Tag: Organic Chemistry

  • Electrophilic Aromatic Substitution Mechanism & Key Concepts

    Electrophilic Aromatic Substitution Mechanism & Key Concepts

    Summary of electrophilic aromatic substitution reactions

    • 1. Mechanism: A nucleophilic aromatic ring attacks the electrophile E+, giving a cation, and loses H+ to regain its aromaticity. This substitutes C-H for C-E.
    • 2. Key reactions: Bromination, chlorination, Friedel-Crafts alkylation (R) & acylation (C(O)R). nitration (NO2), sulfonation (SO3H). Most reactions utilize acid or Lewis acids to create reactive electrophiles.
    • 3. Substituents – Activation: Electron-donating groups at a ring increase nucleophilicity and reactivity. Electron-withdrawing groups work the opposite.
    • 4. Substituent – Regioselectivity: Activators lead to ortho and para products. Deactivating groups direct meta (excl. halogens).
    • 5. Examples: TNT synthesis nicely exemplifies ring activation. Pharmaceuticals use electrophilic aromatic substitution – sometimes with heterocycles!
    • 6. Orbitals: Addition is fastest where overlap of donor (HOMO) and acceptor (LUMO) is best. However, orbital models do not explain the full story!
    • Common mistakes and reaction examples at the end!

    1. mechanism of electrophilic aromatic substitution

    So what is electrophilic aromatic substitution?
    Substitution as it replaces a C-H bond at an aromatic ring with a new C-E bond.
    Electrophilic because our new E group was introduced as an electrophile.

    Because our new group is an electrophile, the double bond of the aromatic ring has to be the nucleophile (just like in electrophilic additions)! Here’s how to identify nucleophiles vs electrophiles.
    Note that the electrophile can be a neutral molecule that’s positively polarized, it does not have to be positively charged.

    Note: The order is ‘form C-E, then break C-H’. While the other way around can work, it requires different reaction conditions (very strong base to deprotonate C-H) and is not as broadly applicable.

    Let’s see what we can learn from this energy diagram.
    1. One of the double bonds attacks the electrophile (here: NO2+). Because this breaks the aromaticity of the starting material, the step requires quite a bit of activation energy (the molecule has to have energy to climb the hill of TS1).


    2. The addition product is a carbocation (the double bond was ‘invested’ by one carbon to form the bond with E+, the other carbon has one electron less in its proximity and is now a non-aromatic carbocation). The positive charge sits next to the other double bonds , so it is somewhat stabilized and delocalized. This is a real intermediate whereas the transition states are just “snapshots at maximum energy”. This is also called Wheland intermediate or sigma complex.

    3. The deprotonation occurs quite easily (the hill to TS2 is lower than the first one) and gives the stable substituted aromatic product. By the way, you don’t need to add base (e.g., KOH) for this step; the proton will get lost to other molecules present in the reaction or solvent. If the final product is lower in energy vs. starting material (more specifically, “enthalpy”), the reaction is exothermic.

    But benzene is very simple and boring. In sections 2-4, we cover:
    2. What types of electrophiles we can add and how we generate them
    3. How other ring substituents can accelerate or slow down this reaction (activation)
    4. How other ring substituents influence where the reaction occurs (regioselecitvity)

    By the way, this is an old reaction! Pioneering work came from the Brit Armstrong in the 1880s already, and the American George Wheland in the 20th century.

    Source: J. Chem. Soc., Trans., 1887, 51, 258

    From our videos, we know that the early days of chemistry were was a bit crazy. Even simple benzene was disputed (left: Armstrong’s “centroid formula”). We can’t blame these OG chemists as our modern knowledge evolved out of the many dubious theories.

    2. Key electrophilic aromatic substitution reactions

    These reactions have the same fundamental mechanism… but they differ in how they generate their reactive electrophile. They all use some sort of reagent (green/purple boxes) to get to the true electrophilic species that is attacked by the aromatic ring.

    Bromination, chlorination and Friedel-Crafts reactions use a Lewis acid (=electrophilic metal compounds that things with electron pairs can coordinate to). This makes the Br, Cl, R or C(O)R centers more positively polarized, so they are more reactive with the double bond.

    Nitration and sulfonation use a ‘normal’ acid (e.g., sulfuric acid) to protonate the reactants and activate them into more electrophilic species. Nitration is a particularly useful reaction as the group can converted to amino or hydroxyl groups.

    After initial electrophile generation, all reactions follow the same steps and experience the same substituent effects (Sections 3. and 4. below). For full clarity, I might explain the nuances of each reaction in more detail in future posts.

    There are two important points I want to point out on the halogenation reactions above: bromination and chlorination.

    1) The typical conditions are bromine or chlorine + Lewis acid, but students will see in more advanced classes that there are other sources of electrophilic bromine or chlorine, like NBS or NCS (N-bromo/chloro-succinimide). I’ll probably explain these reagents more in separate posts.

    In organic chemistry, there are always multiple ways of achieving a certain reaction or generating a certain reactive species, e.g., an electrophile.

    2) Chemistry class syllabus usually ignores the other two cousins in the halogen family: iodine and fluorine. But that doesn’t mean that they cannot participate in these reactions! The point is more that these reactions are less common and straightforward, so they are usually not discussed.
    If you can somehow generate activated/ polarized electrophiles (I+ or F+), they will also react with electron-rich aromatic rings just like Cl+ or Br+ shown above. While there are several options for iodination (using I2 and additional reactants like acids), fluorination is more challenging and requires special reagents (not F2). Aryl fluorides are thus usually made with nucleophilic aromatic substitution reactions like the Balz-Schiemann reaction.

    3. Activating and deactivating groups

    Recall: Our aromatic ring is a nucleophile, attracted to positive charge or polarization (which are electrophiles) because it has a decent amount of electron density.

    The higher the electron-density in a ring, the more nucleophilic and more reactive it will be. This accelerates aromatic electrophilic substitution (higher reaction rate).

    The electron-density of aromatic systems is influenced by the ring substituents. For example, nitrobenzene does not undergo normal Friedel-Crafts acylations.

    Here are the key groups, (directional) strength and primary drivers.
    Activators tend to be π donors (they push/ delocalize their electron pair into the ring) while deactivators tend to be π acceptors (they accept delocalized electrons, acting as an electron sink). If this doesn’t make sense, please read up on resonance.

    Note the key counterintuitive example: halogens deactivate rings more strongly (due to their negative inductive σ effect, think high electronegativity) than they activate them (due to their mesomeric π effect, they have a free electron pair).

    Another way to think about these groups is to revisit our energy diagram. The TS1 is partially positively charged and the intermediate is fully positively charged. Obviously, this positive charge will be very comfortable if there is a lot of electron density in the ring (charges like to be spread across and stabilized across atoms). Inversely, deactivators would make the intermediate unhappy. It’s like robbing someone who’s already very poor – not the best look.

    The stabilizing effects for activating groups mean that TS1 requires a lower activation energy (because the ring is more nucleophilic) and our carbocation intermediate is also lower in energy (the charge is better stabilized by the electron-rich ring).

    Note: It’s critical that these groups are directly attached. If there is an “alkyl spacer” between the ring and a strong (de)activator, the effect will vanish. The donor or acceptor groups need to be conjugated with the ring! The substituents here would be more like σ donors.

    4. Regioselectivity of aromatic electrophilic substitutions (Directing Effects)

    This regioselectivity can be rationalized by looking at the delocalization/ stabilization of the carbocation intermediate. Ortho and para additions favor carbocations where the positive charge sits next to the R group (either directly in case of ortho or after delocalization in the case of para).
    If R can stabilize this positive charge as a σ or π electron donor, it will lower the energy of the carbocation and prefer these pathways over the meta addition.

