Biological Chemistry 1A Singly Bonded Functional Groups

Biological Chemistry 1A: Singly Bonded Functional Groups

Course Overview and Resources

• Lecturer: Dr. Joshua Levinsky, Room 275 – Joseph Black Building (j.levinsky@ed.ac.uk).

• Credit: Dr. Peter Kirsop.

• Synopsis: These five lectures cover the chemistry of singly bonded functional groups, focusing on their synthesis, interconversion, and reactivity.

• Biologically Important Singly Bonded Functional Groups:

  • Alkyl Halides (most important)

  • Alcohols

  • Ethers

  • Amines

• Key Characteristic: All these functional groups are polarized, which significantly influences their chemical behavior.

• Recommended Books:

  • BC1 Coursebook (Chapters 7, 12, and 13) – Primary resource.

  • Chemistry for the Biosciences.

  • Chemistry for Biologists by Reed, Chapter 8 (available in the library).

Alkyl Halides

Definition and Classification

• General Formula: $R-X$

  • $R$ represents a hydrocarbon group.

  • $X$ represents a halogen ($F$, $Cl$, $Br$, $I$).

• Importance: Alkyl halides are highly versatile and serve as crucial starting materials for a vast array of organic reactions.

• Classification by Carbon Substitution:

  • Primary ($1^ ext{ry}$, $1^ ext{o}$): The carbon atom bonded to the halogen is attached to only one other carbon atom.

    • Example: 1-chlorobutane.

  • Secondary ($2^ ext{ry}$, $2^ ext{o}$): The carbon atom bonded to the halogen is attached to two other carbon atoms.

    • Example: 2-chlorobutane.

  • Tertiary ($3^ ext{ry}$, $3^ ext{o}$): The carbon atom bonded to the halogen is attached to three other carbon atoms.

    • Example: tert-butyl chloride.

• Common Industrial Examples:

  • PVC (Polyvinyl Chloride): A widely used plastic.

  • CFCs (Chlorofluorocarbons): Employed in refrigeration, e.g., Freon-11 ($CCl<em>3F$) and Freon-12 ($CCl</em>2F_2$).

Synthesis of Alkyl Halides

• From Alkenes: Via addition reactions.

• From Alcohols:

  • Using thionyl chloride ($SOCl_2$).

  • Using phosphorous tribromide ($PBr_3$): This reaction is particularly effective due to the strong affinity of phosphorus for oxygen.

Reactivity of Alkyl Halides

• Polarity: The carbon-halogen bond is polarized due to the electronegativity difference, creating a partial positive charge on carbon ($C^{ ext{d}+}$) and a partial negative charge on the halogen ($X^{ ext{d}-}$).

  • $C^{ ext{d}+} - X^{ ext{d}-}$

• Electrophilic Carbon: The partially positive carbon atom is susceptible to attack by nucleophiles.

• Nucleophilic Substitution: In combination with a good leaving group ($X$), this leads to nucleophilic substitution reactions.

• Leaving Group Ability: The effectiveness of halogens as leaving groups increases with atomic size:

  • F < Cl < Br < I

• Mechanism of Nucleophilic Attack: A nucleophile ($Nu^{ ext{d}-}$) attacks the electrophilic carbon ($C^{ ext{d}+}$) of the alkyl halide. Simultaneously, the carbon-halogen bond breaks to prevent the formation of a pentavalent carbon intermediate.

  • This is typically an equilibrium, which is displaced towards product formation (right-hand side) when $X$ is a good leaving group.

  • Curly Arrows: Represent the movement of an electron pair.

    • Tail: Indicates the origin of the electron pair.

    • Head: Indicates the destination of the electron pair.

    • Bond Breaking: Arrow starts from the bond and points to the atom receiving the electron pair.

    • Bond Making: Arrow starts from the electron pair (e.g., lone pair or $ext{p}$-bond) of the nucleophile and points to the electrophilic atom.

• Nucleophiles (Electron-rich species): Possess a negative charge or a pair of electrons in a high-energy filled orbital available for donation to electrophiles.

  • Examples of uncharged nucleophiles: Ammonia ($NH<em>3$), water ($H</em>2O$), dimethylsulfide ($(CH<em>3)</em>2S$), trimethylphosphine ($(CH<em>3)</em>3P$).

