Sania Jakati

In this article, we will have a closer approach towards the nucleophilic substitution reaction mechanism, i.e., SN1 with appropriate SN1 examples.

What does the one stands for in the SN1 mechanism? Means that it follows first-order, or we can say the reaction rate depends only on the concentration of substrate. We will analyze the factors governing the reaction mechanism with various SN1 examples like carbocation stability, carbon skeleton, the leaving group, solvent, etc.

This reaction occurs in 2 steps:

Step 1: Formation of the carbocation.

Step 2: Reaction of carbocation with the nucleophile

Factors affecting SN1 mechanism :

• Stability order of carbocations

• Nucleophile

• The effect of leaving group

• Stereochemistry involved in SN1 mechanism

Carbon skeleton structure: compounds forming stable carbocations react by the SN1 mechanism. Also, the substrate, which contains good leaving groups and adjacent substituents like a phenyl group that stabilizes a positive charge mesomerically, are prone to undergo SN1 reaction.

More substituted carbocation, i.e., tertiary carbon, readily forms carbocation, which is very stable. The stability of carbocation formed as an intermediate in the reaction plays a crucial role in determining the efficiency of the SN1 reaction.

Stability order of carbocation:

Tertiary > secondary > primary

Note: Planarity is so essential to the structure of a carbocation that if a tertiary cation cannot become planar, it is not formed.

Allylic electrophiles react well by the SN1 mechanism as the allyl cation is relatively stable , important sn1 example.

Image Credit: Organic Chemistry by Jonathan Clayden, Nick Greeves, and Stuart Warren.

Image Credit: Organic Chemistry by Jonathan Clayden, Nick Greeves, and Stuart Warren.

An exceptional stable cation is formed when the three benzene rings stabilize the same positive charge. The resultant is the triphenylmethyl cation or trityl cation. Trityl chloride is used to form an ether with a primary alcohol group by the SN1 reaction.

Pyridine is used as a solvent for the reaction. Pyridine is not strong enough to remove the proton from the primary alcohol, and there would be no point in using a base strong enough to make RCH2O- as the nucleophile makes no difference to an SN1 reaction. Instead, the TrCl ionizes first to trityl cation, which now captures the primary alcohol, and finally, pyridine can remove the proton from the oxonium ion.

Pyridine does not catalyze the reaction; it stops it from becoming too acidic by removing the HCl formed. Pyridine is also a suitable polar organic solvent for ionic reactions.

Note: The reaction rate depends only on the concentration of substrate alone.

Nucleophile: Since the nucleophile comes into the picture after the rate-determining step, the strength or reactivity of a nucleophile plays no significant role in the SN1 mechanism.

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The effect of leaving group:

• In the SN1 mechanism, the C-leaving group breaks and plays a pivotal role in the rate-determining step.
• It is essential to have an excellent leaving group so that the reaction is exothermic (spontaneous).
• The strength of the bond between the leaving group and carbon should be weak.
• It should be stable enough so that it does not have the ability to recombine with carbon.
• A reliable/preferred leaving group is said to be a conjugate base of a strong acid.

Basicity regarding Ions of Halides

Iodine is the most stable base, and F- is said to be the least stable base.

The efficiency of ions of Halides as leaving group :

I is said to be the best leaving group and F- not an excellent leaving group.

A group that can appropriately accommodate electrons is considered an excellent leaving group.

Triflate ion is considered as an outstanding leaving group.

Conversion of bad leaving group to an excellent leaving group

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1. By carrying protonation
2. Converting ROH into an Ester, i.e., sulfonic Ester group is relatively a good leaving group.

Effect o solvent: It is usually carried out in polar protic solvents because polar solvents stabilize the intermediate carbocation, increasing the rate of reaction. Reduces the effect of the nucleophile, solvates the carbocation and anion, thus imparts stability and hence favors SN1 mechanism.

In Sn1 mechanism polarity of the solvent is proportional to its respective dielectric constant. Ionization occurs faster in solvents with high polarities, such as water or alcohol.

Image credit: https://youtu.be/ep-X4KCvtRk

Example: Consider the rate of solvolysis of 2-Bromo 2-methyl propane is said to be 3 × 10⁴  times faster in 50% aqueous ethanol as compared to in 100% ethanol. This is the charge that is developed in the intermediate ion. As the polarity of the solvent increases, the stability of carbonium ion increases, and therefore rate of SN1 reaction increases. Essential sn1 example.

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Stereochemistry involved in SN1 mechanism:

• Product is obtained with racemization and varying degree of inversion of configuration.
• Carbocation stability is essential as it is directly proportional to racemization.