    Well if R is an electron-withdrawing group, the positive charge will absolutely hate being next to it (electron-sink next to something that already doesn’t have enough electrons). Thus, deactivating groups avoid ortho and para substitution and show meta selectivity.

    Halogens are again sneaky. Regarding ring activation, their negative inductive effect (electron-withdrawal) overrides their positive mesomeric effect (electron pair donation). Regarding regioselectivity, the mesomeric effect is more important (deal with it). Outside of this special case, all groups follow the same rules.

    5. Examples: Tnt & pHARMACEUTICALS

    Our first example is 2,4,6-trinitrotoluene or TNT. One of many ways of synthesizing TNT is exactly what you think: take toluene and nitrate the heck out of it.
    The issue? Substituent effects!
    You see, while toluene is decently nucleophilic (it’s slightly activated through the methyl group), it becomes less and less reactive the more nitro groups are attached.

    The first addition gives a mix of ortho and para substituted products. final nitration only occurs at high temperatures and use of fuming sulfuric acid, a particularly reactive form of sulfuric acid containing additional sulfur trioxide. There are easier and more clever ways to make TNT, but that shouldn’t be our focus.

    You also see that just because TNT is deactivated towards electrophilic aromatic substitution, it still likes to explode violently. Reactivity is always relative. This is because detonation does not depend on the nucleophilicity of the aromatic ring 🙂

    Most pharmaceuticals contain aromatic rings so we can find these reactions in their syntheses. One example is the drug lifitegrast. Its synthesis uses an intramolecular Friedel-Crafts alkylation to create the bicyclic core.

    Final lesson: Heterocycles can also be nucleophiles! (aromatic ring with heteroatom)

    The synthesis of the antibiotic metronidazole is very simple. The first step is nitration of the ring with carbon as the nucleophile. In the second step, the nitrogen acts as the nucleophile and undergoes a SN2 reaction with the alkyl chloride.

    The five-membered rings pyrrole (heteroatom: N) and furan (heteroatom: O) are very electron-rich so we also often see them engage in electrophilic substitution reactions.

    This is because the electron pair can stabilize the positive charge during the reaction mechanism. It’s like having an activating substituent effect within the ring!

    6. Orbitals in aromatic substitutions

    You probably shouldn’t read this section if you’re just learning about aromatic substitutions.
    Drawing resonance structures is useful for us mortal humans. However, they are just tools and don’t correspond to reality. After all, we’re taught that “real structure” of a molecule is a mix of all “good” resonance structures. Advanced readers might ask themselves if orbitals can be useful predictors for aromatic reactions?

    We won’t go through orbital theory here, but in short: When atoms form bonds in a molecule, their atomic orbitals combine to molecular orbitals. These can be filled with electrons or empty (or half-empty, if it’s a radical). The highest-energy filled orbital (HOMO, occupied) influences nucleophilic behavior and the lowest-energy empty orbital (LUMO, unoccupied) influences electrophilic behavior.

    Looking at orbitals can be partially insightful. Here’s a 3D visualization of the early days of an electrophilic aromatic nitration. The HOMO of chlorobenzene (nucleophile) is getting close to the LUMO of the nitronium cation (electrophile). How will they add?

    You can see that on the ring, para and (to a slightly lesser degree) ortho positions have high contributions, while there is “almost no orbital” on meta. Any electrophilic attack at meta would thus be disfavored (low orbital overlap).
    Our nitronium electrophile has a slightly higher LUMO localization at the central nitrogen, meaning the nitrogen is more electrophilic than the oxygens!

    So, it looks like molecular orbitals can nicely predict the regioselectivity that we observe for chlorobenzene. So why don’t people talk about orbitals in the same fashion as they do e.g., for the Diels-Alder reaction?

    1. Aromatic substitutions are one of the first reactions students, so going into orbitals would be an overkill that makes everyone hate chemistry even more.
    2. More importantly, they don’t always give the full picture. Consider the HOMO of nitrobenzene below. This aromatic ring is deactivated and should attack meta.

    We do see that the para position is not contributing to the HOMO at all, but the orbital structure does not tell us why there is no substitution at ortho! In this case, our resonance structure analysis is actually more helpful because it tells us that the ortho-position of nitro groups is particularly electron-poor.

    There are other ways to analyse this, e.g., by computing charge density. Below you can find an atomic charge analysis for benzene, aniline and nitrobenzene. Ignore the method or units – simply put, a more negative number equals more electron-density at a given atom. More electron-density means more nucleophilic and more reactive towards electrophiles.

    Source: Phys. Chem. Chem. Phys., 2016, 18, 11624

    Here are some thoughts:

    1. Benzene: Obviously, hydrogens are more electropositive than carbons (they have a positive charge number). The molecule is symmetrical.
    2. Aniline: Electron-density is higher at ortho and para relative to meta, explaining the directing effect. Relative to benzene, ortho and para have higher electron density, i.e., the aniline ring is more activated and reactive .
      Note that there is a lot of electron density on the amine as well! (Aniline can also react as a N-nucleophile! See common mistakes)
    3. Nitrobenzene: Electron-density is highest at meta relative to ortho and para, explaining the directing effect. Now, the carbons all have lower electron density, in line with deactivation / lowering of reactivity due to the nitro group.
      Sidenote: The nitro group’s electron-withdrawing effect further polarizes the C-H hydrogens as they are more electron-poor in nitrobenzene.

    So, orbital theory is sometimes more, and sometimes less useful. Generally, combining multiple models and perspectives gives us a better appreciation. For now, you can happily ignore orbitals for these reactions (but not for others!).

    Common Mistakes in Electrophilic Aromatic Substitutions

    Students can feel overwhelmed trying to remember effects or specific aromatic substitutions. This can lead to common mistakes or errors, including:

    Mixing up ortho, para and meta: This is the first hurdle for new students. If you’re struggling with this, try remembering it this way: Meta is in the middle between the other two. The letter o comes before p in the alphabet, so ortho is closer to R.

    Thinking too superficially: Although electrophilic substitution is the most common reaction of aromatic compounds you’ll see, don’t jump to conclusions too quickly. In this example, an acyl chloride (electrophile) would lead to O-acylation instead of electrophilic aromatic substitution. The benzene ring is deactivated and thus not nucleophilic enough.

    Along the same lines: In section 6. Orbitals, we saw that charge analysis suggests high electron density at the nitrogen of aniline. Again, under many conditions, anilines can react as N nucleophiles instead of C nucleophiles (e.g., alkylation at nitrogen instead of at carbon).

    Electrophilic or nucleophilic?: Get your terms right. Nucleophilic aromatic substitution reaction does not substitute C-H but rather C-X, where X is a good leaving group. This is the opposite of what saw for the electrophilic substitution: our aromatic ring is the electrophile here. This reaction is explained here.

    Misunderstanding substituent effects: Abbreviations can be confusing, and we might wrongly believe a specific atom or an abbreviated group to be activating or deactivating. Before you go with it, double-check why a substituent would be an electron-donating group or an electron-withdrawing group. E.g., can you really find an electron-pair that is driving a positive mesomeric effect?

    Remember to consider if a newly introduced functional group is more or less activating. Reactions often use an excess of reagents (more moles of reagent than starting material). Adding one activating group? The ring might add more (e.g., polyalkylation in Friedel-Crafts alkylations). Want to add more than one deactivating group? This might be challenging (remember our TNT example)!

    Electrophilic Aromatic Substitution Examples

    Here are additional questions to test your knowledge of the reaction mechanism and directing effects of substituents.

