Lecture'2:'January'17,'2013oakton.chadlandrie.com/resources/224/orgoII... · Grignard.Reagents 11 Br Cl + Mg0 (metal) + Mg0 (metal) MgBr Et2O MgCl THF •magnesium metal (Mg0) added

CHM'224'•'Organic'Chemistry'IISpring'2013,'Des'Plaines'•'Prof.'Chad'Landrie

Alcohols:•Prepara'on*by*Addi'on*of*Organometallics*(17.5,*10.6,*19.7)

•Protec'on*(17.8)•Phenols*(17.9)

Lecture'2:'January'17,'2013

© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)

Slide Lecture 2: January 17

Nucleophiles

4

Nuc E X Nuc E + X

Nucleophiles Add to Electrophiles

• nucleophiles are Lewis bases

• they contain pairs of electrons (usually lone pairs, but not always)

• donate electron pairs to form covalent bonds with electrophilic atoms other than H.

• not all Lewis bases form covalent bonds



Anionic.Nucleophiles

5

Nuc E X Nuc E + X


H3C O

O

O

carboxylate alkoxide hydrogen sulfide

hydroxide cyanideazide

H S

H O N N N N C

• many nucleophiles are anionic (negative charge)

• nulceophilic atom (one forming new bond) highlighted in red



Anionic.Nucleophiles

6

Nuc E X Nuc E + X


anionic nucleophiles are often used/written as their metal salts

H3C ONa

O

OK

carboxylate alkoxide hydrogen sulfide

hydroxide cyanideazide

H SNa

H ONa N N NK N CNa



Electrophiles

7

Nuc E X Nuc E + X


• electrophiles are Lewis acids other than H.

• accept electron pairs to form covalent bonds with nucleophiles

• usually contain a polar covalent bond where one atom is a good leaving group

• not all Lewis acids form covalent bonds



Electrophiles

8

Nuc E X Nuc E + X


E Xδ+ δ+

polar covalent bond when X is strongly

electronegative

H3C Clδ+ δ+

alkyl halides are electrophiles; C of C-X bond, specifically

– –

carbonyl carbons are electrophiles; c-atom is partially +/vely charged

C

Oδ+

δ−

C

O


Sec'on*17.5,*10.6,*19.7

PreparaHon'of'Alcohols'by'AddiHon'of'Organometallics



Grignard.Reac1on

10

nucleophilic additionAlkoxide

protonationAlcohol

Victor Grignard1912 Nobel Prize

R MgBr CO

+ CO

R

Mg Br H3O+COH

R(diethyl ether)

O

(THF: tetrahydrofuran)

Oor

Grignard Reagent:Alkyl magnesium halide;

nucleophile

Carbonyl:Ketone, Aldehyde or Ester;

electrophile



Grignard.Reagents

11

Br

Cl

+ Mg0 (metal)

+ Mg0 (metal)

MgBrEt2O

MgClTHF

• magnesium metal (Mg0) added to aryl and alkyl bromides and chlorides

• ethers are used as solvents; stabilize reagent• magnesium metal coated with MgO which is unreactive; must cut

metal fresh to expose unoxidized surface

We will not discuss the mechanism. It’s a radical mechanism involving single electron transfer (SET) from Mg0 to the halide.



Grignards.are.Nucleophiles.and.Strong.Bases

12

C MgClδ+δ−

C MgCl+−

• C-Mg bond is highly polar-covalent; it is covalent though, not ionic• the electron density in the C-Mg bond lies almost entirely on C; the carbon

atom is the nucleophile in a Grignard reagent• Grignards are very basic and must be prepared in dry environments to

prevent reaction with water (Glassware and solvents must be thoroughly dried! The reaction must be protected from atmospheric moisture!)

• Grignards are not compatible with protic functional groups such as alcohols

H3C MgBr + H2O CH4 + OH—

H3C MgBr + CH3CH3OH CH4 + CH3CH2O—

+ MgBr+

+ MgBr+



Board.Work:.Grignard.Mechanism

13



Examples.of.Grignards

14

O1. CH3CH2MgBr diethyl ether

2. H3O+/H2O

OH

H

O

2. H3O+/H2O

MgBr1. HO H

H H

O

2. H3O+/H2O

1. MgClTHF OH

OCO 2. H3O+/H2O

1.THF

MgBrO

OH

ketone 3º alcohol

aldehyde 2º alcohol

formaldehyde 1º alcohol

carbon dioxide

carboxylic acid



Grignards.in.Synthesis

15

HO H

BrMg

O

H +O

H+MgBr

2º Alcohols by Two Pathways

OHO

O

? O

OOH

Homologation (Chain Extension) of Alcohols

O

O O

H

HMgBr

+O

O

Br

PBr3

Mg, ether

ether



Prepara1on.of.Propargyl.Alcohols

16

H

a. NaNH2, NH3b. then add carbonyl:

