Nucleophilic Reactions and Cancer Drugs By the end of this chapter, you’ll know enough to explain how these drugs work!

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Presentation transcript:

Nucleophilic Reactions and Cancer Drugs By the end of this chapter, you’ll know enough to explain how these drugs work!

S N 2 Orbital Timeline Hughes (left) and Ingold (right) worked Out the mechanism for S N 2 reactions

S N 2 Movie General YouTube comments: “Poor carbonyl keeps getting attacked by nasty Mr Grignard” “that halogen is a creeper” “INVERTED PRODUCT!” “This is the best movie I’ve ever seen”

Predict the S N 2 Products NO S N 2 Rxn (3 o Carbon)

5 Higher-Row Nucleophiles in the S N 2 Reaction Down a column of the periodic table: nucleophiles become larger and more polarizable, but less solvated and less basic. Polarizability means that the loosely held electron cloud of iodide is readily distorted The tightly held electron cloud of fluoride is less polarizable.

Because of their small size, second-row nucleophiles are solvated by polar solvents hindering back-side attack: Therefore water and alcohol solvents are not suitable for S N 2 reactions with second-row nucleophiles. Larger, more polarizable groups, like Iodine, do not have this effect.

S N 2 reactions with second-row nucleophiles are carried out in polar aprotic solvents: Includes DMSO, DMF, and acetonitrile (CH 3 CN) Consequently, the anionic nucleophile is unsolvated and reactive

Pick the Best Nucleophile for S N 2 Bulky Neg charge Stronger Base (Aprotic Solvent) More Polarizable (Protic Solvent) More Polarizable (Protic Solvent) Stronger Base (Aprotic Solvent) Stronger Base (Aprotic Solvent) More Polarizable (Protic Solvent) Bulky Stronger Base

Note: This table will be included on your tests

Determine the Direction of the S N 2 Reaction HBr (pKa = -9) NH 4 (pKa = 9.4) HCl (pKa = -7.0) H 2 S (pKa = 7.0) In equilibrium

Methyl Bromide – Effective at Putting Bugs to Sleep … for good (aka Insecticide) Proteins perform reactions in cells to keep an organism alive. Proteins contain Amino Acid Which can do S N 2 reactions w/methyl bromide Once reacted, the proteins function in the cell is destroyed X Methyl Bromide used to kill all kinds of insects Is still frequenly sprayed on crops Alternative Methods are being developed

S N 1 Reaction General YouTube comments: “lol” “This rocks,dudez.” “very n1”

Predict the Product for the Following Reactions

S N 1 or S N 2? 1o1o Vinyl Neither 3o3o 1 o benzyl (look at solvent + Nu) Strong Polar Aprotic 3 o benzyl Keep in mind that the reaction may not proceed due to heavy S N 2 Condions 3 o benzyl 2 o (look at solvent + Nu) Polar Aprotic Strong 2 o (look at solvent + Nu) Polar Protic Weak Neither Benzyl

Good Polar Protic Solvents Good Polar AProtic Solvents

Predict the Intramolecular Product

S-Adenosyl methionine (SAM) SAM, a Biological Methylating Agent A sulfide leaving group

Methyltetrahydrofolate, Another Biological Methylating Agent An amine leaving group

Nucleophilic Reactions and Cancer Drugs By the end of this chapter, you’ll know enough to explain how these drugs work!

Mechlorethamine, a Nitrogen Mustard Mustard: refers to odor and color of the impure warfare agent. Now used to treat lymphomas, breast and lung cancers. Crosslinks DNA, which triggers cell to kill itself. This affects only rapidly dividing cells, both normal and cancerous.