# Structural Biochemistry/Organic Chemistry/Organic Synthesis
## Introduction

Organic Synthesis is the part of Organic Chemistry that deals with the creation of compounds from other available compounds. There are lots of different ways to make substances and synthesis studies this. There are four very basic reaction schemes that can help in seeing what synthesis consists of: S$_N$1 (Unimolecular Nucleophilic Substitution), S$_N$2 (Bimolecular Nucleophilic Substitution), E1 (Unimolecular Elimination), and E2 (Bimolecular Elimination).

### S$_N$2

As the name implies, S$_N$2 reactions deal with the substitution of some group for another. There are certain things the group coming in and the group leaving need to have in order for the reaction to happen because, for example if the leaving group cannot leave or is a group that does not want to leave, the reaction will not happen. The group coming in is referred to as the nucleophile. The nucleophile has electrons that can be donated to some atom lacking electron density, the electrophile. in an substitution reaction, the electrophile has the leaving group attached. To be considered a good nucleophile, the group needs to have lots of electron density usually being charged, and are not able to balance these extra electrons. There are several ways a molecule can balance its electron density. Three of these ways are: resonance, atomic radius, inductance. Of these, resonance is the biggest factor although atomic radius also plays a big role. inductance could be important but it is a balancing force that loses its power rather quickly. Resonance refers to the phenomenon where a molecule oscillates between two different states, usually by moving around double bonds. This makes it so that charges move around in a molecule. This moving of the charge is more of an oversimplified way of seeing this. In reality, the molecule exist in a hybrid state of all the different resonance forms. This hybrid state actually spreads the electron density all around the molecule.
Atomic radius plays a role in stabilizing charge. For example, all the halogens have a -1 ionic form. The charge is the same for all of them. What changes is the atomic radius. a larger radius means the electron density can be dispersed more, thus balancing the charge better.
Inductance is the ability of electronegative atoms to pull electron density towards themselves and can stabilize charge in that way. This force dies out rather quickly though as the electronegative moves farther away from the charge.
A molecule that can donate electrons is called a Lewis base and indeed most nucleophiles are basic, although a good base is not necessarily a good nucleophile. A molecule that can withstand a negative charge (by using what was mentioned above) could be a good leaving group.
In the molecule of bromomethane, the leaving group is the bromo group and the electrophile is the carbon. this bromo group is very electron withdrawing and because it has a big atomic radius it can dissipate the charge, a term called polarizability. A typical S$_N$2 reaction involves this bromomethane and NaOH
After the reaction has occurred the stereochemistry of the new product will be the exact opposite than before. For example if it was an (R)-iodopropane reacting with bromine it would because (S)-bromopropane. The reason for this inversion of the stereocenter is because of the backside attack the nucleophile does in Sn2 reactions.
Ways to increase the rate of the reaction
1. Increasing the concentration of either the nucleophile or substrate will increase the rate of the reaction. This is because it is a bimolecular reaction, where rate = k[nucleophile][substrate]: the rate is dependent on the concentrations of nucleophile and substrate. Increasing the concentration of nucleophile will increase the rate, since rate is proportional to the concentration of nucleophile and concentration of substrate. The same applies to the substrate.
2. Using a good leaving group.
3. Increasing the temperature of the system.
4. Anything that will not sterically hinder the nucleophile will increase the rate of the reaction.
5. Using a polar aprotic solvent, meaning the solvent does not contain an acidic proton.

### S$_N$1

The reason for the 2 in and S$_N$2 reaction is the fact that the leaving group and the nucleophile are both in the rate law of the reaction. This means that the concentration of both bromomethane and NaOH affect the rate of the reaction. This is because the reaction happens in one step with one intermediate where the leaving group-electrophile bond is breaking and the nucleophile-electrophile bond is forming. In an S$_N$1 reaction there are two steps and two intermediates. The first is the formation of a carbocation where the leaving group leaves and the carbon is left with a positive charge. The second is the formation of the nucleophile-electrophile interaction. Of these two The first is the slowest and called the rate determining step. This means that no matter how much nucleophile there is the rate of reaction will not changed until the concentration of the substrate changes. The first step is very slow because forming a carbocation is not very favorable. The only way for this to happen is if the leaving group is a really good one and for there to be a way to stabilize the carbocation. The first one is simple, find a molecule with a very good leaving group. By making the carbocation a secondary or tertiary carbocation, the charge is stabilized better. This is done by resonance or hyperconjugation. The electrons in the methyl group(s) interact with the carbocation and give it some stabilization.
The nucleophile can attack the carbocation from both faces, the alpha or beta face of the substrate. As a result one will generally see a racemic mixture, or 50:50 mixture of a R and S conformation of the resulting compound.
In order for the slow first step to happen, the second faster step needs to be slowed down. The way to do this is to have not have a very good nucleophile. instead of the hydroxide ion, water its conjugate acid can be used.
Ways to increase the rate of an Sn1 reaction
1. Another way to increase the rate of the reaction for Sn1 reactions is to use a polar protic solvent. The polar protic solvent will increase the rate of the reaction because it will help stabilize the leaving group. It will stabilize the leaving group because it will solvate the charge. Anything that can help stabilize the leaving group will make it more likely to leave because it will be going to a lower energy state.
2. Another way to increase the rate of the reaction for Sn1 reactions is to add a salt. The salt will help stabilize the leaving group through ionic interactions, and because the leaving group would be more stable it is more likely to leave and form the carbocation that much faster.
3. Another way to increase the rate of the reaction for Sn1 reaction is to increase the polarity of the solvent. The polarity of the solvent will help stabilize the carbocation by hydrogen bonding. Therefore if one wants to increase the rate of reaction of an Sn1 reaction he or she simply needs to increase the polarity of the solvent used.
4. Another way to increase the rate of the reaction is to increase the temperature of the system.
5. Using a polar, protic solvent, meaning the solvent has acidic hydrogens.
Beta branching effect on the rate of the reaction
Beta branching means that there is a carbon chain on the carbon next to the carbon that is bonded to the leaving group. . For SN2 reactions beta branching will slow down the reaction because of steric hindrance, thus the less beta branching the alkyl halide has the faster the reaction will be for SN2. Based on the experiment results in SN1 reactions more beta branching will slow down the Sn1 reactions because of steric hindrance that hinders the nucleophilic attack on the carbocation.
Ring effect
Experiments has shown that the bromocyclopentane reacted instaneously while the bromocyclohexane required some time for the reaction to proceed showing that 5 membered ring reacts faster than a 6 member ring. The reason behind this is because of transannular strain, the unfavorable interactions between ring substituents on non-adjacent carbon, the less transannular strain there are the slower the reaction will be for SN1 and SN2. A 5-member ring is the only exception to this rule, but in general 3, 4, 6 member ring will react slowly because it is more stable and low in energy.
Aromatic Ring Effect
Aromatic rings will enable primary alkyl halide to proceed SN1 reactions because the aromatic ring can stabilize the carbocation through resonance. The position of the aromatic ring has to be one carbon away from the leaving group so the electrons can resonate and stabilize the carbocation. Electron-donating groups will contribute to the electron density so it will “activate” the ring and make it more susceptible to electrophilic attack, increasing the rate of reactions, while electron-withdrawing group will decrease the rate of reactions because it removes electron density from the aromatic ring, as shown with experiments the methoxybenzyl chloride, an electron donating group, reacted, while the nitro, an electron withdrawing group, did not react at all.

## Reference

1. Vollhardt, K. Peter C., and Neil Eric Schore. Organic Chemistry: Structure and Function. New York: W.H. Freeman, 2011. Print.