    The first exercise is pretty straight-forward, with the fluoro-substituted ring being less activated (thus, bromination occurs on the other one, para to the aryl-aryl bond).
    The same idea applies to the question on the right, where we expect the inductive acceptor effect of the trifluoromethyl group to deactivate the ring towards sulfonation.
    The Friedel-Crafts acylation is pretty obvious (para to the electron-donating ether group).
    Last, we have a Friedel-Crafts like C-C bond formation. Instead of a alkyl halide and Lewis acid, we generate our carbon electrophile by protonation of the double bond with sulfuric acid.

    Hope this summary helped you get a good overview of this class of aromatic reactions.
    Feel free to check out my other posts and videos for more content.

  • Bredt’s Rule Definition and Exceptions (Anti-Bredt Olefins)

    Bredt’s Rule Definition and Exceptions (Anti-Bredt Olefins)

    BUT: “Anti-Bredt olefins” defy this rule. They are not often talked about, but chemists have known them for decades.
    In this post, we explain when Bredt’s rule becomes invalid – a good read for any student willing to go beyond their curriculum. This is particularly relevant as recent news headlines touted the “synthesis of impossible molecules” by chemists. More visuals can be found in my video on this topic.

    Interactive 3D model of 1-norbornene, an anti-Bredt olefin

    BredT’s rule: History and its original form

    To understand Bredt’s rule, we need to go back in time. Julius Bredt was one of the oldschool German chemists of the 19th century, and much of his early work centered on the molecule camphor. This pleasantly smelling terpenoid natural product is found in camphor and other trees, and saw a move towards large scale use for the plastics industry in the 1870s. Various chemists proposed pretty freaky structures, including the legendary August Kekulé.

    Julius Bredt's camphor structure

    However, it was Julius Bredt who identified camphor’s real structure with a bridged bicyclic ring system. He would spend years validating his findings and correcting the errors of his predecessors.

    Julius Bredt's experiments

    Ring Strain in Bredt’s Rule

    In his seminal 1924 paper, Julius Bredt had already correctly stated that ring strain is behind the apparent impossibility of these olefin compounds. But what is the source of that ring strain, and when is this rule really valid? And how strained are these forbidden rings really?

    So we all know that a normal olefins are completely flat with a co-planar arrangement of substituents. However, involving a bridgehead creates an (E)-alkene where a substituent on one carbon is connected to a substituent on the other carbon.

    If there are only few carbon atoms in this bridge, they would need to stretch out to ridiculous proportions to accommodate for this planar geometry. So, the molecule tries to find a middle ground regarding ring strain and distortion. This means our double bond is not coplanar but actually twisted. This twisting leads to a suboptimal overlap of the p-orbitals in the pi-bond, which is also destabilizing.

    Speaking of p-orbitals, remember how normal alkenes are sp2 hybridized? In the anti-Bredt olefin, we see significant rehybridization to sp3 character as the carbons are pyramidal. This reorientation is key to boost the bond order to a surprisingly high value of 1.86. We have good evidence to believe this is a legit double bond and not something like a di-radical – more on this later.

    We have seen why this system is destabilized or strained, but how strained is it? You might know that some thermodynamics shenanigans called homodesmotic equations can help out. Essentially, we are comparing the total strain energies of the saturated and unsaturated molecules to evaluate the pure strain contribution of the anti-Bredt double bond.

    Such computations were established in the 1980s, as physical organic chemists tried to understand the limits of these olefins based on their size and strain energy.
    Here it becomes useful to quantify the size of a bridged ring by simply adding up the number of atoms in the bridges (referred to as S).

    The pioneers found that the ring strain estimation can pretty accurately predict if an olefin is stable at room temperature, if it’s olefin observable only at lower temperatures, or if it’s so unstable that we can’t form it or observe it at all.

    Quick knowledge test

    Let’s briefly check whether you understood the concept or not. A typical exam question goes along the lines of: Does the alkene shown below violate Bredt’s rule? Look at the four olefins below and identify if they violate Bredt’s rule. Why (not)?

    First examples of Anti-Bredt Olefins

    The quest to find such larger rings (which don’t obey Bredt’s rule) started in the mid-20th century, with notable efforts from chemists Prelog and Ruzicka. Over time, chemists figured out that such rings even occur in natural products. Prominent examples are the anti-cancer compound taxol or the CP molecules which have a ring size S = 8.

    Over the last decades, chemists brought forward clear evidence for these anti-Bredt olefins, even ones with S values below 7. Most of these used trapping experiments to capture short-lived anti-Bredt olefins, like 1-norbornene. In this case, the chemists ran a lithium-halogen exchange reaction of a di-halo precursor in the presence of furan. As they isolated the corresponding Diels-Alder adducts, it seems reasonable to assume that an anti-Bredt olefin with S = 5 was formed and very rapidly intercepted by furan.

    Even more impressive is the case of this anti-Bredt olefin with S = 7. Considering the delicate nature of the product, it seems really ironic that the chemists made it by brute-force pyrolyzing this quaternary ammonium precursor through a Hofmann elimination. They also did some nice trapping, but even managed to get NMR data at -80 °C. This is really remarkable and only case to date of a theoretically unstable anti-Bredt olefin being observed directly. Evidently, using the total ring size S as proxy for stability does not work every time.

    “Solution to the Anti-Bredt Olefin Synthesis Problem”?

    So, we see that the question is not if anti-Bredt olefins can be made, but rather if there are more practical and useful approaches than what we know already. We might not be content with having to incinerate our molecules to get crappy yields of product in a soup of unwanted side products (e.g., due to their low stability, anti-Bredt olefins can intramolecularly rearrange).

    Recent research by Garg used fluoride-mediated elimination to create the anti-Bredt olefins, but found that the relative stereochemistry was critical. You see, the precursor with an equatorial silyl group proved unreactive even under forcing conditions while its diastereomer was more useful. By computing the structures, the chemists realized that the reactive diastereomer features a relatively smaller angle between the silyl electrofuge and the leaving group. Because this is a syn-elimination that requires overlap of the carbon silicon sigma and the carbon-oxygen sigma star orbitals, a narrow angle is better. The equatorial diastereomer has a very large angle and low overlap, suppressing any reactivity.

    The chemists optimized the conditions by using anthracene as a trapping agent. They found success with a low temperature option using the classic fluoride source TBAF, or alternatively a high-temperature option using a slow-release source of TBAF which helps to control the reaction. The high yield is remarkable as you would expect 16 hours at 120 °C to cause quite some damage. Well, it does not, and the experimental procedure is pretty simple.

    So what’s the scope of this method? Other trapping agents were less efficient but still a major improvement to what we knew before – we have furan and its aromatic friends, as well as 1,3-dipoles. They also saw good breadth in terms of anti-Bredt olefins, with some larger and functionalized rings being tolerated. If you are paying attention, you will have noticed that the figure reports diastereomeric ratios of products. But what stereoselectivity does this even refer to?

    Our anti-Bredt olefin is actually one specific diastereomer with the hydrogen retaining a pseudo-axial position after the initial elimination.

    Remember how we said that instead of a coplanar geometry, we said the system is twisted to a significant degree? Well, the epi diastereomer with a pseudo-equatorial hydrogen would be even more distorted with larger twisting angles and pyramidalization. This elevates its energy and explains why we don’t see any cycloaddition adducts with an equatorial hydrogen at this carbon.

    What happens if we use an olefin precursor with just one chiral center?