Image Credit: YouTube

Ion pairs in SN1 mechanism:

We know that carbocation carbon atoms consist of sp2 hybridization, so it should be planar and hence achiral. In the reaction of a chiral substrate, the attack can be at either side of the plane, yielding equal amounts of enantiomeric products formation, giving a racemization mixture.

At the time of many SN1 reactions, sometimes there is 6 to 21% inversion, and a sometimes small amount of configuration is retained. These results can be explained by citing the formation of ion pairs.

Image credit: Organic Chemistry mechanism by Ahluwalia

In contact or intimate ion pair, i.e., R+ does not act as a free cation of dissociated species. It is observed that the bond formation between R+ and X-  the symmetry is adequately maintained, i.e., the originality of stereochemical configuration is retained by individual ions.

Hence in the SN1 mechanism, X- solvates a cation from the side where it is leaving, and the molecules of solvent around the intimate ion pair solvate only from the opposite side. This gives rise to the situation when carbocation is unsymmetrically solvated. On the attack of nucleophiles, the solvent molecules produce inverted products.

When a nucleophile attacks carbocations of solvent separated ion pair, the carbocations stereochemistry is not maintained tightly. There are chances that the leaving group can block the approach of a nucleophile to that particular side of the carbocation. Therefore formed products will have configuration inverted, giving a mixture of racemization.

Energy profile diagram of SN1 reaction: sn1 example t-butyl bromide and water

Image credit: Jonathan Clayden, Nick Greeves, and Stuart Warren

The carbocation is shown as an intermediate- a species with a finite (short) lifetime. And because we know that the first step,  the carbocation formation, is slow,  that must be the step with the higher energy transition state.

The energy of that transition state, which determines the overall rate of the reaction, is closely linked to the stability of the carbocation intermediate, and it is for this reason that the most important factor in determining the efficiency of the SN1 mechanism is the stability or otherwise of any carbocation that might be formed as an intermediate.

FAQs

1.How is the C-X bond polarized in the sn1 mechanism ?

It happens due to the electronegativity of halogens .

2. Why are sn1 reactions ?

It is said unimolecular because the rate of reaction depends only on concentration.

3.Why is it that the SN1 mechanism prefers polar protic solvents?

It prefers polar protic solvents because it stabilizes carbocation intermediate and reduces the activity of nucleophiles, and favors SN1 reaction.

4.What role does concentration play in the SN1 mechanism?

It depends only on substrate concentration and has no effect on the concentration of nucleophiles.

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In this article, we are going to have a closer approach towards the nucleophilic substitution reaction mechanism i.e.S_N2 using the appropriate sn2 examples and why there is a need for us to analyse this mechanism.

We will study the mechanism in detail using the S_N2 examples, the factors affecting the mechanism such as nucleophile strength, carbon skeleton, leaving group, solvent etc. The stereochemistry involved in the reaction, rate-determining factors and the healthy ways to carry out the reaction to achieve the desired result.

First of all, why there is a need for us to know which mechanism a reaction will follow? It is simply because it helps in predicting the type of conditions that are required for a substance to react in order to obtain good yield of products. So we shall have closer approach using S_N2 examples.

Note: Rate of the reaction depends on the concentration of both nucleophile and substrate.

The name S_N2 stands for nucleophilic substitution – second-order reaction. In this reaction mechanism, a nucleophile attacks a substrate and a leaving group leaves and this occurs simultaneously. The reaction occurs in one single step only.

In the above reaction of S_N2 example OH acts as a nucleophile attacks and simultaneously chlorine which is a good leaving group leaves, OH comes and attaches at that point.

Factors affecting S_N2 mechanism:

• Nucleophile strength

• Carbon skeleton

• Leaving group

• Solvent

Nucleophile: It plays a very important role in the mechanism as it determines the rate of the reaction and the stronger the nucleophile faster will be the reaction. Negatively charged species are more nucleophilic as compared to neutral molecules. OH is preferred over other nucleophiles as it is an anion and hence very reactive.

Carbon skeleton: It always prefers primary carbon over tertiary carbon because if the carbon is more substituted(tertiary) than due to steric hindrance it becomes difficult for a nucleophile to attack the substrate.

Note: Methyl and primary alkyl group always react by S_N2 mechanism and never by S_N1 mechanism because it cannot form carbocation.

Leaving group : If the leaving group is good then the reaction will proceed faster resulting in an increase in the rate of reaction. Usually, the weak bases are good leaving groups which include ions of halides I-, Cl- and Br- also H₂O. The important factors for leaving groups such as halide is the strength of the C-halide bond and the stability of the ion of halide.

