Tag: Named Reactions in Organic Chemistry

  • Diels Alder Reaction Mechanism, Orbitals & Examples

    Diels Alder Reaction Mechanism, Orbitals & Examples

    The Diels Alder reaction is a [4+2] cycloaddition reaction between a conjugated diene and a dienophile. Here we explain its mechanism, orbital theory, stereoselectivity and endo rule using 3D models and examples.

    3D model: Diene (top – ignore the tilt, it’s drunk) and dienophile (bottom) approaching for a Diels Alder reaction. Can you see the HOMO and LUMO orbital overlap?

    Summary

    • 1. Mechanism: The Diels Alder reaction is a concerted [4+2] cycloaddition of a diene in its s-cis conformation with a dienophile.
    • 2. Selectivity: Diels Alder reactions can be regioselective and stereoselective. As there are no intermediates, they are also stereospecific.
    • 3. Substituent effects: Normal electron demand DA reactions feature a nucleophilic, electron-rich diene reacting with an electrophilic, electron-poor dienophile. Resonance structures explain regioselectivity, while secondary orbital overlap explains the endo rule.
    • 4. Orbitals: In the normal electron demand DA reaction, the diene’s HOMO reacts with the dienophile’s LUMO. Higher reactivity (substituents, Lewis acids) arises from smaller energy gap between those interacting orbitals.
    • 5. Hetero Diels Alder reactions: Involve reactants with non-carbon heteroatoms
    • 6. Inverse electron demand Diels Alder: Feature electron-poor dienes and electron-rich dienophiles.
    • In case you are working on retrosynthesis problems, the DA is often the easiest way to synthesize six-membered rings!

    1. reaction mechanism

    As the Diels Alder is a pericyclic reaction, it proceeds in one step / concerted.
    The diene, containing two conjugated alkenes, reacts with a dienophile which is usually an alkene or alkyne (the name means something that likes dienes; sorry, chemistry is strange). Both reactants are flat (double bonds and diene is conjugated) and approach each other in a face-to-face manner.

    The driving force of the Diels-Alder reaction is the formation of two σ-bonds (σ-bonds are stronger than π-bonds) in the cyclohexene product. The four atoms linked to these sigma bonds all change from sp2 to a sp3 hybridization in the product.

    Note that the cycloaddition initially gives the cyclohexene in its boat conformation. Try to really visualize how the transition state. If the dienophile approaches from the bottom (as drawn here; the alternative approach from the top is equally likely for achiral molecules), we form the boat conformation where the hydrogen that was previously pointing away from the diene, the Hexo, “looks up” (wedge in the product). As we see below, the reaction is stereospecific so both Hexo and Hendo in the diene retain their relative orientation (i.e., they look the same way in the product).

    The diene has to be in the s-cis conformation to react (bonds form simultaneously).

    Unlike π-bonds in alkenes, the single bond can rotate and thus change its conformation. However, given the steric interactions that the CH2 groups experience when they are on the same same of the bond, the s-cis conformation is higher energy than s-trans. The energy difference is ~2.9 kcal/mol [ref 1], so only ~1-2% of butadiene molecules are actually in the s-cis form at a given time.

    Note that some dienes like cyclopentadiene are extremely reactive because they are locked in the s-cis conformation.

    By the way, we do not say [4+2] because 4 electrons from the diene react with 2 electrons from the dienophile. This is indeed the case – the transition state can actually be considered to be aromatic – but [4+2] refers to the number of atoms involved. For instance, there are so-called [3+2] dipolar cycloadditions which also operate with 6 electrons in total, but only 5 atoms are involved.

    Chemistry would be so easy without substituents! By adding substituents on the diene and dienophile, we start to observe reaction selectivity and increased or decreased reactivity. Let’s first understand this in theory, and then check out the specific substituent effects.

    2. Selectivity in Diels Alder reactions

    Diels Alder reactions are usually regioselective, stereospecific and stereoselective.

    Depending on which atoms of the diene and dienophile make contact, we can get two regioisomers (A is either next to E, or A is next to F). The actual regioselectivity is driven by the nature of the substituents (see below).

    Because 1) there are no intermediates in the Diels Alder, and 2) both σ-bonds are created from the same side/face, the relative orientation of substituents is fully retained in the product. This is why the reaction is stereospecific.

    Beyond the different orientation leading to regioselectivity, the dienophile can also be oriented outside or inside of the diene. This again gives two different products, exo and endo. Note that the example here shows just one regioisomer (it does not show products where A is next to F).