    Here, the chemists synthesized the symmetrical [2.2.2] ring with high enantiometric excess through separation of diastereomeric derivatives. We’ve already seen the diastereoselectivity and stereospecificity of the reactions so it shouldn’t be too surprising: The chirality is fully transferred to the cycloadduct. This once again suggests a concerted elimination step and a chiral alkene with high barrier to racemization and a low, if any, diradical character of the anti-Bredt olefin.

    Conclusion

    So, we’ve known about small anti-Bredt olefins for a long time. This means Bredt’s rule was already plenty broken in the past. The new research confirms the current interpretation of Bredt’s rule: small olefins are unstable but not necessarily impossible to form. However, the new research adds very practical experimental methods and deeper computation understanding. Thus, anti-Bredt olefin intermediates might get into reach of synthetic chemists. However, the structures of the trapping products are not common so the utility is currently debatable. Maybe, this will encourage more rule-breaking in other areas. Only time will tell!

    References on Bredt’s Rule

    • Generation of strained alkene by the elimination of .beta.-halosilane. On the nature of the double bond of a bicyclo[2.2.2] bridgehead alkene | JACS 1977, 99, 936
    • A solution to the anti-Bredt olefin synthesis problem | Science 2024, 386, eadq3519
    • Total Synthesis of Natural Products Containing a Bridgehead Double Bond | Chem 2020, 6, 579
    • Evaluation and prediction of the stability of bridgehead olefins | JACS 1981, 103, 1891
    • Do Anti-Bredt Natural Products Exist? Olefin Strain Energy as a Predictor of Isolability | ACIE 2015, 54, 10608
  • Exceptions to the Octet Rule? Hexamethylbenzene Dication

    Exceptions to the Octet Rule? Hexamethylbenzene Dication

    Did you know that carbon was allegedly found to engage in six bonds? The strange hexamethylbenzene dication has attracted significant attention due to structure featuring a hyper-coordinated carbon. But can carbon be hypervalent?

    To add more confusion, this system is apparently like a transition-metal complex – though no metal can be found. If you want to make this at home, you just need some equally cursed Dewar benzene, one of the strongest super-acids we know, some hydrofluoric acid for good measure – and the utmost care to not turn your reaction into black tar. Here, we explain if this cursed molecule is an exception to the octet rule.

    Octet rule definition

    To refresh our memory, elements in the second period typically form compounds that satisfy the Octet rule which states that atoms strive to surround themselves with 8 valence electrons or 4 bond equivalents. However, once we go to lower periods, larger elements start to misbehave. For example, the halogen fluorine can’t expand its octet, but hypervalent iodine compounds like the Dess-Martin periodinane oxidant are common. Similarly, nitrogen is limited by the octet rule but it’s heavier and strange cousin antimony can form more than the four permissible bonds.

    But what about carbon, the favorite element of organic chemists? Does carbon follow the octet rule?

    We have previously discussed several exotic carbon species, like carbon 2+. This compound is an exception to the Octet rule but it’s hypovalent, not hypervalent. It’s made by oxidizing an already electron-deficient carbene, leaving it with only four instead of the desired eight valence electrons. To pick another example, we’ve also talked about carbones when looking at a dual Diazo-Wittig reagent. This stabilized bis-ylide looks very strange but is not out of order if you count its valence electrons.

    CH5+ (Methanium) and 2-Norbornyl cations

    To understand other compounds where carbon appears to have more than four bonds, we need to watch out for non-classical bonding. The simplest case, if you can call it simple, is protonated methane or CH5+. On first sight, you might think this is a pentavalent carbon – but beware, as carbon only has four available orbitals. The solution is that instead of having 5 2-center 2-electron bonds, two hydrogens are bound as H2 and partially share their sigma bond with carbon in a 3-center 2-electron bond. This means CH5+ looks more like H2 coordinated to CH3+.

    Because of their elusive nature, such non-classical cations were typically not isolated and just observed with methods like spectroscopy. One major breakthrough was in 2013, when a team of chemists finally managed to isolate the 2-norbonyl cation. It was long debated whether this was a rapidly equilibrating classical cation or rather non-classical, penta-coordinated carbon. The chemists cleverly used bromide abstraction from this precursor to generate the cation.

    The byproduct bromoaluminate anion nicely stabilizes this species, allowing the growth of, as they put it, slightly brownish but nearly colourless crystals. These were extremely labile towards normal atmosphere and room temperature, so the x-ray analysis had to be highly controlled at low temperatures of just 120 and even 40K.

    Still, they somehow made it work and confirmed the non-classical, symmetrical structure. The C-C double bond interacts with the primary carbocation through a 3-center 2-electron bond. As you would expect, this interaction is longer than a normal C-C single bond.

    The Hexamethylbenzene dication

    So compared to the disputed norbornyl cation, the hexamethylbenzene dication received much less attention. The cursed structure was however directly proposed upon its first synthesis 50 years ago, which I find quite impressive, based on just  NMR and some ancient computational methods. Still, it wasn’t clear which   structure was present – and we still need to answer if the carbon is truly hypervalent here.

    Fast forward to 2017, chemists finally rose to the challenge. Similar to the norbornyl cation, the key task was to stabilize the cation in a crystalline matrix that allowed characterization via x-ray analysis.

    Synthesis of a hexa-coordinated carbon

    You might think that the simplest way of generating the cation is to take hexamethylbenzene and oxidize the living hell out of it. This would be too easy for such an epic compound, so it doesn’t work. Instead, the strained, high-energy Dewar benzene isomer is more susceptible to the intended manipulations.

    It looks strange itself but can be made by bicyclo-trimerization of alkynes through [2+2] additions with aluminium trichloride as a Lewis acid. Oxidizing one of the double bonds is pretty simple, with one equivalent of perbenzoic acid delivering the epoxide. If we count the atoms, we simply need to remove O2- to get to the correct sum formula.

    Magic Acid for O2- abstraction

    This calls for magic acid. This is a mixture of fluorosulfuric acid, a super acid with a pKa equivalent of -10, and the hypervalent antimony pentafluoride. This Lewis acid forms very stable adducts with anything that has electron pairs. This leads fluorosulfuric acid to react with itself, generating an acid so devilish it can protonate the C-H bond in methane to give CH5+, the compound we’ve talked about earlier.

    The reaction is performed at extremely low temperatures given the dication instability. It requires masterful rinsing of frozen dewar benzene epoxide with the super acid mixture. If you swirl too fast – whatever that means – your precious reactants will turn into black tar. You know what we are missing? Of course, after forming the dication, we apparently need to add an excess of anhydrous HF to crystallize it out after some days at -80 °C. I like how the authors wrote ‘in the aftermath’, indicating this reaction is a wicked battle that will require attempts to get it just right.

    But how does this work mechanistically? It’s just guessing, but likely, the protonation of the epoxide triggers a rearrangement from the Dewar benzene framework into the bridged five-membered ring. The positive charge ends up at the top of the pyramid, stabilized by a 3 center 2 electron bond, reminiscent of the 2-norbornyl example we covered.

    This intramolecular rearrangement is very fast, but remember we are still in a soup of excess super-acid. Thus, another protonation finally gets rid of the oxygen, giving another carbocation. In similar fashion, we again oxidize the top carbon and create a cyclopentadiene at the bottom of the pyramid. This dication crystallizes with an entourage of two SbF6 anions and one molecule of fluorosulfuric acid.

    Crystal Structure of the Hexamethylbenzene dication

    The apical carbon binds the methyl group on the top and seems to interact with all five carbons of the pyramid base at a distance of roughly 1.7A. This is quite a bit longer than normal C-C single bonds, so you should not be surprised that these are not fully-fledged, classical two-electron bonds.