Stereochemistry : When the leaving group is attached to a chiral carbon, inversion of configuration of substrate takes place. It happens because the nucleophile attacks just opposite to the leaving group .

Transition state tells us the type of structures that react reliably and stereochemistry of the reaction.

Effect of solvent : It is mostly carried out in polar aprotic solvent as the polar solvent aids in dissociation of the C-X bond where X is the leaving group and aprotic solvents solvate the leaving group thus accelerating the reaction.

Other factors influencing reaction mechanism using sn2 examples :

When adjacent C=C or C=O π systems are present, they increase the rate of reaction mechanism. Consider the S_N2 examples of Allyl bromide ,it reacts with alkoxides and forms ethers . It is observed that in the S_N2 mechanism compounds of Allyl bromide react rapidly as the π system which is adjacent to the double bond stabilizes the state of transition by conjugation .

The p orbital present at the centre of the reaction makes two partial bonds having only two electrons (electron-deficient) so additional electron density can be gathered from adjacent π system which stabilizes the state of transition and hence the rate of reaction increases.

S_N2 Example :Benzyl bromide and alkoxides react to give Benzyl Ethers

In the above reaction of S_N2 examples , amine reacts to form aminoketone which plays vital role in the synthesis of drugs .

Mostly alcohols are not good leaving group, so to resolve this problem :

• We can protonate the OH group with strong acid. This converts alcohol to it’s respective oxonium ion which can be lost as water.

• We know that sulfonate’s are good leaving group, so we can use the Tosyl group such as Tosyl chloride or Mesyl chloride replace the H with the Tosyl group thus resulting in alkyl sulfonate .

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Reaction with Nitrogen nucleophile :

Amines are great nucleophiles but the reaction of ammonia and alkyl halides will not always form single products. This is because the product formed from the substitution is almost equally nucleophilic like the starting material and hence competes with alkyl halide in the reaction.

This alkylation continuous leading to the formation of secondary, tertiary and stops only on formation of non-nucleophilic tetra-alkylammonium ion. This extra groups of alkyl push the electron density onto N resulting the product to be more reactive than the previous one.

This problem can be overcome by replacing ammonia with the azide ion. It is a triatomic species which is nucleophilic at both it’s ends. It is a slender rod consisting of electrons which is capable to insert itself in all kinds of electrophilic site. It’s availability is in the form of water soluble sodium salt NaN₃.

Azide reacts only once with alkyl halides as the product formed i.e alkyl halide is no longer in nucleophilic state.

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Let’s have a closer approach towards the potential energy profile of the S_N2 reaction.

When we go from left to right in the periodic table the nucleophilicity decreases followed by increase in electronegativity from left to right. Hence high electronegativity is unfavourable as the tightly held electrons are relatively less available for the donation to the substrate in the S_N2 reaction. Therefore OH is said to be more nucleophilic than F- and NH₃ is more nucleophilic than H₂O.

Note: Harder nucleophiles increase the rate of reaction as compared to soft nucleophiles.

The potential energy profile of the S_N2 mechanism above shows that only one transition state exists and there is no formation of intermediate between reactant and product as it’s a single step reaction. The energy of reactants is slightly higher than that of products as the reactions is an exothermic reaction.

The energy of transition state is quite higher as it involves a five- coordinated carbon atoms consisting of two partial bonds. The hill which is on the topmost part corresponds to the transition state of the Sn2 reaction. The free energy of activation corresponds to the difference in the free energy between the reactants and the transition state.

The free energy change for a reaction corresponds to the difference in free energy between the reactants and the products. A reaction will occur faster when it has low free energy of activation as compared to the one having higher free energy of activation.

Hard nucleophiles include- H-, CH3-

Moderate nucleophile – R-O- , R-NH-

Soft nucleophile – Cl-,

Frequently Asked Questions–

1. Why is Sn2 reaction mechanism not favorable or slower in polar protic solvents ?

Ans.It is so because nucleophiles are solvated by polar protic solvents which inhibits it’s ability to participate in Sn2 mechanism.

2. In a reaction where CH3 is nucleophile which one below will proceed faster a) CH3-Br b) CH3-I ?

Ans.The reaction will be faster with CH3-I as I- is good leaving group also it is more stable as compared to Br- as it has less charge density.

3. Why Sn2 reactions prefer primary carbon ?

Ans. It is so because if the carbon is more substituted than due steric hindrance it becomes difficult for nucleophile to attack the substrate.

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