    3. Substituent effects in diels alder reactions

    Substituents critically influence selectivity and reactivity of Diels Alder reactions.

    Normal electron demand DA reactions are cases where the diene is electron-rich, while the dienophile is electron-poor. Typically, the diene has electron-donating groups (EDG; e.g., -OMe) while the dienophile has electron-withdrawing groups ( EWG; e.g., -CO2Me). The majority of reactions follow this polarity, so let’s focus on such examples first. The opposite happens in inverse electron demand DA reactions (explained further below).

    The regioselectivity of Diels-Alder reactions can be predicted by considering potential resonance structures of the two reactants.
    ➡️ The most nucleophilic position of the diene will prefer to add to the most electrophilic position of the dienophile.

    Diels Alder reactions can give endo (kinetically preferred) or exo products (thermodynamically more stable).
    ➡️ If the dienophile carries substituents with π-electrons, the endo product is usually preferred. (explanation requires orbital theory, see below)
    ➡️ If you are struggling with drawing endo versus exo, draw the transition state in 3D (e.g., as here, diene adding from the top) and draw the resulting boat conformation to compare which groups point which way.

    4. Frontier Molecular Orbital (FMO) Analysis

    The Diels Alder reaction, just like many other reactions, can be explained by purely looking at the so-called frontier molecular orbitals (FMO). These are the HOMO (highest occupied molecular orbital; filled) and LUMO (lowest unoccupied molecular orbital; empty) of the π-system.

    The Diels Alder reaction is exergonic (ΔG<0) – the Hammond postulate tells us that such a reaction has a relatively “early” transition state that looks similar to the starting materials. Thus, the orbitals of the starting materials are a good “proxy” for what will happen in the transition state.

    In case you cannot construct the MO diagram for butadiene or ethylene, I refer you to other web sources that explain this.

    In the normal electron demand scenario, the HOMO of the diene reacts with the LUMO of the dienophile. Notice how the orbital lobes (positive and negative, grey and black) that overlap have the same phase.

    The closer the orbitals in energy (small HOMO-LUMO energy gap), the easier the reaction! This is because when orbitals of similar energies overlap, they experience a higher stabilization of the newly formed orbitals. We want as high of a stabilization as possible, as this decreases the energy of the electrons that we use to populate the new molecular orbital.

    Electron-donating groups raise the energy of all molecular orbitals; electron-withdrawing groups decrease the energy of all molecular orbitals.

    By having an electron-rich diene and an electron-deficient dienophile, we lower the HOMO-LUMO energy gap (new green line). This means the stabilization experienced by orbital interaction for the purple electrons will increase (they will go down in energy, which is good). This effect is additive – the more substituents we add, the easier and faster the reaction.

    The stereoselectivity and endo rule can also be explained through orbital considerations. If the dienophile is oriented endo, the π-orbitals of the carbonyl group (or any other group that has π-system) can interact with the “central” diene orbitals. This lowers the transition state (TS) of the endo approach compared to the exo approach – and thus, the two substituents in our example above point in the same direction.

    This might be a bit clearer from the 3D model here. Ignore the non-planarity of the butadiene (my orbital computation was trolling me).

    Substituents do not only influence the energy of molecular orbitals, they also change the orbital coefficients at the different atoms. A larger coefficient means that an orbital is relatively more localized on a given atom – e.g., for the HOMO, the atom with the largest coefficient is most nucleophilic. This explains the regioselectivity of Diels Alder reactions more truthfully than the resonance structures which we have mentioned above. However, because this article is not intended to be fully exhaustive, we will not explain coefficients in detail here.

    For dienophiles with basic sites on electron-withdrawing groups, Lewis acids can function as catalysts and increase the regio- and stereoselectivity. Coordination of the Lewis acid makes the dienophile even more electron-deficient, and increases the relative polarization (and orbital coefficient).

    5. Hetero Diels Alder reaction

    Hetero Diels Alder reaction

    DA reactions are not limited to only carbon atoms. Both the diene or the dienophile can feature non-carbon heteroatoms.
    An example for such hetero Diels Alder reactions is the cycloaddition above with an aldehyde as the dienophile. This works well with the normal electron demand scenario as the carbonyl π-system has a low-energy LUMO.

    6. Inverse electron demand Diels Alder

    Inverse electron demand Diels Alder reactions are cases where the diene is electron-poor, while the dienophile is electron-rich. Now, the HOMO and LUMO are mapped the other way around: the electron-rich dienophile is nucleophilic and has a high-energy HOMO – while the electron-poor diene is electrophilic and has a low-energy LUMO.