    Based on orbital computations, the multi-center p-electron interactions can be seen as having bond orders of roughly one half each. In total, the apical carbon experiences just below four bond equivalents. This means that just because it’s hexa-coordinated does not mean its hexavalent.

    By the way, the carbon NMR spectrum is pretty interesting – we see the ring carbons, the apical carbon, the five methyl groups at the base and at a negative chemical shift, the top methyl group which is extremely shielded. The chemists initially proposed that the system corresponds to a cyclopentadiene cation interacting with an ethyl-ylidene cation through a total of six electrons in the pyramid.

    However, subsequent research showed that there might be more than meets the eye here. Based on some fancy computations of effective oxidation states, they believe the cyclopentadienyl ligand is not cationic. Instead, it’s an aromatic cyclopentadiene donor anion and the top group is actually a formal methyl cation . This means the central carbon behaves like a transition metal with two modes of coordination. On one hand, it binds a donor anion as a Lewis acid, and on the other it donates an electron pair to the acceptor cation.

    Overall, this is an awesome system that remarkably, is stable enough for crystallization and x-ray analysis. It definitely adds to the list of strange carbon species.

    Thanks for reading!

    References

  • 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.

    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.

    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 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.

    ➡️ 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):

    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:

  • Troc Protecting group Mechanism & (De)Protection

    Troc Protecting group Mechanism & (De)Protection

    Troc (also 2,2,2-trichloroethoxycarbonyl) is a really exotic but versatile protecting group. Let’s learn why.

    What is the Troc Protecting Group?

    Troc (2,2,2-trichloroethoxycarbonyl) can convert amines or alcohols into stable carbamate or carbonate derivatives. This leads to a similar effect that we see in groups like Fmoc or Boc: the previously nucleophilic amine or alcohols loses its reactivity (driven by delocalization of electrons into the carbonyl system).

    The nice thing is that Troc is orthogonal as the deprotection conditions for Fmoc (base), Boc (acid) or silyl groups like TBS (fluoride) do not remove it. Instead, it has a unique mechanism of reductive beta-elimination to release the free group.

    Troc Protection Mechanism

    The Troc protecting group is introduced by reacting the free amine or alcohol with 2,2,2-trichloroethyl chloroformate (Troc-Cl) with addition of a base.

    Most common protection conditions are Troc-Cl with pyridine in CH2Cl2 or THF. If the starting material is very polar, Troc-Cl with NaOH or NaHCO3 in water.

    Troc Deprotection Mechanism

    The Troc protecting group can be removed with certain reductive methods which all function via beta-elimination. Most common is use of zinc or other single-electron reductants that reduce the terminal carbon. The beta-elimination gives a free carbamate – an intermediate seen in mechanisms of many other protecting groups – that rapidly decarboxylates to the deprotected amine (or alcohol).

    Most common deprotection conditions are Zn powder in THF/H2O or so-called couples/alloys consisting of mixtures of Zn-Pb or Cd-Pb. More rarely used, reduction with electrolysis also removes the Troc group.

    Always remember protecting group stability or lability are always general (e.g., here: removal by reduction). Nothing in chemistry (or life) is black and white 🙂
    Here is a neutral method (not reductive) using trimethyltin hydroxide. [1]

    A fascinating point is that under the right conditions, Me3SnOH actually deprotects Troc selectively in the presence of methyl esters (you would expect that the methyl ester is quite labile to hydrolysis with hydroxide).

    Troc PRotecting grouP in total synthesis

    The very first introduction of the Troc protecting group was already… very advanced! Woodward and co-workers used the starting material below in the synthesis of cephalosporin C, an antibiotic natural product. [2]

    This is a cool example where one of the three Troc groups does not decarboxylate (the one on the right). This is because it was not attached to a free alcohol, but rather, only the trichloroethoxy was masking the free acid. Because this is not a free carbamate or carbonate, we do not see a decarboxylation.

    Thanks for checking out this article – feel free to read about other protecting groups!
    Below you can find typical Troc protection and deprotection conditions.

    Troc Protection conditions [3]

    To a solution of the alcohol (0.80 g, 1.48 mmol) in methylene chloride (30 ml) at 0 °C was added pyridine (0.96 ml, 11.84 mmol, 8 equiv) followed by 2,2,2-trichloroethyl chloroformate (0.8 ml, 5.92 mmol, 4 equiv), and the reaction mixture was stirred at 0 °C for 1 h. Saturated aqueous sodium bicarbonate (50 ml) was added and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3 x 50 ml), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (2% EtOAc/hexanes) afforded protected product (0.98 g, 93%) as a colorless oil.

    Troc deprotection conditions [4]

    To a solution of protected Troc-amine (40 mg, 57 µmol) in 4 mL of MeOH was added activated zinc (400 mg). The mixture was stirred at 25 °C for 5 min, and glacial HOAc (4 mL) was added. The mixture was heated at 60 °C for 30 min, cooled and concentrated under reduced pressure. The residue was treated with 5 mL of 5% aqueous NaOH, and the solution was extracted with EtOAc (5 × 5 mL). The combined extracts were washed with brine, dried over anhydrous K2CO3, and concentrated under reduced pressure. Flash chromatography on silica gel (100:1 CH2Cl2/MeOH) gave 25 mg (86%) of the free amine as a viscous oil.

    TROC Protecting Group References

    • P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
    • [1] Highly Chemoselective Deprotection of the 2,2,2 Trichloroethoxycarbonyl (Troc) Protecting Group | Barry M. Trost, Christopher A. Kalnmals, Jacob S. Tracy, and Wen-Ju Bai | Org. Lett. 2018, 20, 8043−8046
    • [2] The Total Synthesis of Cephalosporin C. | Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.; Oppolzer, W.; Ramage, R.; Ranganathan, S.; Vorbruggen, H. | J. Am. Chem. Soc. 1966, 88, 852− 853
    • [3] Patent WO2007/15929, 2007, A2
    • [4] Total Synthesis of (±)-Symbioimine | Yefen Zou, Qinglin Che, Barry B. Snider | Org. Lett. 2006, 8, 24, 5605–5608
  • THP Protecting Group (Tetrahydropyranyl Ether)

    THP Protecting Group (Tetrahydropyranyl Ether)

    THP is a much less common hydroxyl protecting group than silyl-based ones like TBS. It’s very simple but still has a unique nature and mechanism.

    What is the THP Protecting Group?

    Tetrahydropyranyl ethers were one of the first protecting groups for alcohols. Nowadays, they are seen less commonly, though still used. The THP group is easily removed under acidic conditions (mechanism below) and stable to organometallic nucleophiles, electrophiles (as the protected oxygen is less nucleophilic), reduction or base. The protected THP ethers are actually a type of acetal (‘double-ether’).

    THP Protection Mechanism

    THP protection uses acid catalysis and 3,4-dihydro-2H-pyran. The mechanism proceeds by THP pre-activation with acid, leading to a stabilized cation. Here, the oxonium is drawn but you can imagine the other resonance form with the positive charge on the carbon which is ultimately where the ion is most electrophilic.
    Our free hydroxyl group then attacks the carbon in a nucleophilic addition, and loses a proton to give the protected THP ether. The last step regenerates our acid catalyst.

    The most common protection conditions are catalytic TsOH or pyridinium p-toluenesulfonate (PPTS, a form of TsOH with lower acidity) together with 3,4-dihydro-2H-pyran in dichloromethane.

