortho/para to leaving group -the more EWG’s present the faster the reaction rate (intermediate is stabilized)

2)  The leaving group ability does not parallel SN2 reactions -follows electronegativity trend (F > Cl > Br > I)

Benzyne Mechanism

A second nucleophilic aromatic substitution reaction is a benzyne mechanism

Benzyne is an extremely unstable intermediate which will react with any nucleophile present

HBr

NH2NH2

NaNH2, NH3

benzyne

Need strong base at moderate temperatures, but do not need EWG’s on ring

Chapter 18 Ketones and Aldehydes

New routes to synthesize ketones and aldehydes

From carboxylic acids:

O

OH

RLi(2 equiv.)

O

R

SOCl2 O

Cl

O

HLiAlH(OtBu)3

R2CuLi

O

RFrom nitriles:

C N1) RMgBr

2) H+, H2O

O

R1) DIBAL

2) H+, H2O

O

H

O

OR

O

H

1) DIBAL

2) H+, H2O

From dithianes:

S S S S

H

BuLiS S

R H

RXH+, HgCl2

H2O

R

O

H

Reactions of Ketones and Aldehydes

R

O

R

NUC O NUCR

O

R

H

R R

O HNUC

R R

HO NUC

Base mechanism Acid mechanism

Types of NUC : RMgBr LAH ylide Types of neutral NUC: cyanide H2O ROH RNH2

Reactivity

As electrophilicity of carbonyl carbon increases, the reactivity increases

R

O

R R

O

H H

O

H Cl3C

O

H< < <

Wittig Reaction

The carbanion of the ylide is nucleophilic and will react with the carbonyl

H3C

O

CH3(Ph)3P

(Ph)3P O

CH3CH3H3C

betaine

oxyphosphetane

The betaine structure will form 4-membered ring between phosporous and oxygen

(Ph)3P O

CH3CH3H3C

(Ph)3P O

H3CCH3

CH3

The oxyphosphetane will collapse to form a second phosphorous-oxygen bond

(Ph)3P O

H3CCH3

CH3 H3C CH3

CH3(Ph)3P O

Overall an alkene is formed from the initial carbonyl compound

Acetals

Acetals are related to hydrates, Instead of geminal dialcohols have geminal ethers

This process is once again an equilibrium process

Aldehydes (which are more reactive than ketones) typically favor acetals

H3C

O

CH3 H+ H3C CH3

ORROROH

When both alcohols to form an acetal are intramolecular (on same molecule) then a cyclic acetal is formed

H3C

O

H H+ H3C H

HO OH OO

Cyclic acetals and ketals are often used because they have a higher equilibrium for the acetal form

Baeyer-Villiger

Allows conversion of ketone to ester

R

O

RRCO3H

R

O

O R

Mechanism of oxygen insertion?

R

O

R H O O

O

R R

O

RO O

O

R

H

R

HO

O

RO

O

RR

O

O R O

O

R

H

Mechanism is not an insertion, but rather a reaction at carbonyl followed by a migration

Weak oxygen-oxygen single bond

Chapter 19 Amines

The basicity, and hence pKb, is determined by the stability of the amine after protonation

The lone pair of electrons on nitrogen can act as an acceptor (hence Brønsted-Lowry base)

R NH

HH2O

KbR N H

H HOH

H3CN

H3CH3C

N

H3C C N

As the percent s character increases for the orbital holding the lone pair of electrons, the electrons are held more closely to the positively charged nucleus

sp3 hybridization

sp2 hybridization

sp hybridization

pKb = 4.26

pKb = 8.75

pKb = 24

Other effects, such as whether lone pair is in resonance or involved in aromatic system, also will affect the pKb for the amine

Synthesis of Amines

Nucleophilic:

NH2CH3I

NH

NCH3I

problem is overalkylation

NH

O

O

1) KOH2) CH3I NH2NH2N

O

O

CH3 H3C NH2

Gabriel allows only 1 addition

Reduction: N OH

O

NHN3

CN

LAH NH2

LAH

LAH

LAH

NH

NH2

NH2

oxime

amide

azide

nitrile

Elimination of Amines Hoffman Elimination

With quaternary ammonium salts, E2 reaction occurs to eliminate trimethylamine

Cope Elimination

With N-oxide, syn elimination occurs to eliminate dimethylhydroxy amine

anti-elimination

syn-elimination

F H(CH3)3N

FH(H3C)2N OH

NFH

N OFH

Both eliminations favor the less substituted alkene to be formed

Arenediazonium Salts

Arenediazonium salts can be generated from aniline derivatives

NH2 NaNO2

HCl

N N

The diazonium salt can then be converted into a number of different functional groups

NN

OH

H2SO4

F

HBF4

I

KI

CN

CuCN

H

H3PO2

Unique phenol derivatives

Unique F substitution

Easier I substitution

Versatile CN (Sandmeyer)

