Chapter 9: Nucleophilic substitution
What controls a substitution reaction?
1) the type of electrophile; substitution of the substrate (teriary, secondary, primary) and leaving group--how stable is it (halogen or others?)The more stable the quicker the rx. 2) the type of nucleophile; is it neutral, anionic, how many LP/electronegativity, how big/bulky is it? 3) solvent type: is it aprotic or protic?
What affects the type of substitution reaction?
1- the size and mechanism of the alklyl halide will affect the rate of substitution The substitution pattern of the carbon bearing the leaviing group (methyl, primary, secondary, or tertiary) The stability of the leaving group. 2) The reaction conditions: type of nucleophile-- is it large (bulky--slower) Type of solvent; will indicate the type of RX. mechanism and will affect rate. ** The pattern of how many electrons are attached to the carbon bearing the leaving group (b:) **The carbon attached to the leaving group is the most important to determine if the type of rx is SN1 or SN2.
Just like with our carbocation intermediate rx's on alkenes, the product of an SN1 reaction of an allyl halide will depend on where the carbocation was formed..Due to resonance, the carbocation could form at 2 locations (the two resonance contributors). What are the products obtained from the SN1 rx of CH3CH=CHCH2Br?
2 constitutional isomers formed, each resulting from the carbocation forming on a different carbon based on the two possible resonance contributors..
How many members of a resulting ring must there be to thermodynamically favor an intramolecular SN2 reaction? Intramolecular (between 1 molecule): one part of molecule is the nucleophile that attacks the carbon bearing the leaving group (the halogen).
5-6 members forms stable product 3-4 membered rings are less stable--3 membered forms faster than 4 membered!
What is solvolysis?
A solvolysis reaction is one where a molecule reacts with the solvent!
What is the substrate in a substitution reaction
Alkyl halide
To summarize the rate of leaving group in the substrate of an sn2 rx. as it relates to the rate of the rate of the reaction:
As relative stabilities of the leaving group increase, the rate of the substitution rx. increases. In general, a good leaving group is large, low electronegativity (affects stability), low nucleophilicity and is more stable after it leaves. Look at the comparison of the bond dissociation energy for the followng c-halogen bonds:
How does the size of the substrate affect the rate of alkyl halides?
As the degree of substitution of the alpha carbon increases, the rate of the reaction drops off markedly:
Why is a polar, protic solvent needed for an SN1 reaction?
As the solvent polarity increases the reaction rate increases! By acting as a proton source, the solvent will also help to stabilize the carbocation intermediate formed in an SN1 reaction, thus speeding up the reaction and lowering the activation energy needed to form the intermediate. The solvent then can act as the nucleophile and attack the carbocation to form the substituted product.
Why are SN2 reactions generally irreversible (hint: involves strength of base of nucleophile)
Because a strong base (very weak conj. acid) is displacing--ie substituting--for a weak base, like I- or Br- which are both very stable bases (strong conj. acids).
The rate of an SN2 reaction is dependent on the concentration of what?
Both the alkyl halid and the nucleophile (so both reactants)! Increasing either will increase the rate!
What is the solvent effect on an SN2 reaction? Think about the relative concentration of solvent compared to reactant in a rx. mixture! What are 3 good aprotic solvents used in SN2 reactions?What is there common characteristic?
For an SN2 reaction, an aprotic solvent is preferred-- something that can solubilize the reactant (is polar) but won't sequester the nucleophile in the reaction (like H2O would) DMSO, Acetone, and DMF; They all have carbonyl groups in them which means they have resonance and have strong enough dipoles to be polar solvents, but not strong nucleophiles.
Remember: where does inversion occur in the resulting sn2 molecule?
ONLY at the carbon that bears the leaving group! If that carbon is not chiral, then the resulting molecule has no change in its configuration at that carbon! If it is R and the chiral carbon does not bear the leaving group, then the product will be R!
Sn2=concerted one step reaction
Rate is controlled by the nature and concentration of both the electrophile and nuclephile. Has 1 transition state and no intermediates
SN1= reaction involves intermediate carbocation step (1+ steps)
Rate of reaction is controlled by 1 reactant; If it forms the reactive intermediate quickly then the reaction will occur quickly It must first form the carbocation intermediate
What are the affects the rate of an SN1 reaction?
SN1 reaction rates are controlled only by the electrophile and its concentration! The slow step with the highest activation energy is the carbocation formation step--the carbocation is then the electrophile that will be attacked by the nucleophile in the second step.
Typical SN2 reaction: Bromomethane + HO- ---> Methanol + Br-
SN2,so only 1 transition state and no intermediates: The reaction is bimoleculare and therefore depends on the concentration of both reactants: RATE LAW: r=K [alkyl halide][nucleophile] so; r=k[CH3Br][HO-] Type 2 Substitution REaction: Typically the nucleophile is anionic--we want to use a strong nucleophile (fully - charge) The nucleophile will have the characteristics of a strong base (but is more stable so therefore has a lower pka)
What alkyl halides can undergo SN2 reactions? What alkyl halides can undergo SN1 reactions?
SN2: Methyl, Primary, and Secondary SN1: Secondary and tertiary
What effect would a protic solvent have on the rate of an SN2 reaction? Why don't nonpolar, aprotic solvents work as solvents?
Since the solvent has a proton source, it would stabilize the nucleophile's negative charge (remember;need to have a strong nucleophile for an SN2 rx, so it must be full anion)--thus the concentration of the nucleophile is effectively lowered since much of the nucleophile is sequestered by the protic solvent. If the solvent is aprotic and nonpolar, it won't solubilize the reactant(s) and therefore the reaction will not occur.
Based on the last table, why will tertiary alkyl halides not undergo SN2 reactions?
The amount of steric hindrance will make the backside attack almost impossible, but instead favor (and stabilize via conjugation the carbocation intermediate of an SN1 rx.
What describes the nature of the bond in an alkyl halide between the C-X (halogen)?
The bond is polar; there is a dipole: C is partial positive and Halogen is partial negative this explains why it works in substitution reactions!
Why are the relative rates different among different substitution patterns on the alkyl halide?
The more crowded transition state is higher in energy.
The leaving group in an SN2 reaction affects the rate of the reaction
The more stable the leaving group of the substrate, the faster the sn2 reaction will occur: rate in SN2 (relates to the stability of the base after dissociation): r-I>r-Br.r-Cl>r-F---follows the same trend as acidity, and increasing size increases the stablility down a group.
Why is an SN2 reaction called bimolecular?
The nucleophile and the electrophile must be approached at the same time; so activation energy is the energy to bring the molecules together to form the transition state.
If the halogen (leaving group) carbon of the molecule is chiral, what will be the product of an SN1 type reaction in regards to stereochemistry?
The product would be a racemic mixture (50/50 mix of pair of enantiomers) 50% R, 50% S!
If the starting alkyl halid is chiral at the halogen, what will the product look like? If the reactant is R, what is the reactants stereochemistry?
The reactant will be inverted. If the reactant is chiral and in an R configuration, then the reactant will be S
How does the size of the nucleophile affect its nucleophilicity in an substitution rx.?
The steric hindrance of a more substituted base (tert-butoxide anion vs. ethoxide anion) can overwhelm the base strength in determining if a the nucleophile will act as a nuclephile in an SN2 reaction or as a base in an SN1 type reaction.
Because an SN2 rx. is bimolecular and therefore, rx. rate depends on the concentration of both the alkyl halide and the nucleophile. What are some characteristics of nucleophiles for SN2 reactions?
The stronger the base (weaker conjugate acid)=better nucleophile 1)A nucleophile with a negative charge is a stronger nucleophile than its conjugate acid: ie: OH- > H2O NH2- > NH3 2) Within the same period (row) nucleophilicity parallels basicity: Anionic forms of: H3C: - > H2N: - > HO: - > F- Note that this trend follows the order of decreasing pKa (increasing base stability).
Why can't aryl benzenes or vinyl halides undergo substitution reactions (SN1 or SN2)?
They cannot undergo substitution reactions because: SN1-cant form a carbocation intermediate that is stable enough to undergo nucleophilic attack in step 2. SN2--The pi system of the double bond is too electron dense and therefore will repel the electron dense end of the nucleophile--thus the nucleophilic backside attack is not possible. **note that the bottom right structure is vinyl halide, not allyl halide
A substitution reaction is where an electronegative group is replaced by another group.
Typically the leaving group is an halide because they are very stable as a conjugate base.
referring to the 3 good aprotic, polar solvents to know for SN2 reaction; What does the structure of acetone look like?
a ketone--has a carbonyl group
What is the solvent effect on an SN1 reaction? Think about the relative concentration of solvent compared to reactant in a rx. mixture!
because solvent is abundant in the rx. mixture, for an SN1 type reaction, we want to use a protic solvent because it will help stabilize the carbocation intermediate (which will increase the rate since the formation of the carbocation is the rate-determining step). In an SN1 reaction, the solvent and the nuclephile are often the same thing!
Why do methyl and primary alkyl halides not undergo sn1 type reactions?
because the carbocation intermediate is not stable enough (lack of hyperconjugation) to form the carbocation--no carbocation formed in the slow step, then there is no electrophile to undergo nucleophilic attack in the second step to form product. In fact, the energy diagram profile is essentially the same as in hydration (3 transition states, 2 intermediates)!
referring to the 3 good aprotic, polar solvents to know for SN2 reaction; What does the structure of DMF look like?
dimethyl foramide--has carbonyl group
referring to the 3 good aprotic, polar solvents to know for SN2 reaction; What does the structure of DMSO look like?
dimethyl sulfoxide--has carbonyl group
Allyl halides and benzyl halide are both primary alkyl halides, BUT they can undergo SN1 substitutions in addition to SN2 reaction (like other primary alkyl halides). WHY??
in looking at the structure of an allyl halide or of benzyl halide, both have the carbon bearing the leaving group (the alpha carbon) attached directly to an sp2 carbon that has a pi bond to the adjacent sp2 carbon. Thanks to electron delocalization energy as the electrons resonate to the alpha carbon, the carbocation intermediate can be stabilized and therefore will undergo an SN1 reaction if given proper conditions! Recall that a primary alkyl halide cannot undergo SN1 because the carbocation is too unstable to be formed--thus if the pi system were 2 carbons away from the carbon of the leaving group, there could be no resonance and as a result, an SN1 mechanism is not possible.
For SN2 reactions where the nucleophile is same and the concentration of alkyl halide and nucleophile is the same, What is the trend of the reaction rate in regards to substitution pattern? What about chain length?
methyl > Primary > Secondary If substiution is the same, then the rate is: Shortest chain > Longest chain.
The relative rate of the reaction is what ( in regards to the degree of substitution of the reactant alkyl halide?
methyl>Primary>secondary
The rate for an intramolecular SN2 (6 memberered) would be faster than that of an intermolecular, why?
the probabilty of favorable orientation/collision is higher when the nucleophile and the leaving group are on the same molecule.