    THP Deprotection Mechanism

    THP deprotection proceeds really similarly to THP protection – acid catalysis activates the acetal system towards dissociation of our initially protonated alcohol. Again, it’s the same stabilized cation intermediate but based on the choice of solvent used, we have different potential byproducts. The solvent is obviously present in large excess, so it will preferentially attack the carbocation instead of our just liberated hydroxyl group. For example, methanol gives the methyl-substituted THP ether while use of water would give the free hydroxyl group (this can open to the linear aldehyde).

    The most common deprotection conditions are AcOH:THF:H2O or PPTS in EtOH.

    THP PRotecting grouP Diastereomers

    One of the drawbacks of the THP protecting group versus the TBS protecting group, beyond its lower stability, is that it introduces a second chiral center.
    If our starting material has already at least one chiral carbon, we form diastereomers. This can complicate the separation and identification (e.g., NMR) of products – because as you know, diastereomers have different physicochemical properties.

    Interestingly, some older research [1] tried to make use of this ‘drawback’. In this work, the chemists used a THP-derivative as a chiral auxiliary for nucleophilic additions to an aldehyde in the molecule.

    In these derivatives, one side of the aldehyde is shielded from nucleophilic attack while the other is exposed. This leads to very high diastereoselectivity at the newly formed carbon (a tertiary alcohol). It’s not terrible useful but interesting that a protecting group can be used to exert diastereoselectivity. You could imagine this potentially being useful in some complicated total syntheses.

    Thanks for reading, and check out the other protecting group articles!

    THP Protecting Group References

    • P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
    • [1] The tetrahydropyranyl group as a chiral auxiliary for the nucleophilic addition to α-alkoxy ketones | André B. Charette , Abdel F. Benslimane , Christophe Mellon | Tetrahedron Letters 1995, 36, 8557
  • Acetal Protecting Group & Mechanism

    Acetal Protecting Group & Mechanism

    There is no single acetal protecting group! Rather, this is a broader family of similar protecting groups. Let’s check out the properties and mechanisms of acetal protection and deprotection.

    What is the Acetal Protecting Group?

    Acetals always protect carbonyl compounds. But how? This is where the variety can come from. On one hand, acyclic acetals form by reaction with an alcohol (-OH) or thiol (-SH) and catalytic acid. On the other, cyclic acetals form when carbonyls react with a diol or dithiol and catalytic acid.

    You will know that carbonyls are nucleophilic at the carbon. Any acetal protecting group renders it stable to these nucleophiles: aqueous and non-aqueous bases, organometallic reagents and hydrides. As always, we want to avoid unwanted reactions of one group (here, the carbonyl) to instead perform chemistry at another functional group. As we will see below, formation of acetals involves a two-step mechanism, including nucleophilic attack and subsequent dehydration, which drives the equilibrium towards product formation.

    Difference between Acetal and Ketal

    You might not be aware, but back in the day, people used to separate acetals – made from aldehydes – and ketals – made from ketones. Nowadays, acetal is the umbrella term that describes both – while ketal remains restricted to ketones (link to IUPAC definition).

    acetal ketal difference

    Types Of Acetal Protecting groups

    As mentioned, there are several relatives in the acetal protecting group family. The good thing is that they work very similarly!

    => You should simply know that acetals can be oxygen-based or less commonly, sulfur-based. The simplest acyclic acetal is the dimethyl acetal. Cyclic acetals have five-membered rings (1,3-dixolane; 1,3-dithiolane) six-membered rings (1,3-dioxane, 1,3-dithiane).

    Acetal protection mechanism

    As an example, 1,3-dioxolanes are prepared by treating carbonyls with ethylene glycol and acid.
    => Acetal protection or acetalization requires catalytic acid to activate the carbonyl (but only catalytic because the proton is regenerated in the final step)
    => Acetalization is a condensation as the original oxygen is kicked out as water

    acetal protecting group protection mechanism

    Typical conditions: Ethylene glycol and cat. TsOH (acid) in C6H6 as solvent at reflux.

    Because every reaction is an equilibrium (imagine the arrows also going from right to left), chemists use ways to remove water from the reaction to ensure it can’t react back. For acetalizations, this involves using a Dean-Stark trap. The Dean-Stark trap is a glassware that collects water formed in a reaction through an azeotropic distillation. You might have heard about it – if not, does not matter.
    This is a physical removal – alternatively, dehydrating agents like trimethyl orthoformate can chemically remove the water by reacting with it (“scavenger”).

    The same mechanism applies if we use other diols (e.g., to form six-membered 1,3-dioxanes), alcohols (e.g., methanol to form dimethyl acetals) or thiols to form sulfur-based acetal protecting groups.

    Acetal Deprotection Mechanism

    Deprotecting acetals is very similar to introducing them!
    The most common is an acid-catalyzed hydrolysis. Again, make sure you understand why it only requires catalytic acid (i.e., less than 1 “equivalent” of moles).

    acetal deprotection mechanism

    Typical conditions: Cat. pyridinium tosylate PPTS or HCl (as the acid) in a mixture of water (for the deprotection) and an organic solvent (to dissolve the starting material).

    The sulfur-based acetals are special as they can also be removed with heavy metal salts – so Lewis acids like mercury(II) or silver(I) – or oxidants. The oxygen-based acetals are stable to these conditions.
    We will go into 1,3-dithianes and 1,3-dithiolanes into more detail in another post.

    Acetal protecting group stability

    Cyclic acetals are more stable than acyclic ones. Why? Acidic hydrolysis starts with protonation (catalytic acid), and goes via the oxonium intermediate.

    For the cyclic acetal, the newly released hydroxyl group is still in the same molecule – so the reverse reaction would be an intramolecular reaction which is very fast (entropically favored).

    For acyclic acetals, formation of the oxonium cleaves off an alcohol as a separate molecule. Because the deprotection is in aqueous solvent, we have a lot of water molecules around. It is now much more likely water will attack the oxonium (leading to deprotection of the carbonyl) instead of the alcohol attacking. This is because we only have 1 molecule of alcohol formed for 1 molecule of starting material; on the other hand, we have a large excess of water molecules.

    Acetal Protecting Group References

    • P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
  • 🧠 Is Organic Chemistry Hard? (Spoiler: Kinda)

    🧠 Is Organic Chemistry Hard? (Spoiler: Kinda)

    “Why do they call it organic chemistry? Nothing about this feels natural.”

    A student, somewhere out there

    Organic chemistry is often perceived as one of the most challenging subjects for students. Unfortunately, this creates a lot of anxiety and misconceptions about its complexity and requirements, particularly for students in adjacent fields like medicine, pharmacy or biology.

    But why the bad reputation?

    1. Concepts: Yes, organic chemistry is complex! After all, it deals with the literal wizardry of transforming living matter. The complexity (and bad teaching) can make many students feel overwhelmed – amplified by cumulative learning: missing foundational concepts makes it difficult to understand advanced ones.
    2. Representation: Organic chemistry requires abstract thinking and relies on molecular drawings that are often not intuitive or tangible. After all, we are drawing 3D things on 2D paper. Fischer projections anyone?! (I hated these)
      (how to change: look at 3D model, simulate it online, practice practice)
    3. Process: Teachers rush through content without explaining it properly, leading students to fall behind completely and/or rely on memorization to stay afloat (how to change: try to maximize the support at your uni with open doors, ask more senior students – if no support environment, look online and try to understand the why, write as many things out as you can to build your mental muscle…)

    But do not despair – organic chemistry can be more accessible than you might think. Here are some ways to help you address these issues.

    1. Organic Chemistry Concepts

    Build the foundation: Whatever level of class you are taking, first go back to your older materials. For introductory organic chemistry lectures this means understanding basic models like the atomic model (electrons, protons, neutrons) and orbitals and hybridization (if relevant in your class). Why do molecules inherently repel each other, and why do reactions occur nevertheless? What is a chemical reaction? Then, revisit concepts like electronegativity, nucleophilicity and electrophilicity (link), …
    I might work on a full list of concepts in future.