    Typically, inverse electron demand reactions as part of multi-step cascade reactions.

    Draw the correct product for the given Diels Alder reaction!

    So the heteroaromatic ring clearly has a diene, but where is our dienophile [ref 2]? The first step of the reaction is a condensation-enamine formation of the amine with our ketone. The enamine is an electron-rich olefin, so a perfect dienophile in the inverse electron demand scenario. To figure out which regioisomer will be preferred, we need to consider which resonance structures are stabilized by the EDG and EWG, respectively.

    After the first Diels Alder reaction, we have a twist: The N=N group can be kicked out in a reverse or retro Diels Alder reaction. It works the exact other way around, with the very stable N2 driving the reaction forward (irreversible step). The last step is aromatization to the much more stable product after elimination of pyrrolidine. I will work on a separate article on the retro Diels Alder reaction in future.

    If you learned something, feel free to check out my other articles!

    Diels Alder Reaction: Exemplary procedure [ref 3]

    To a Schlenk tube charged with 3,5-dibromo-2-pyrone [diene] (20, 561 mg, 2.21 mmol) in 7 mL of toluene was added alkenyl boronate [dienophile] (600 mg, 1.70 mmol) at rt. The resulting mixture was heated in an oil bath at 110 °C for 3 days. The reaction mixture was cooled to rt, concentrated in vacuo, and chromatographed (20:1 hexane/EtOAc → 5:1 hexane/EtOAc) to give cycloadduct as a white solid (720 mg, 70%).

    Diels Alder reaction references

  • Wittig Reaction Mechanism & Examples

    Wittig Reaction Mechanism & Examples

    The Wittig reaction is an olefination reaction in organic chemistry. Let’s explain its mechanism and stereoselectivity using some examples and 3D models!

    👀 Interactive 3D model of methylenetriphenylphosphorane (simplest Wittig reagent)

    Wittig reaction mechanism

    Step 1 – Wittig reagent generation: Every Wittig reaction is based on a carbonyl compound and a Wittig reagent. This is a phosphonium ylide species that can be drawn in two resonance structures: the neutral phosphorane structure or the ylide structure.
    Chemists generate this species by deprotonating a precursor, a phosphonium (positive charged phosphorous) salt, with strong base. The choice and strength of the base depends on the stabilization of the Wittig reagent (see below). A Wittig reagent that can stabilize the negative charge through other groups can be formed by using a milder base.

    How does this work in the laboratory? To avoid cross-reactions (you might know that carbonyls can also be deprotonated by strong bases), chemists add the carbonyl to the reaction only after the base was used to deprotonate the phosphonium. At the very bottom, you can find two exemplary procedures. Some Wittig reagents are so stable that they can be isolated.

    Step 2 – Olefination: The ylide/phosphorane is very nucleophilic at the carbon, so it can intermolecularly attack the electrophilic carbonyl carbon. At the same time, the oxygen is nucleophilic and attacks the electrophilic phosphorous. This step likely occurs in a one-step [2+2] addition [see reference 1]. The four-membered ring product is called an oxaphosphetane.

    The ring can fragment the ‘opposite way that it was made’ – releasing triphenylphosphine oxide (the driving force) and our alkene product. This is why the Wittig reaction can be classified as an olefination reaction.

    The orientation of substituents at the oxaphosphetane determines the stereoselectivity of the reaction. There are two chiral centres on the ring – so cis and trans diastereomers are formed. The stereochemistry of the oxaphosphetane translates into the product following the retro-[2+2]. Cis leads to (Z), trans leads to (E). Here, we note that because the Wittig reagent is a so-called non-stabilized ylide, the (Z) olefin is preferred (see below).

    What type of betaine is this? What diastereomer do you expect in the product?

    What is the Driving force in the Wittig Reaction?

    This is a common question for students. The driving force of the Wittig reaction is the oxidation of triphenylphosphine to form triphenylphosphine oxide or Ph₃P=O. This new phosphorus-oxygen double bond is very strong, making its formation highly favorable from a energetic (thermodynamic) standpoint.
    You could say there is also a kinetic driving force as the ylide reagent is highly nucleophilic and thus, reactive with the electrophilic carbonyl starting material.