c. H3O+/H2O

H3C CH3

O OHCH3

CH3

Bases Commonly Used to Deprotonate Alkynes

N

Li+LDA: lithium

diisopropyl amide

n-butyllithium(n-BuLi)Li

NaNH2 sodium amide

Anatomy of Alkenes and Alkynes

H3C

H H

CH3

vinylic allylic homoallylic

H H

CH3H3C

H

H

acetylenic

propargylic homopropargylic


17.8

ProtecHon'of'Alcohols



Silyl.Protec1ng.Groups

19

A protecting group is a temporary functional group that is unreactive toward the desired reactions conditions and can be easily removed to reveal the original functional group.

O BrSiHO Brtrimethylsilyl chloride (TMSCl)

or chlorotrimethylsilane

(CH3CH2)3N

(CH3)3SiCl

alcohol silyl ether

Step One: Protection

• silanes are common protecting group for alcohols• need an amine base like triethylamine (TEA) to neutralize HCl produced; HCl

would react with the silyl ether to give the alcohol back• silyl ethers are sensitive to acids and are not compatible with acidic reactions• silyl ethers are stable (do not react) under basic conditions like Grignard reaction



Silyl.Protec1ng.Groups

20

Step Two: Reaction

O BrSi

1. Mg, ether

2.

3. H3O+/H2O

H

O

OSiOH

If a strong enough acid is used in the third step, the silyl group may be removed here at the same time as protonation of the alkoxide intermediate

Step Three: Deprotection

OSiOH H3O+/H2O

or commonly fluoride (F–) reagents:e.g., tetrabutyl ammonium fluoride (TBAF)

HO

OH

• F and Si form very strong bonds, strong than O and Si• fluoride undergoes SN2 on Si to break Si-O bond


17.9

Phenols'and'Their'Uses



Phenols

22

∆9-tetrahydrocannibol (THC)psychoactive component of marijuana

cannabis sativa



Naturally.Occurring.&.Synthe1c.Phenols

23

morphine(analgesic)

serotonin(neurotransmitter)

dopamine(neurotransmitter)

∆9-tetrahydrocannibol (THC)psychoactive component of marijuana



Phenols.in.the.Lab:.Phenophthalein

24

• conjugated π-systems are often chromophores

• chromophores can absorb visible light and promote a π-electron to an excited state

• basic solutions deprotonate phenolphthalein, creating a fully conjugated π-system that absorbs blue light (red more visible)

all π-systems not fully conjugatedoes not absorb visible light (colorless)

π-systems are fully conjugateabsorbs blue light (pink)

pH = 0-8.2 pH = 8.2-12



Phenols.in.Synthesis

25

OCH3

OHOCH3

HO

HO

combretastatin A4combretastatin A1

OCH3

OHOCH3

HO

HO

OH

Combretum caffrumAfrican bush willow

Biological Activity

• tubulin inhibitors = tumor cell occlusion

• selective vascular-disrupting agents = hypoxia of tumor cells

• cytotoxicity against human cancer cell lines

• nitrogen analogues may be significantly more potent



Phenols.in.Synthesis

26

O

1. n-BuLi, Ti(OPri)4 THF, 50 ºC, 48 h 2. H2O

O

PSDVB

HOCl

PSDVB +

immobilization

Merrifield Resin 4-(phenylethynyl)phenol (PEP)

combretastatin A1

OCH3

OHOCH3

HO

HO

OH

PSDVB

Landrie, C.L. et al. Reduction of Solid-Supported Olefins and Alkynes. J. Org. Chem. 74, 9535-9538 (2009).

Stereoselective Reduction of An Alkyne to a cis-Alkene(Research conducted by undergraduate students)



Nomenclature

27

• Historical name for benzene was phene.• Phenol is the preferred IUPAC & 2004 parent name for hydroxybenzene

derivatives• Substituents listed in alphabetical order; C-1 bears hydroxyl group.• Follow first point of difference rule when two sets of locants are possible.• Do not use CIP rules to determine locants for aromatic systems.



Choose the locant set with the lowest value at the first point of difference.

Nomenclature

28

1

4-bromo-2-ethyl-6-isopropyl

4-bromo-6-ethyl-2-isopropyl

X

√

OH

Br4

Remember: Substituents must be listed in increasing alphabetical order



Nomenclature

29

Common Names for Benzenediols



Quick.Review:.Benzene

30

C–C bond length: 150 pmC=C bond length: 134 pm

All bonds = 140 pm

H

H

HH

HH H

H

HH

H

H

Predicted Actual

Instead of alternating single and double bonds, all of the C-C bonds in benzene are the same length.