    Understand the functional groups (link): Learn the structures of the most common functional groups in organic chemistry. Sorry, but there is some memorization involved. It’s just like learning a new language: you need to memorize at least new words! For this, you have to understand what a skeletal formula is, and how it differs to normal molecular drawings (next section).
    Again, I will go into more details in future but here are two easy exercises:
    => Get a list of the 15-20 most common functional groups and draw their structures in skeletal formulas. Can’t remember a particular one, like the nitro group and its partial charges? Well, simply draw it 5 times for 2-3 days. You will know all of them in no time.
    Then, look at them and think about their similarities: For example, a thiol group is like a hydroxyl group (or an alcohol), just that the oxygen is replaced by sulfur which is in the same “group” in the periodic system. An ester is similar to a tertiary amide, just that the -OR group bound to the central carbonyl carbon is replaced by a -NR2 group. Tertiary amides are similar to secondary and primary amides, just that the number of alkyl rests versus hydrogens bound to nitrogen differ.
    => Google “pharmaceuticals” and check out their structures on Google images. Pick a random pharmaceutical – what functional groups can you identify? Which groups are ones you do not know yet? Do they look similar to any which you know already?

    Work your way up the complexity of reactions:
    😔 The bad news : There are a literal TON of reactions in organic chemistry.
    😊 The good news: Thankfully, you don’t have to know all of them, and many of them share the same logic and concepts. Here you should again start easy and build up.
    => Before trying to understand SN1 reactions or more difficult name reactions, first review acid-base reactions and oxidations/reductions. Then, get into additions. Then, substitutions and eliminations (SN2 and E2 first because they are just one step – then, SN1 and E1). After these, you can start to look at name reactions and complex transformations. For example, if you have are discussing electrophilic aromatic substitutions in class, you need to know how much simpler additions and substitutions work!

    Focus on conceptual understanding: It’s normal to memorize things at the start, but really strive to understand the “why” behind reactions and mechanisms. For example: Why does a molecule X react in a substitution – where is its nucleophilic group? Why is the reagent Y an oxidant – which atom has a high oxidation number and gets reduced? Why does the reaction occur regioselectively at this position of the aromatic ring – are there electron-donating or electron-withdrawing substituents somewhere?

    Create mind maps: Look at all the reactions you have studies in your class, and try to connect them based on their similarities. Or, connect different concepts: resonance impacts many other factors like acidity of a molecule. How? Electronegativity impacts intermolecular forces like hydrogen bonds and dipole effects. How? Diastereoisomerism impacts melting and boiling points. Why

    Create analogies: Whenever you find a concept confusing or can’t remember it, create an analogy. For example, nucleophiles and electrophiles can correspond to rich and broke people, respectively. Electrophiles would like to borrow the electrons of the nucleophiles, creating a strong attraction. The process of the rich lending money to the poor is the nucleophile giving its electrons to the electrophile.

    2. Representation

    Master skeletal formulas: Organic chemistry relies on skeletal formulas which omit the explicit indication of carbon and most hydrogen atoms. Remember, each “bend” or end of a line represents a carbon atom, and hydrogen atoms are implied to fill the carbon’s required bonds.

    Change your perspective: Molecules can be represented in various ways: Lewis structures, skeletal structures, Newman projections, Fischer projections… Each emphasizes different aspects of a molecule (e.g., stereochemistry). Practice switching between them to strengthen your spatial awareness.
    => Practice converting between full structures and skeletal formulas until it’s your second nature. Make sure you understand where electron pairs are present!
    => Convert between Newman projections and skeletal formulas. Are your Fischer projections your enemy? Well, go and solve literally 20 different problems. You will get the hang of it.

    Use molecular models to visualize stereochemistry: Stereochemistry is a tricky topic because because it involves 3D thinking. Physical or digital 3D models of molecules can help you see how atoms are arranged in space.
    => Use online resources like MolView to visualize molecules. Struggling with chirality, enantiomers, and diastereomers? Go to town on the visualization. Rotate, inspect and understand the structures! If you have an university ChemDraw license, use Chem3D!

    Practice electron pushing: Organic reactions are governed by electron movement. Curved arrows indicate this electron flow. Whenever you’re learning a new reaction, focus on understanding the arrows, which show how bonds are made and broken. If you can follow the electrons, you’ll have a better grasp on the mechanics of reactions. The same applies to resonance. Pick any molecule of your choice and draw all the different resonance structures. Why resonance structure is the most stable? How does resonance impact the reactivity of the molecule?

    Color code drawings for clarity: Use different colors if that helps you. For example, always use red to indicate movement of electrons. Does the reaction involve partial charges? Color code them!

    “Play chess” – think several moves ahead: At the beginning, you should write out every single step in a reaction. Once you are at the intermediate level (when you get to practicing retrosynthesis), try visualizing several transformations at once. How would my final product look like if I oxidize the alcohol in the molecule to the aldehyde and perform a Wittig reaction?

    3. How to learn organic chemistry

    Stay consistent with daily practice: We’ve all been guilty of cramming at some point. However, organic chemistry is best learned through regular practice. Even if you only have 15 minutes, do something related to the course every day—whether it’s reviewing notes, drawing mechanisms, or solving practice problems. The more often you engage with the material, the more familiar it becomes.
    => Every day, read about one new molecule of your choice. Think drugs against neurodegeneration are cool? Research the structures of Alzheimer’s drugs. What are their functional groups? How are they synthesized? Maybe you are into doing sports? Look at the different types of steroids and performance-enhancing drugs that there are! (Do NOT take them, just read about them…)

    Activate your little brain cells: Look, we all are guilty of passively consuming information and entertainment. But instead of just reading textbooks or watching videos, actively engage with the content. Draw out mechanisms as you learn them, explain concepts in your own words, or quiz yourself on reaction types and mechanisms. Basically, anything you are not writing down or creating yourself, you will probably not remember!

    Test yourself with practice problems: Organic chemistry is problem-solving heavy, so doing lots of practice problems is essential. Don’t be discouraged by mistakes or getting stuck – this is part of the learning process. The rate-limiting step (see what I did there?) might be how many good problems you can find – you know, ones with proper explanations. The quality of your problems will depend on your luck and teacher.
    I’m working on a problem book for chemistry myself – but yeah, go to town on Google and YouTube.

    Emphasize understanding over memorization: I mentioned this one already – but given we are talking about the learning process here, I wanted to reiterate.

    Create your own study materials: Summarize concepts, reactions, and mechanisms in your own words. Create summary sheets, mind maps (see above), or flashcards tailored to your learning style. Experiment and see what works for you! For the things that you will need to memorize (e.g., functional groups, pKa values, named reactions…), you should have a clear approach.

    Team up: Organic chemistry is almost always more manageable when tackled with peers. Explain concepts to each other, discuss exercises together, and discuss tricky mechanisms. Your classmates are ahead of you? Great, you can suck out their insights and ask questions. You are ahead of your classmates? Great, help them and in doing so, you will further elevate your capabilities. Are you in university and not against earning an extra buck? Tutor students that are 1-2 years below your level.

    Use office hours and ask for help early: If something doesn’t make sense, ask for help right away. Afraid of looking like a moron? Well, the odds are at least half of your class is feeling like morons as well, so don’t feel bad! Visit your professor or teaching assistant during office hours to clarify any misunderstandings. Addressing confusion early prevents small gaps in knowledge from turning into major issues later.