Reduce to H

Chapters 20&21 Carboxylic Acids & Derivatives

Reactions of Acyl Compounds

There is a commonality amongst carbonyl reactions, they have a nucleophile react at the carbonyl carbon

O

X

NUC

O

NUCX

O

NUCX

Generate a tetrahedral intermediate that can expel a leaving group

Interconversion of Carboxylic Acid Derivatives

O

OH

O

Cl

The carboxylic acid can thus be converted into any other carboxylic acid derivative, In addition each carboxylic acid derivative can be converted to a carboxylic acid

O

O

O

O

O

O

NH2

O

O

Acid chloride

Anhydride

Ester

Amide

Carboxylate

Reactivity of Carboxylic Acid Derivatives

All carboxylic acid derivatives can also be converted back to the carboxylic acid (by either acidic or basic hydrolysis) or the derivatives can be directly

interconverted to a less reactive form

O

NH2

O

Cl

O

O

O

O

O

O

O

reactivity

Acid chloride

Anhydride

Ester

Amide

Carboxylate

But cannot interconvert a less reactive acyl derivative into a more reactive

Predicting Reactivity Patterns for Carboxylic Acid Derivatives

All of the carboxylic acid derivatives can react with a nucleophile to generate the same carbonyl product – the difference is the leaving group

O

ClNUC O

NUC Cl

O

O

O O

ONUC O

NUC

O

O ONUC O

NUC

O

NH NH

NUC O

NUC

pKa of conjugate for leaving group

-7

~4-5

16

35

The stability of the leaving group affects the reactivity pattern for the acid derivatives

Chapter 22 Reactions at α-Carbon

A type of reaction with carbonyl compounds is an α-substitution (an electrophile adds to the α carbon of a carbonyl)

O O

E

E+

In the preceding chapters, we primarily studied nucleophiles reacting at the electrophilic carbonyl carbon

O NUC OH

NUC

Reactions of Enols

The enol form can react with electrophiles

A common reaction is halogenation

Under basic conditions it is hard to stop at one addition due to hydrogen abstraction of product is more favored than starting material

O OHNaOH Br Br OH

Br

O OHNaOH Br2 O

Br Br Br Br

Enolates

Enolates are similar to enols but they are far more nucleophilic

In order to generate an enolate, need a base to abstract an α-hydrogen

LDA will quantitatively form enolate

H3C

O

CH3 H3C

O

CH2LDA

Using LDA the enolate will be formed quantitatively, with weaker bases will only form the enolate in a small fraction

Enolate as a Nucleophile

Have already observed many reactions with a negatively charged nucleophile (most SN2 reactions)

An enolate is simply another type of nucleophile, it can react in similar manner as other nucleophiles

H3C

O

CH2E+

H3C

O

CH2E

One common reaction is to alkylate the enolate

H3C

O

CH2 H3C

O

CH2CH3

CH3Br

This reaction will place an alkyl substituent at the α-position of a carbonyl Any electrophile that will react in a SN2 reaction can be used

Thermodynamic vs. Kinetic Control

With unsymmetrical ketones, different enolates can be generated

The enolate can be preferentially generated at either site depending upon conditions

O LDAO

H H

O

Kinetic enolate easier hydrogen to abstract

O

Thermodynamic enolate more stable double bond

Lower temperature favors kinetic product

Higher temperatures (in this case usually room temperature and above) favors thermodynamic product

Aldol Condensation

Instead of reacting the enolate with an alkyl halide, we can also react the enolate with a carbonyl compound

The carbonyl can react as an electrophile

OO

O OH

Upon work-up obtain a β-hydroxy ketone

O OH -H2O O

The β-hydroxy ketone that is formed can also lose water to form an α,β-unsaturated ketone

Greater the conjugation, the easier for loss of water

Claisen Condensation

There are many “Name” reactions that are modifications of the aldol condensation, A Claisen condensation is an aldol where one carbonyl compound is an ester

By using an ester, the chemistry is changed due to the presence of a leaving group

OCH3ONaO O

O

Can run reaction with both carbonyls present with weak base due to

differences in pKa (ketones ~20, esters ~24)

O

OO O

O

O O

With ester leaving group, obtain diketone product

Dieckmann

A Dieckmann condensation is an intramolecular Claisen condensation

CH3OO

O O

O O

O O

O

OO

OOCH3

O

O

OConvenient method to

form 5- or 6-membered rings

Michael Addition

If we add stabilized enolates to α,β-unsaturated system, the reaction can occur with 1,4-addition

O1

23

4

ONUC

O

NUC

Michael product (1,4 addition)

Whether a reaction occurs with 1,2- or 1,4-addition, selectively often depends on the stability of the nucleophilic anion. A more stable anion occurs with 1,4 selectivity while a less stable

anion occurs with 1,2 selectivity.

O O O NCH3MgBr (CH3)2CuLi

1,2 1,2 1,4 1,4 1,4

Enolate anions prefer 1,2 but β-diketone or enamines favor 1,4

Grignard reagents prefer 1,2 but Gilman reagents prefer 1,4