Resonance.Formula1on.of.Benzene

31

The structure of benzene is best represented, not as an equilibrium between two isomers, but as a resonance hybrid of two Lewis

structures.

HH

HH

H

HH

H

HH

H

H

Electrons are not localized in alternating single and double bonds, but are delocalized over all six ring carbon atoms.



Structure.&.Bonding.in.Phenol

32

• Phenol is planar• Bond angles around oxygen are nearly tetrahedral• The C–O bond in phenol is shorter than in methanol.• Why?




33

Q: Why is the C–O bond in phenol shorter than the C–O bond in methanol?

A1: The carbon in phenol is sp2-hybridized and has more s-character than the sp3-hybridized carbon in methanol. An orbital with more s-character exhibits better overlap and gives stronger σ-bonds.

sp2 sp3



Hybridiza1on.Effects.Degree.of.Orbital.Overlap

34

pure p

sp3

sp2

sp

pure s

• Electrons are diffuse, spreadout throughout the molecular orbital.

• As s-character increases, the percentage of overlap compared to the rest of the MO increases.

• A greater percentage of overlap means greater electron density between the atoms.

• More electron density between the two nuclei = stronger bond.

overlap




35

Q: Why is the C–O bond in phenol shorter than the C–O bond in methanol?

A2: Resonance delocalization of oxygen’s lone-pair with the aromatic π-system leads to partial double-bond character for the C-O bond. This bond is thus stronger and shorter.




36

• These structural features are responsible for the physical and chemical properties of phenol.

• The phenol oxygen is less basic than in alcohols.• Phenols are more acidic than alcohols.• SArE is faster, especially at ortho and para positions due to electron

donation by the hydroxyl group.


17.9;*Review*Ch.*2

Physical'and'AcidMBase'ProperHes'of'Phenols



Physical.Proper1es

38

Phenols have:• higher m.p.s• higher b.p.s• higher water

solubility



Physical.Proper1es

39

Each trend explained by hydrogen bonding:

• increased intermolecular H-bonding = higher crystal lattice energy (m.p.)

• = lower Pº = higher b.p.

• increased intermolecular H-bonding with water = increased solubility



Physical.Proper1es

40

Ortho-nitro substituted phenols generally have lower melting and boiling points than meta and para substituted phenols.

m.p. = 46 ºCb.p. = 215 ºC(@ 760 Torr)

m.p. = 97 ºCb.p. = 194 ºC(@ 70 Torr!)

• increased intramolecular H-bonding in ortho =

• decreased intermolecular bonding

• = lower crystal lattice energy

• = higher Pº



Physical.Proper1es:.Acidity

41

• Phenols are more acidic than alcohols but less acidic than carboxylic acids.• Electron delocalization stabilizes the phenoxide conjugate base.

pKa = 4.7+ +

Res

onan

ce

Stab

iliza

tion




42

• Phenols are more acidic than alcohols but less acidic than carboxylic acids.• Electron delocalization stabilizes the phenoxide conjugate base.

Electron density is delocalized onto the ortho and para carbons only.




43

Conjugate bases stronger than phenoxide (whose conjugate acids are weaker than phenol) react nearly completely with phenols.



AcidPBase.Equilibria:.Determining.the.Direc1on.of.AcidPBase.Reac1ons

44

You must identify the ACID on each side of the equilibrium:pKeq = pKa (acid left) - pKa (acid right)

Keq = 10-[pKa (acid left) - pKa (acid right)]

• remember: p = -log10

• this equation works for any acid-base reaction; doesn’t matter which way equilibrium is written

Keq = 10-[10 - 15.7] = 10-[-5.7] =105.7

Example:

Acid-base equilibria always lie to the side with weaker conjugate acids and bases.




45

Conjugate bases weaker than phenoxide (whose conjugate acids are stronger than phenol) do not react significantly with phenols.

Keq = 10 -[10 - 6.4] = 10 -[3.6] =10–3.6

Acid-base equilibria always lie to the side with weaker conjugate acids and bases.




46

Acid pKa FormulaConjugate base

(CB)Conjugate base

(CB) Keq

PhOH + CB

hydrogen chloride –3.9 HCl Cl– chloride 10 –13.9

hydronium ion -1.7 H3O+ H2O water 10 –11.7

acetic acid 4.7 CH3COOH CH3COO– acetate 10 –5.3

carbonic acid 6.4 H2CO3 HCO3– bicarbonate 10 –3.6

phenol 10 C6H5OH C6H5O– phenoxide –

methyl ammonium 10.7 CH3NH3+ CH3NH2 methyl amine 10 0.7

water 15.7 H2O OH– hydroxide 10 5.7

ethanol 16 CH3CH2OH CH3CH2O– ethoxide 10 6

acetylene 26 HC≡CH HC≡C– acetylide 10 16

diisopropylamine 36 [(CH3)2CH2]2NH [(CH3)2CH2]2N– diisopropyl amide 10 26

methane 60 CH4 CH3– 10 50

completedeprotonation

PhOH + CB– ➞ PhO– + HCB



Aqueous.Extrac1on

47

R

O

O HR

O

OOH+ + H2O

carboxylic acid(conjugate acid)

carboxylate anion(conjugate base)