    Use multiple resources: Don’t rely solely on one textbook or lecture notes. Different resources may explain the same concept in slightly different ways, and sometimes a different perspective makes things click. Use videos, alternative textbooks, online platforms, and forums to diversify your learning. No access to textbooks? Go to town on LibGen (google it).

    Prioritize your effort: As mentioned, building the foundation is key. But once you get into intermediate territory, there are SO many things you could theoretically read about. In the best case, your textbook and/or teacher might have clear objectives or checklists of topics to know. Assess on what you need to work on most, and then go hard.

    Is Organic Chemistry Hard?

    So, is organic chemistry hard? Honestly – yes, it’s hard.

    Is it as hard or terrifying as people make it out to be? No, not really. The great thing is that at some point, every new concept or reaction will be based on something you know already. After enough effort, there will be almost no cases where you really have absolutely no clue of how to approach a problem.

    Is it the hardest subject you will study? Maybe, maybe not. Depending on your area of focus, it might come least naturally to you, versus other subjects. If you dislike chemistry and math, physical chemistry will haunt you even more.

    To end on a positive: I loved organic chemistry more than any other subject but even I had been struggling with it initially.
    Resonance? Confusing as hell. Fischer projections? I couldn’t draw a single one correctly. The abbreviation of -Me for a methyl group (-CH3)? I thought it stood for “a generic metal” (lol).
    I asked A LOT of stupid “questions” (or in many cases did not ask them, which slowed down my progress). What had been a guessing game and brain-dead memorization, became almost second nature.

    Whatever your journey in organic chemistry, I hope you can figure out how to make it a bit more bearable and more successful – however you define it: just passing, improving your grade, or really going beyond the class and mastering it.

    I’m working on materials to help students unlock and practice organic chemistry. So if you are just getting started, stay tuned!

  • Trityl Protecting Group: Trityl Chloride Protection & Deprotection

    Trityl Protecting Group: Trityl Chloride Protection & Deprotection

    Trityl protecting group

    The trityl group is another acid-labile protecting group that might remind you of Boc! Here we explain the “standard” trityl and exciting, more advanced versions!

    What is the Trityl Protecting Group?

    Trityl stands for triphenylmethyl, a group most commonly used to protect free alcohols as ethers. As seen with other PGs, amines and thiols can also be protected (as they are also nucleophilic).

    Trityl ethers saw most application in carbohydrate chemistry as their hydrophobicity was useful for protection of polar building blocks. In addition, their bulky size allows for selective protection of primary hydroxyls due to sterics.
    Over time, silyl PGs like TBS have replaced much of the use of Tr outside of carbohydrate chemistry. Nevertheless, we can learn some things by studying it!

    Trityl Protection Mechanism

    Trityl protection usually uses trityl chloride in pyridine which conveniently functions as a base, capturing the HCl by-product. Added DMAP (4-dimethylaminopyridine) can function as a base but also as a catalyst. You likely remember from other protecting groups (e.g., TBS) or reactions like acylation that DMAP works as a transfer reagent via initial nucleophilic addition to the activated reagent and transfer to our group of interest (not shown above).

    Watch out as there are some pages online that imply a direct SN2-like attack of the free alcohol to Tr-Cl. You should know this is impossible; quaternary carbons do not undergo SN2! Instead, the protection proceeds as a SN1 via the stable trityl cation intermediate [1].
    The large size allows the selective tritylation of primary alcohols in the presence of secondary alcohols as these react much slower due to steric hindrance.

    No surprise, there are other ways to introduce trityl like TrOTf (recall just like for TBS) or trityl-pyridinium tetrafluoroborate, an even more reactive transfer reagent.

    Trityl DeProtecTION Mechanism

    Trityl is deprotected with Bronsted acids or less commonly also Lewis acids. In both mechanisms, the highly stable trityl cation is a common theme. This should remind you of the Boc group: The trityl cation here is basically a t-butyl cation (acidic Boc deprotection intermediate) on steroids.

    Case 1: The deprotection with a Bronsted acid starts with protonation of the ether oxygen. This increases the “pull” on the O-C bond which can fragment to give our deprotected hydroxyl group. The resulting trityl cation is still reactive, so adding nucleophilic scavengers like 2-methyl-2-butene can avoid undesired reactions.
    By using acetic acid or formic acid, it is possible to deprotect trityl ethers in the presence of TBS ethers. If no sensitive groups are present, stronger acids like TFA obviously work as well.

    Case 2: Using Lewis acids like BF3 works in a similar way; coordination to the oxygen lone pair facilitates O-C bond breaking and deprotection. Other Lewis acids like ZnBr2 or MgBr2 can be used for some substrates as well, particularly if two coordination sites are present (e.g., carbohydrates). In these cases, neighbouring group effects with bidentate coordination can be observed.

    p-Methoxy Trityl Protecting Group

    As a twist on the standard trityl group, chemists have also explored variants such as p-methoxy trityl. A nice synthetic study on nucleotides led to the discovery of such groups – already in 1962 [2]! Their results were as you might expect: By adding a p-methoxy group, we increase stability of the intermediary trityl cation due to the mesomeric electron-donating effect! This makes deprotection easier.

    It turned out introducing one methoxy group increased the rate of deprotection by a factor of ten. While standard 5′-trityl-uridine required 48h for complete hydrolysis in 80% acetic acid at room temperature, the mono-methoxy-trityl MMTr group took just 2h! They also developed di- and trimethoxy trityls (i.e., one p-methoxy on each phenyl ring) which cleave in 15min and 1min, respectively. By the way, this change makes initial protection easier too because we also go through the trityl cation.

    This di-methoxy DMTr group is one of the most used members of the trityl family due to its reactivity and selectivity for primary alcohols (primarily seen in automated solid-phase synthesis of nucleotides).

    I hope you learned something new today!

    Trityl Protection experimental procedure [3]

    A mixture of di-TBS gemcitabine (671 mg, 1.47 mmol) and tritylating reagent (2.94 mmol, 2 equiv.) in dry pyridine (7.3 mL) was stirred overnight at room temperature. Methanol was added to the solution for quenching. After removal of the solvent, the residue was purified by flash column chromatography on silica gel to obtain the title compounds.

    Trityl deprotection experimental procedure

    Bronsted acid [4]: Compound II (200mg, 0.4mmole) was treated with 3ml of cold formic acid (97+%) for 3 min and then evaporated with an oil pump at room temperature. The residual gum was evaporated twice from dioxane, followed by evaporations from EtOH and Et2O. Finally, the residue was extracted with 10ml of warm H20, the insoluble triphenyl-carbinol was filtered, and the filtrate was evaporated in vacuo. The residual gum was dissolved in EtOH(1ml), dry Et2O (20ml) was added, and the product was precipitated with petroleum ether (30-60°, 10ml) (the gummy precipitate was chilled and scratched to induce crystallization). Recrystallization from the same solvent system gave fine needles of VI.

    Lewis acid [5] To a mixture of 4 (2.0 mmol, 994 mg, 1.0 equiv) in CHCl3/MeOH (16 mL/4 mL) was added BF3·OEt2 (4.0 mmol, 0.5 mL, 2.0 equiv) at room temperature. The mixture was stirred at rt for 45 min and was then poured into EtOAc/H2O (100 mL/100 mL). The organic layer was washed with brine (100 mL), dried (Na2SO4), and filtered. After removal of solvent, CH2Cl2 (10 mL) and hexane (30 mL) were added sequentially to the crude product. The resulting solid was filtered and was washed with Et2O/hexane (2/3, 20 mL). The product was dried to give 474 mg of 12 (93%) as a white solid.

    Trt Protecting Group References