  • Examples of negatively charged nucleophiles: Hydroxide ($OH^-$), bromide ($Br^-$), cyanide ion ($CN^-$), methanethiolate ($CH_3S^-$).

• Electrophiles (Electron-deficient species): Possess a positive charge or an empty atomic orbital/low-energy antibonding orbital available to accept electrons.

  • Examples of uncharged electrophiles: Carbonyl groups ($C=O$), aluminum trichloride ($AlCl<em>3$), boron trifluoride ($BF</em>3$).

  • Examples of positively charged electrophiles: Proton ($H^+$), nitronium ion ($NO<em>2^+$), hydronium ion ($H</em>3O^+$).

Alkyl Halide Reactivity with Specific Nucleophiles

• Carbon-based Nucleophiles:

  • Nitrile Synthesis: Utilizing cyanide ($CN^-$) to form a new carbon-carbon bond.

    • $R-X + CN^- <br>ightarrow R-CN + X^-$

    • Nitriles can then be reduced (e.g., with $LiAlH<em>4$) to primary amines ($R-CH</em>2-NH_2$). This route increases the carbon chain length by one.

  • Retrosynthesis: A method of planning organic synthesis by working backward from the target molecule to simpler starting materials. A retrosynthetic arrow ($<br>ightarrow$) often indicates a functional group interconversion (FGI).

  • Alkyne-based C-C bond formation:

    1. Deprotonation of a terminal alkyne ($R-C ext{≡}C-H$) using a very strong base like sodium amide ($Na^+NH_2^-$). Sodium amide is prepared by adding sodium metal to liquid ammonia at low temperatures. Alkynic protons are weakly acidic, allowing deprotonation.

       • $R-C ext{≡}C-H + NH<em>2^- ightarrow R-C ext{≡}C^- + NH</em>3$

    2. The resulting alkynide anion acts as a nucleophile on the alkyl halide.

       • $R-C ext{≡}C^- + R'-X <br>ightarrow R-C ext{≡}C-R' + X^-$

    • This method forms a new carbon-carbon bond and creates an alkyne, which can undergo further useful reactions.

• Nitrogen-based Nucleophiles:

  • Quaternary Ammonium Salt Formation: Tertiary amines can act as neutral nucleophiles with alkyl halides to form quaternary ammonium salts ($(R)_4N^+X^-$).

    • This reaction does not work well with primary and secondary amines as starting materials, a topic to be covered later.

  • Primary Alkyl Amine Synthesis (via Azide): A superior route to primary alkyl amines involves sodium azide.

    1. Formation of alkyl azide ($R-N_3$):

       • $R-X + N<em>3^- ightarrow R-N</em>3 + X^-$

    2. Reduction of the alkyl azide to the primary amine ($R-NH<em>2$) using a reducing agent like $LiAlH</em>4$.

       • $R-N<em>3 + LiAlH</em>4 <br>ightarrow R-NH_2$

    • Note: This method retains the original number of carbon atoms, unlike the cyanide route.

• Oxygen-based Nucleophiles:

  • Alcohol Formation: Reaction with hydroxide ($OH^-$) yields the corresponding alcohol.

    • $R-X + OH^- <br>ightarrow R-OH + X^-$

    • Note: This is generally not useful for small molecules as alcohols are usually more affordable and readily available than alkyl halides.

  • Williamson Ether Synthesis: A highly useful reaction for ether formation.

    1. Formation of an alkoxide nucleophile ($R-O^-$) by deprotonating an alcohol ($R-OH$) with a strong base.

    2. Reaction of the alkoxide with an alkyl halide ($R'-X$) to form the ether ($R-O-R'$).

       • $R-O^- + R'-X <br>ightarrow R-O-R' + X^-$

    • This method also works effectively with thiols ($R-SH$) to produce thioethers ($R-S-R'$).

  • Ester Formation: Alkyl halides can react with carboxylate anions ($R'-COO^-$) to form esters.

    • $R-X + R'-COO^- <br>ightarrow R'-COO-R + X^-$

    • While effective, esters are more commonly synthesized from carboxylic acids and alcohols.

• Halogen-based Nucleophiles (Finkelstein Reaction):

  • Purpose: Useful for preparing alkyl iodides from alkyl chlorides or bromides.