    Stabilized ylides and non-stabilized ylides

    Depending on the substituents attached to the α-carbon (next to the phosphorous), ylides are categorized into stabilized or non-stabilized ylides. The stability refers to the ability of the substituent to stabilize the negative charge.

    Stabilized ylides have electron-withdrawing groups (EWGs) attached to the α-carbon. These can include carbonyls like esters, or nitriles. The mesomeric effect of electron-withdrawing groups stabilizes the negative charge through resonance.
    This makes the Wittig reagent less reactive but more selective, usually favouring the more thermodynamically stable (E)-alkene product. These Wittig reactions can operate at higher temperatures.

    Non-stabilized ylides lack such electron-withdrawing groups and feature alkyl groups. Due to the lack of stability (there is no resonance with alkyl groups), non-stabilized ylides are more reactive. They usually form the kinetically favoured (Z)-alkene product. To maintain stability and the kinetic selectivity, reactions with these ylides are performed at low temperatures.

    Semi-stabilized ylides aryl or alkenyl substituents. They fall between the stabilized and non-stabilized ylides and their stereoselectivity is typically poor, leading to similar (E) and (Z) alkene mixtures.

    Question for you: Which type of ylide is easier to form by deprotonation? What are their rough pKa values in DMSO?

    ➡️ Stabilized ylides are more easily formed by deprotonation as they are by definition compounds that stabilize the negative charge on carbon. This means the respective conjugative acid has a lower pKa value (i.e., is more acidic).

    Is the Wittig Reaction Concerted or Step-wise?

    Over much of its history, the Wittig reaction has been described as a stepwise ionic process. Instead of concerted (one-step) [2+2] cycloaddition, it was assumed that the addition to the carbonyl proceeds step-wise, forming a betaine intermediate. However, modern research suggests that the cycloaddition is more likely [ref 1].

    But hey, if your course teaches you the step-wise one, just write that one. Rather get full marks than trying to be right and a smart ass 🙂

    Wittig Reaction: Advanced Example [Ref 2]

    Here’s a final question (2nd year undergrad level):

    What is the mechanism of this two-step sequence? Is the ylide stabilized?

    The answer is given below to avoid spoilers.

    If you liked this post, feel free to check out other articles on my page!

    Wittig reaction conditions [ref 3]: non-stabilized ylide

    Under an N2 atmosphere, methyltriphenylphosphonium bromide (40 mg, 0.113 mmol) was suspended in dry THF (1 mL) in a Schlenk tube at 0 °C. BuLi (2.5 M in hexane, 45 μL, 0.113 mmol) was added dropwise. After stirring for 30 min at this temperature, the mixture was cooled to –78 °C, compound 20 (22 mg, 0.057 mmol) was added dropwise as a solution in THF (1 mL). The reaction was continued at the same temperature for 1 h and then at 0 °C for 30 min. Water (1 mL) was added to quench the reaction and the mixture was extracted with CH2Cl2 (3 × 2 mL). The organic extracts were then combined, dried with anhydrous Na2SO4, filtered, concentrated, and purified with by chromatography on silica gel (pentane/EtOAc, 2:1) to give compound 21 (22 mg, >99 % yield).

    Wittig reaction conditions [ref 4]: stabilized ylide

    To a solution of aldehyde (+)-17 (1.40 g, 2.81 mmol, 1 equiv) in dry THF (35 mL) was added crystalline (α-carbomethoxyethylidene)triphenylphosphorane (1.96 g, 5.62 mmol, 2 equiv). The reaction mixture was stirred and heated from room temperature to 50 °C for 2 h under argon. The solvent was then removed under reduced pressure. The residue was purified by flash chromatography (PE/EtOAc 4/1) to give the ester (+)-18 as a white solid (1.31 g, 82%).

    Wittig Reaction answer [Ref 2]:

    The advanced example above is a Wittig reaction, followed by a Claisen rearrangement. The latter is a [3,3]-sigmatropic rearrangement, a type of pericyclic reaction. It converts allyl vinyl ethers to γ,δ-unsaturated carbonyls. This is an interesting transformation as it looks like it preserves the aldehyde, but moves it one carbon further away from the aromatic ring.

    The ylide substituent (-OR) is a mixture of electron-withdrawing (sigma-effect) and electron-donating (mesomeric effect). Thus, one can argue the ylide is semi-stabilized. This is reflected in the rather close ratio of (E) to (Z) alkene after the Wittig. Fortunately, the mixture is not an issue as the Claisen rearrangement gives the same product regardless of diastereomer in this system.

    Wittig Reaction references: