Professor David L. Van Vranken Chemistry 201: Organic Reaction Mechanisms I

Topic 20: Phosphorus Chemistry

References: Literature cited Phosphorus Functional Groups

■ Here’s how to name phosphorus functional groups:

R R R OR R OR O O R P P P R P P(III) R R OR O R phosphine phosphinite phosphonite phosphite (ester)

O O O O R R R OR R OR O O P P P R P R P(V) R R OR O R phosphine oxide phosphinate phosphonate phosphate (ester)

■ Few of these functional groups are common.

O O O H P N P HO OH O CH HO F 3 glyphosate sarin Phosphorus Functional Groups

■ pKas reveal the difference in basicity between trialkylphosphines and triarylphosphines

Et Ph .. + + N N Ph2N Et Et Ph Ph resonance H H reduces l.p. basicity pKa 11 ~ -5

.. Bu Ph Ph P + + 2 P P not so much Bu Bu Ph Ph H H resonance

pKa 9 3

■ Trialkylphosphines are way more nucleophilic than triarylphosphines

Bu Ph Bu P: Ph P: Bu Ph way more nucleophilic

Howard ST, et al. Can. J. Chem. 1997, 75, 60. Allman, T.; Goel, R. G. Can. J. Chem. 1982, 60, 716.. POCl3 is a Very Reactive Electrophile

■ Old conditions for elimination of OH groups. Contrast the outcomes.

SOCl Cl 2 pyridine OH POCl3

pyridine (solvent)

■ Phosphates don’t substitute very quickly, but Cl3P=O is special

■ Vilsmeier-Haack Reaction - amides attack Cl3P=O

+ NMe O Cl NMe 2 2 E.A.S. MeO + MeO H2O MeO H OMe OMe workup OMe

POCl3 + DMF

Mechanism for formation of the Vilsmeier reagent:

: .. + + O O -O O NMe O NMe O O - + 2 O 2 P NMe P .. P P Cl 2 Cl Cl N Cl Cl Cl Cl Cl Cl Cl Cl :Cl- Phosphates as Leaving Groups and/or Electrophiles

■ Phosphates are good leaving groups. In biology magnesium-diphosphophate is the most common leaving group

leaving group leaving group

.. - O O O OR O O P P P nucleoside P P -O O O O -O O O R O O O O O Mg Mg

■ In acid-hydrolysis of trimethyl phosphate, C-O bond cleavage competes with P-O bond cleavage because phosphates are good leaving groups and it is difficult to attack a phosphate.

O HCl O P HOCH H3CO OCH P 3 3 H3CO OH H3CO H2O H3CO

- H + H + ..

O O .. - HO OH P P CH3 H3CO OCH3 H3CO O H3CO H3CO Hydrolysis of Phosphites and Phosphates

■ Phosphites hydrolyze much faster than phosphates.

phosphate phosphite O .. P P F. Westheimer RO OR RO OR RO RO JACS 1988, 181 Chem. Ber. 1960, 1220

HO- 1 1,000

H3O+ 1 1,000,000,000,000

■ If you want to synthesize P-O bonds use phosphites, n ot phosphates because you can always oxidize a phosphite up to a phosphate later. Modern DNA synthesis is based on the chemistry of phosphites + acid. acid DMTO N DMTO N O NHBz N O NHBz N HN N N N N N N N O pKa 4.9 O NC P NC P O .. N + O .. O + OH 1 minute HN DNA DNA

Letsinger, R. L. JACS 1976, 98, 3655. Caruthers,M. H. TL 1983, 24, 245. Mechanism: Fast Acid-Catalyzed Exchange at Phosphites

■ Recall dehydrobromination from sophomore organic chemistry.

(cat HA) Br OH 3 OH 3 Br P P Br Br HO OH

phosphorane tetrahedral intermediate intermediate don't draw one-step SN2 Nu O - H O: .. P C L.G. R P Br Br L.G. Nu Br

■ The mechanism involves protonation of the phosphite

-A: H .. H A Br .. P P P + EtOH Br Br HO Br HO Br Br Br Br

H -Br A .. H H O.. H EtO H H Et + + - + P P P : P Br Br Br O Br O Br Br Br Br Br Br P=O Bond Formation Drives Many Reactions

■ Mechanism for oxidation by I2 /H2O in DNA synthesis

H B: H H2O: O O O R R B: R R R R P R P R P R P R P R .. + R + R R R I I I I

■ Phosphines oxidize easily

.. O O - C O 89 kcal/mol O–O Clayden, et al. R P Ph3P=O 137 kcal/mol R P P + JCS 1960, 3284 R R R R R Bu3P=O 128 kcal/mol R R

Bu3P fast, very air sensitive Ph3P slower

■ Convention: Draw P=O, but all the reactivity is best explained by +P—O– D. G. Gilheany “Structure and bonding in tertiary phosphine chalcogenides” Chemistry of Organophosphorus Compounds p. 1-52 Nucleophilicity of Phosphorus

■ Phosphites act as nucleophiles in the Michaelis-Arbuzov reaction; a phosphate acts as a leaving group.

OEt O O O . ∆ P . P EtO OEt OEt EtO OEt EtO Br

-Br: O O P EtO + OEt EtO

Kosolapoff, G. M. Org. React. 1951, 6, 276. Michaelis, A.; Kaehne, R. Ber. 1898, 31, 1048. Arbuzov, A.E. J. Russ. Phys. Chem. Soc. 1906, 38, 687; Chem. Zentr. 1906, II, 1639. Ph3P=O as a Leaving Group

■ Appel reaction. Note attack at halogen in a Br-C bond and the ability of haloform anions to act as leaving groups.

Br C—Br :PPh Br 3 3 Ph3P=O + Br3C—H O bromoform H

- + : Br3C Br PPh3

-Br : Br Ph Ph PPh Ph O O - O: 3 P Ph P + Br + Ph Ph

■ Note the stability of haloform estimated anions and the ability to act as a cpd pKa (MeOH) leaving group. F3C-H 30.5 Cl3C-H 24.4 Br3C-H 22.7 Streitweiser, A.; et al. I3C-H 22.5 JACS1976, 5229 Ph3P=O as a Leaving Group

■ The Mitsunobu reaction for ”inversion" of alcohols

N CO2Et EtO2C N Ar OH + Ph P: PPh 3 3 S 2 O N O O Ph3P=O + HO O .. H O O - N CO2Et Ar EtO2C N Ar H

O. Mitsunobu Synthesis 1980, 1 D. L. Hughes Org. React. 1983, 29, 1.

Mechanism depends on order of addition Varasi, M.; Walker, K. A. M.; Maddox, M. L. JOC 1987, 52, 4235. The Staudinger Reaction of Azides

■ Recall the stereoelectronics for anti addition to π*.

.. antiperiplanar .. X -X

■ The Staudinger mechanism is easily understood if you draw the right resonance structure for N3.

easily hydrolyzed R + .. - H2O :N N N: - Ph3P N Ph3P N: Ph3P O H2N + .. Ph3P: R R R

-N2

.. .. N N N N Ph P :N R 3 + .. - Ph3P N R cis

Gololobov, Y G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353. The Staudinger Reaction of Azides

■ The Staudinger ligation takes place under physiological conditions

protein O pH 7 O OMe .. N N - H O .. N .. 2 H N reporter PPh2 + reporter P O Ph Ph

O

OMe .. N -N2 reporter +P - Ph2

Bertozzi, C. R.; et al. JACS 2005, 127, 2686. The Wittig Reaction - Review

+ ■ Makes C=C bonds from O PPh3 O PPh3 O PPh3 C=O : R' R - R' R R' R phosphonium ylide

transition state draw as ■ Concerted [2+2], b u t th e C- concerted C bond forms slightly before the P- δ- H O CH3 H O C CH O bond. 1% 44% 3 bond bond .. R3P C H Restrepo-Cossio, A. A.; et al. P H + - Heteroat. Chem. 1997, 8, 557. δ+ R R

■ P=O elimination: above -20 °C if R = alkyl, O PPh3 O PPh3 < -20 °C below -20 °C if R = EWG CO2Et R CO2Et R

■ Making phosphonium ylides .. CH - .. Br- CH3 2 CH2 CH3-Br + n-BuLi + Ph P Ph P Ph P Ph Ph P Ph C H Ph Ph Ph 6 6 Ph ether, rt Ph Ph rt, 2 days pKa 18 this res. struct. not very useful