OOH H2O

phenol(conjugate acid)

phenoxide anion(conjugate base)

O+ +

H2O

amine(conjugate base)

ammonium cation(conjugate acid)

+ +R NH2

H

H OH2

deprotonation

deprotonation

protonationR NH3

R R

When R is small (generally ≤8 carbons; although exceptions) these ions are soluble in water.



Separa1on.of.Phenol.from.Mixtures.by.Alkanline,.Aqueous.Extrac1on

48



Subs1tuent.Effects.on.Phenol.Acidity

49

1. Alkyl substituents have negligible effects on acidities. When they do, they are slightly electron donating; thus, they may increase the electron density on the phenoxide oxygen and make the phenol less acidic.

p-cresol(pKa = 10.2)

phenol(pKa = 10.0)




50

2. Weakly electronwithdrawing substituents have negligible effects on acidities. When they do, they may decrease the electron density on the phenoxide oxygen and make the phenol more acidic.

p-chlorophenol(pKa = 9.4)

phenol(pKa = 10.0)




51

3. Nitro substituents have significatnt effects on acidities, particularly at ortho & para positions. They decrease the electron density on the phenoxide oxygen (stabilize the conjugate base) inductively and through resonance and make the phenol more acidic.

o-nitrophenol(pKa = 9.2)

p-nitrophenol(pKa = 9.2)


Reac'ons*of*phenols*(17.9;*Ch.*16)Ethers*and*Epoxides*(18.1M18.4)

Next'Lecture.'.'.


Exp.'33:'ProperHes'and'IdenHficaHon'of'Alcohols



Ceric.Ammonium.Nitrate.Test

55

(NH4)2Ce(NO3)6 R-OH (NH4)2Ce(NO3)5

OR+ HNO3+

ceric ammonium nitrate (CAN);

orange

R = alkyl (red)R = aryl (brown)

OHOH

OH

O O

1-butanol phenol diethyl ether butanal 2-butanone

color?

•Based on your results, what class of nucleophilic oxygen atoms form complexes with CAN?•What other functional groups might form similar complexes?



Solubility.Tests

56

OH OH OH OH

OH OH

Cl

ethanol 1-butanol 1-hexanol 1-octanol phenol p-chloropehnol

water solubility (s: solubleps: partiallyin: insoluble)

1.0 M NaOH solubility

•Why are some alcohols soluble and some not if all do H-bonding? Use VWFs to explain.•Which insoluble alcohols can be made soluble by NaOH? Why?



Jones.Oxida1on.(Chromic.Acid).Test

57

OH OHOH OH OH

1-butanol 1-hexanol 2-butanol cyclohexanol 2-methyl-2-propanol unknown

?

substitution(3º, 2º, 1º)

color change

•Which alcohol(s) did not undergo oxidation? Why?•What is the mechanism for this reaction?

OH

Cr

O

OO+H2SO4 H2O + Cr

O O

HO OH

OCr

O O

OH+

Cr(VI)orange-brown

Cr(II/III)blue-green



Lucas.Test

58

OH OHOH OH OH

1-butanol 1-hexanol 2-butanol cyclohexanol 2-methyl-2-propanol unknown

?

substitution(3º, 2º, 1º)

observation

•What is the mechanism for this reaction? What is the intermediate?•Rank the substitution of alcohols in order increasing rate of reaction with Lucas reagent.•Why does the solution become cloudy or form two layers upon reaction?

OH

+ HClZnCl2Cl

homogeneous (one layer) cloudy or two layers



Single.Displacement.Redox.of.Alkali.Metals

59

2Na(s) + 2H2O(l) → 2NaOH(s) + H2(g)0 +1 –2 +1 +1–2 0

2Na(s) + CH3OH(l) → 2NaOCH3(s) + H2(g)

•Why is the sodium metal washed with hexanes first?•Why is the sodium metal cut before it’s placed in the alcohol?•What does phenolphthalein indicate? Why should it be added last and not first?

Br CH3ONa+ OCH3

Alkoxides can be formed this way and used in the Williamson Ether Synthesis.

Documents

Lecture'2:'January'17,'2013oakton.chadlandrie.com/resources/224/orgoII... · Grignard.Reagents 11 Br Cl + Mg0 (metal) + Mg0 (metal) MgBr Et2O MgCl THF •magnesium metal (Mg0) added