  • Mechanism: Involves reaction with an iodide salt, such as potassium iodide ($KI$), in an organic solvent (e.g., methanol).

    • $R-X + I^- <br>ightarrow R-I + X^-$ (where $X = Cl$ or $Br$)

  • Driving Force: The reaction is driven forward because $KCl$ and $KBr$ (the byproducts) are insoluble in organic solvents and precipitate out.

  • Significance: $I^-$ is an excellent leaving group, and alkyl iodides are generally more reactive, thus increasing the yields of subsequent reactions with other nucleophiles.

Nucleophilic Substitution Mechanisms ($S<em>N1$ and $S</em>N2$)

• Two primary mechanisms govern how a nucleophile ($Nu$) attaches and a leaving group ($L.G.$) cleaves in nucleophilic substitution, depending on reaction conditions.

$S_N1$ Mechanism (Substitution, Nucleophilic, unimolecular)

• Nature: A two-step process.

  1. Step 1 (Rate-Determining Step): The leaving group departs as an anion, forming a carbocation intermediate.

  2. Step 2 (Fast Step): The carbocation is rapidly attacked by the nucleophile.

• Energy Profile: Characterized by two transition states and a carbocation intermediate (a local minimum in the potential energy diagram). The carbocation is highly reactive, making the second step fast.

• Kinetics:

  • The slow step involves only the alkyl halide ($RX$).

  • Rate Law: $Rate = k[RX]$

  • The concentration of the nucleophile ($[Nu^-]$) does not appear in the rate equation.

• Substrate Considerations:

  • Favored by Substrates forming Stable Carbocations:

    • Stability order: R3C^+ > R2CH^+ > RCH2^+ > CH3^+ (i.e., tertiary > secondary > primary > methyl).

    • Tertiary alkyl halides are most reactive, as the $3$ electron-donating alkyl groups stabilize the positive charge of the carbocation.

  • Stabilization through resonance (e.g., in allylic or benzylic carbocations) also highly favors $S_N1$ reactions.

• Stereochemical Implications:

  • If the starting material is chiral, an $S_N1$ reaction will result in a racemic mixture (an equal mixture of both enantiomers).

  • This is because the carbocation intermediate is planar, allowing nucleophilic attack from either face with equal probability.

• Solvent Considerations:

  • Favored by Polar Protic Solvents: Such as water ($H_2O$) or alcohols ($ROH$).

  • These solvents stabilize the intermediate carbocation and the departing halide anion through solvation, lowering the activation energy for the rate-determining step.

  • Example: For a tertiary alkyl halide, the relative rate in water is $100,000$ compared to $1$ in ethanol.

$S_N2$ Mechanism (Substitution, Nucleophilic, bimolecular)

• Nature: A one-step, concerted process.

  • The attack of the nucleophile and the loss of the leaving group occur simultaneously.

• Energy Profile: Characterized by a single transition state (a local energy maximum). This transition state involves partial bond formation between the nucleophile and carbon, and partial bond breaking between carbon and the leaving group.

• Kinetics:

  • The slow step (which is the only step) involves both the alkyl halide ($RX$) and the nucleophile ($Nu^-$).

  • Rate Law: $Rate = k[RX][Nu^-]$

• Substrate Considerations:

  • Disfavored by Sterically Hindered Substrates: The transition state has a sterically crowded carbon center, with both the nucleophile and leaving group partially bonded.

  • Reactivity Order: CH3X > RCH2X > R2CHX > R3CX (i.e., methyl > primary > secondary > tertiary).

  • Tertiary alkyl halides are generally very unreactive in $S_N2$ reactions due to steric hindrance preventing rear-side attack.

  • General Rule: No $S_N2$ reaction occurs at $sp^2$ hybridized carbons (e.g., vinyl or aryl halides) because rear-side attack is impossible.

• Stereochemical Implications:

  • Stereospecific: $S_N2$ reactions are stereospecific, meaning they have a well-defined and 100% predictable stereochemical outcome.

  • Walden Inversion: Rear-side attack is always observed, leading to a complete inversion of configuration at the chiral center. This phenomenon was discovered by Walden in 1896.

• Solvent Considerations:

  • Favored by Aprotic Solvents: Such as acetonitrile ($CH_3CN$), DMSO, or acetone.

  • Aprotic solvents do not extensively solvate the nucleophile, leaving the nucleophile