ochem week 7 part 2

Good Leaving Groups & Stereochemistry

• Review of previous concepts: Phosphorous tribromide ($PBr<em>3$) and thionyl chloride ($SO Cl</em>2$) convert alcohols into alkyl halides, creating good leaving groups. Tosylates also serve as good leaving groups.

• Stereochemical implications:

  • Converting an alcohol to a tosylate does not change the stereochemistry of the carbon. The -OH is replaced by -OTs with retention of configuration.

  • Converting an alcohol to an alkyl halide using $PBr<em>3$ or $SO Cl</em>2$ does affect the stereochemistry of the carbon. For example, $PBr_3$ often leads to inversion of configuration at the stereocenter.

  • Understanding these stereochemical outcomes is crucial for synthesis problems.

Elimination Reactions of Alcohols

Three main types of elimination reactions were discussed, focusing on forming alkenes from alcohols.

E1 Elimination (Acid-Catalyzed Dehydration)

• Context: A common reaction in organic chemistry I (Orgo 1), especially predominant with heat.

• Conditions: Typically strong acid (e.g., $H<em>2 SO</em>4$, $H<em>3 PO</em>4$) and heat ($\Delta$).

• Mechanism: The mechanism is very quick and follows the general E1 pathway:

  1. Protonation of alcohol: The alcohol (a poor leaving group) is protonated by the acid to form an alkyloxonium ion, which has water as a good leaving group.

     • Example: $R-OH + H^+ \rightarrow R-OH_2^+$

  2. Loss of leaving group: Water leaves, forming a carbocation intermediate. Tertiary carbocations are preferred due to their stability. This is the unimolecular step ($E_1$).

     • Example: $R-OH<em>2^+ \rightarrow R^+ + H</em>2 O$

  3. Deprotonation: A base (often water) abstracts a beta-hydrogen from an adjacent carbon, and the electrons from the C-H bond form a new C=C pi bond, leading to the alkene product. The more substituted (Zaitsev) product is usually preferred.

     • Example: $R-CH<em>2-CH</em>2^+ + H<em>2 O \rightarrow R-CH=CH</em>2 + H_3 O^+$

• Key takeaway: Requires heat, forms a carbocation, and is often a desired side reaction when substitution is favored at higher temperatures.

E2 Elimination (Using $POCl_3$/Pyridine)

• Purpose: Provides an alternative to E1 dehydration, avoiding harsh acidic conditions and high temperatures, which can lead to unwanted side reactions (e.g., rearrangement with carbocations).

• Conditions: Phosphoryl chloride ($POCl<em>3$) and a base (e.g., pyridine or triethylamine, $Et</em>3 N$) at cold temperatures.

• Pyridine characteristics: A nitrogen-containing aromatic base, similar to benzene but with one carbon replaced by nitrogen. Its lone pair on nitrogen makes it a decent base and also acts as a solvent.

• Mechanism (instructor's preferred interpretation):

  1. Nucleophilic attack on phosphorus: The alcohol oxygen attacks the phosphorus of $POCl<em>3$, and a chlorine atom leaves (SN2-like displacement). This step might involve the pi bond of $POCl</em>3$ temporarily moving to oxygen, then reforming and kicking off chloride. The instructor prefers a Grignard-like attack (pi bond moves up, then reforms kicking out Cl) over a direct SN2 attack described in the textbook due to sigma vs. pi bond strength considerations.

  2. Chloride abstraction/proton transfer: The liberated chloride or the base (pyridine) removes the hydrogen from the protonated alcohol oxygen, forming an intermediate where oxygen is bonded to phosphorus and two chlorides, with a P=O double bond.

     • Instructor's note: The hydrogen on the alcohol oxygen is often pulled off by the base (e.g., pyridine) before or during the attack on phosphorus since alcohols are acidic (pKa $\approx 16$) compared to amines (pKa $\approx 38$ for conjugate acid).

  3. E2 Elimination: The base (e.g., pyridine) abstracts a beta-hydrogen from the carbon adjacent to the alcohol-derived leaving group. Simultaneously, the C-H bond forms the new C=C pi bond, and the oxygen-phosphorus complex (e.g., $O-POCl_2$) leaves as the leaving group.

• Characteristics: Similar to a classic E2 reaction: concerted, simultaneous removal of beta-hydrogen, formation of pi bond, and departure of leaving group. Occurs under milder, basic conditions and cold temperatures.

E1CB Elimination (Carbanion Mechanism)

• Rarity: A much rarer, niche E1 mechanism compared to the typical E1. The