CHEM 3311 Final Exam CU Boulder

Organometallic Synthesis from Alkyl Halides

R(delta-) - M(delta+)

Rxn of alkyl halide with Mg, Li, or Na (neutral) and alkyl halide (generally Cl, Br)

Assume 1 e- transfer

Regiospecfic: C:(-) forms at C(alpha)

Stereospecific: n/a, top and bottom add'n

Organometallic Properties

Acts as carbanion (C:(-))

Acts as strong base if acidic H(+)s available

If carbanion is small/linear, behaves as nucleophile

Used as C chain extension reagent

Degradation of Organometallic Compound

Hydrolysis

Halogen Rxn

O2 reactions

Making/using carbenes

Making Carbenes from R-X derivatives

Y(2)C: + R-X derivative -> tri or di halide

If B:(+) is a strong base: di-halide, product will be trihalide+ B-H + X:(-)

If B = Zn-Cu, product will be dihalide + ZnI(2) + Cu

Hydrolysis of Organometallic

Any alcohol (-OH(-)) attacks, adds H to C(alpha) and forms salts

Halogen Rxn of Organometallics

X(2) with organometallis + polar (or induced polar) material via sub'n to form alkyl halide and metal compound (Li(+)-Cl(-))

Carbene Reactant Properties

Y(2)C:

Empty p orbital -> trig planar geometry

Dual Rxn Nature: 1 group is electrophilic and nucleophilic

Carbene Rxn with Alkene

Add'n Rxn forms cyclopropane derivatives

No I*

Regiospecific: n/a

Stereospecific: syn add'n of Y(2), overall mix is racemic

Free radical Mono-Halogenation of Alkenes to Form Alkyl Halide

Radical substitution of R(3)C-H + X(2) -> R(3)X + H-X

Requires light/heat

Regiospecific: Br at more sub'd sites, Cl at less sub'd sites

Stereospecific: n/a, flat C radicals

Characteristics of Radical Halogenation Rxn of Alkanes to R-X

- selective for breaking C-H bonds only

- complex/multi-step Rxn with flat C.

- polyhalogenation occurs without termination of chains

- follows dihalogen trends

Dihalogenation Radical Trends

- F. Too reactive, not used

- Cl. Is reactive, faster at 1st degree C sites (less sub'd)

- Br. Less reactive, but more reactive at 3rd degree sites (more sub'd)

- I. Relatively unreactive at normal temps

Hydration of Alkenes to synth R-OH

- acid catalyzed hydration (H2SO4, HNO3 or HClO4) and H2O

- oxymercuration-reducation hydration

- hydroboration-oxidation hydration

Nucleophilic Sub'n of R-X with OH-/H2O to form R-OH

- SN2 rxn with a 1 degree R-X

- SN1 rxn of a 3rd degree R-X at low temperatures

Conversion of R-OH to ether (R-OR')

- SN2 under basic conditions (Williamson ether synthesis)

- SN1 and SN2 under acidic conditions (alc dehydration)

Conversion of R-OH to Alkene

acidic conditions, dehydration via elimination

Conversion of Alcohol to R-X

sub'n of -OH for -X via:

- SN2 and SN1 rxns with H-X under acidic conditions

- SOCl2 and organic amine base (SN2) to R-Cl

- PBR3 (SN2) to R-Br

Conversion of Alcohol to Sulfonate Esters

R-OH to R-OSO2R'

Oxidation of R-OH to Molecules Containing C=O

1 degree -> aldehyde

2nd degree -> ketone

1st degree -> carboxylic acid

Conversion of Alcohol to Ether via SN2

(Williamson Ether Synth)

**basic conditions

1) form alkoxide anion (RO-) from ROH

2) React KO- with non-hindered R-X via SN2

- works best in 1st degree R-OH and R-X (favors SN2)

- more alpha/beta branching and strong, bulky bases has more E2 rxn products

**Regiospecific: RO- affs to C(alpha)

Stereospecific: inversion of C(alpha)

Conversion of OH to Ether (ROR) via SN2 & strongly acidic conditions

x2-1st degree ROH form a symmetrical ROR molecule

Regiospecific: ROH is NU: so adds to C(alpha)

Stereospecfic: C(alpha) inversion

Conversion of ROH to ROR via SN1 to a non-symmetrical ROR under strongly acidic conditions

3rd degree ROH with a 1st or 2nd degree ROH to form ROR'

*C+ intermediate

Regiospecific: less sub'd ROH (as NU:) adds to C(alpha)

Stereospecific: n/a, less-sub'd ROH adds to either face

Dehydration of ROH's to form Alkenes

acid catalyzed Beta-elimination to convert -OH into good leaving group

-E1 mechanism for 3rd degree and 2nd degree ROH substrates (scrambled products)

-E2 based mechanism for 1st degree ROH substrates (stereoselective)

Zaitsev's Rule

if there is more than one Beta-alkene possible, the most substituted product will be the major product

*thermodynamic rxn control under H+-catalyzed rxn conditions

Trans-Cis Selectivity in Acid-Catalyzed ROH elimination

trans stereoisomer is major product formed (largest groups farthest apart, least steric crowding)

Exception: alkene product is cyclic molecule

E1 Elimination

Acid catalyzed: thermodymanic control, major product is most sub'd

Base catalyzed: kinetic control, major product is least sub'd

SN2 and SN1 conversion of ROH to R-X (acidic)

Acidic conditions -> brute force conversion

SN2: steroselective with C(alpha) inversion

SN1: racemic mixture

ROH to R-Cl Conversion with SOCL2

SOCL2 and organic amine base gives R-Cl

*converst R-OH to a sulfite ester (resonance stability = better leaving group)

- used with methods that react with H+

-Regiospecific: Cl- adds to C(alpha)

-Stereospecific: C(alpha) inversion

**only 1st and 2nd degree ROHs

ROH to R-Br Conversion with PBr3

-OH converted to better leaving group, followed by SN2

-each -Br group replaced by RO-

- Regiospecific: Br- adds to C(alpha)

- Sterospecific: C(alpha) inversion

*1st and 2nd degree ROHs

Sulfonate Ester

R-OH -> R-OSO2R' is a good leaving group (resonance stabled, not basic)

-Convert with Pyridine, CH2CL2 (results in ROSO2R' + H+ + Cl-)

Oxidation of Alcohols

1st degree ROH-> aldehyde

2nd degree ROH -> ketone

1st degree ROH -> carboxylic acid

Regioselectrive: only 1st and 2nd degree C(alpha)-OH oxidized to C(alpha)=O

Racemic mix of C=O

Oxidation

gain in # bonded O atoms, loss of bonded H atoms

Reduction

loss in # bonded O atoms, gain in bonded H atoms

Oxidation of 1st Degree ROH to aldehyde

use PCC, CrO3, Py, HCl

Oxidation of 1st Degree ROH to Carboxylic Acid

Strong, fully oxidized

Na2CrO4+H2SO4+H2O, KMnO4+HO-+H2O

Oxidation of 2nd Degree Alcohol to Ketone

any Cr or Mn based reagent set

Synthesis of Linear Ethers

1) React alkoxide with alkyl halide (basic conditions via SN2)

2) Dehydrative Coupling of two alcohols (acidic conditions, SN2 or SN1)

3) Acid catalyzed addition of ROH to alkene (C+ intermediate with Markovinikov addition, racemic mix)

4) Alkoxymercuration-reduction addition of ROH to alkene (cyclic mercurium cation, Markovnikov addition, racemic mix-- RO attacks most sub'd C of cyclic cation)

ROR and H-X acid Reaction

ROR + 2 HX -> R-X + R'-X + H2O

heat required

1st degree C(alpha) = SN2

3rd degree C(alpha) = SN1 with C+ intermediate

Epoxide

Cyclic Ether, nucleophilic addition relieves ring strain (substitution)

Opening Epoxides under Acidic Conditions (H-Nu:)

H2O: trans-1,2-diol formation

ROH: trans-1,2-hydroxy-ether formation

SN2 based mechanism

Regiospecific: incoming HO or RO adds to most-sub'd C of ring

Stereospecific: anti formation of new HO group

Opening Epoxides Under Basic Conditions (Nu:-)

OH- followed by neutralization: trans-1,2-diol formation

Other Nu:-: same as above

Regiospecific: Nu:- adds to least sub'd C of ring

Stereospecific: anti formation of HO group and Nu:-

Synthesis of Epoxides from Alkene + Peroxy Acid

(RC(O)OOH) under acidic conditions forms epoxide ring

Regioselective: n/a, bridges both C

Stereospecific: syn addition of O to flat C=C bond (but can add top or bottom)

Synthesis of Epoxide from 1,2-halohydrin

Basic conditions

SN2 based INTRAmolecular cyclization rxn: ROH deprotenates to form ring

Regiospecific: formed O- adds to C(alpha) of C-X bond

Stereospecific: inversion of C(alpha) group