In this issue, we have selected several papers from February's "Some Items of Interest to Process R&D Chemists and Engineers" for in-depth reading.
Photocatalytic C-H alkylation with sulfonylhydrazones
The first paper is on photocatalytic C-H alkylation with sulfonylhydrazones by Professor Timothy Noël from the University of Amsterdam, the Netherlands. The reaction involves the addition of an alkyl radical to the electrophilic carbon of the aldimine, 4-trifluoromethylsulfonylhydrazone, which is derived from the aldehyde.
The synthesis of the corresponding hydrazine for the synthesis of the substrate 4-trifluoromethylsulfonylhydrazone is straightforward. Simply add hydrazine hydrate (3 equivalents) dropwise to a solution of the corresponding sulfonyl chloride (6 mmol) in 30 mL of THF at 0°C. The N-H bond (ca. 430 kJ/mol) and S-Cl bond (ca. 260 kJ/mol) → S-N bond (ca. 460 kJ/mol) and H-Cl bond (ca. 430 kJ/mol) conversion takes place, with the formation of the H-Cl bond (ca. 430 kJ/mol) being the main driving force. Since hydrazine hydrate (3 equivalents) is used for the generated H-Cl, it is likely that hydrazine hydrochloride is formed. The addition of hydrazine hydrate dropwise at 0°C is recommended to minimize the heat of the neutralization reaction.
For purification, dilute the reaction mixture with ethyl acetate and wash it five times with brine to remove hydrazine hydrochloride. The organic layer is then dried over Na2SO4, filtered, and the solvent is removed under reduced pressure to complete the process.
The key step in the reaction is the addition of an alkyl radical to the electrophilic carbon of the aldimine, 4-trifluoromethylsulfonylhydrazone, which involves the conversion of a C=N bond (ca. 640 kJ/mol) and a C-H bond (ca. 385 kJ/mol) to a C-C bond (ca. 300 kJ/mol) to another C-C bond (ca. 385 kJ/mol) to a C-C bond (ca. 300 kJ/mol) to a C-N bond (ca. 285 kJ/mol) to an H-N bond (ca. 430 kJ/mol). As a rough estimate of the binding energies before and after the addition, there is not much advantage, but as the authors mention, the matching polarity of the radical and the substrate undergoing the addition seems to be the key. In the extreme case presented in the paper, the alkyl radical is nucleophilic, so it adds to electrophilic substrates such as aldimines but not to nucleophilic olefins such as silyl enol ethers. The nucleophilic activity of alkyl radicals derived from THF may be explained by the superconjugation effect of the non-covalent electron pair of oxygen on the orbital of carbon radicals.
Although the substrates are likely to undergo the Shapiro reaction, the use of aldimines without active α-hydrogen as the main substrate and the use of TFT instead of toluene as the solvent may not work if there is a competitor in the radical formation stage.
As for the photocatalyst 4,4'-dichlorobenzophenone, there are more detailed explanations in the paper about why benzophenone is good and energy transfer than mine, so I will leave it there.
https://www.jstage.jst.go.jp/article/yukigoseikyokaishi1943/24/12/24_12_1183/_pdf/-char/ja
http://www9.gunma-ct.ac.jp/staff/nakajima/Lecture/photochem5K/RS_20150701.pdf
http://www9.gunma-ct.ac.jp/staff/nakajima/Lecture/photochem5K/RS_20160613.pdf
I had a slight doubt about the proposed reaction mechanism. When the ketyl radical returns to benzophenone after withdrawing the hydrogen radical from THF, does the hydrazinyl radical, after the addition of the alkyl radical to the electrophilic carbon of the aldimine, withdraw the hydrogen radical from THF? This is the point. I asked the author about this point, and he answered that the key here, too, is the matching of polarity. That is, since the nitrogen-centered radicals of the hydrazinyl species are quite nucleophilic (unlike amidyl radicals, which do not have a carbonyl function like amidyl radicals and are known as HAT agents), they do not cleave the C-H bond in THF via HAT (a polarity non-matching event).
Ugi-type four-component linkage polymerization via intramolecular aza-Wittig ring closure
Moving on to the next paper, it discusses Ugi-type four-component linkage polymerization via intramolecular aza-Wittig ring closure. The substrates are aromatic aldehydes, secondary amines, (N-isocyanoimino)triphenylphosphorane, and carboxylic acids. Of particular note is (N-isocyanoimino)triphenylphosphorane, which is commercially available, but it can also be synthesized using formic acid hydrazide, carbon tetrachloride, triphenylphosphine, and triethylamine. I tried to come up with a presumptive reaction mechanism on my own, but I included an element in which PPh3 is added to the azo moiety, similar to the Appel reaction and the Mitsunobu reaction. However, there are some parts that are unclear, so I will just use it as a reference.
The original paper presenting the idea of the polymerization reaction can be found here, and the intramolecular aza-Wittig ring closure during the Ugi reaction is a major feature. The use of iminium instead of imine is also an interesting idea, and although the development of this polymerization reaction seems simple, it is fascinating to observe the ingenuity employed in designing the various substrates used. For instance, when dibenzylamine is replaced by diethylamine in P1 and P3, the yield decreases significantly, but the Mw dramatically increases. The Mn, which represents the average molecular weight, also increases. I speculate that this is due to the fact that solubility did not decrease as the molecular weight increased, and the Mw increased because low molecular weight components decreased as a whole. In P2, since glutaraldehyde is used instead of benzaldehyde, the iminium formation simply slowed down, resulting in a slight decrease in the high molecular weight component, which led to a decrease in Mw. I believe that the Mw decreased because the iminium formation simply slowed down.
Indole synthesis using halogen atom transfer (XAT)
The following describes an indole synthesis using halogen atom transfer (XAT) with aryl diazonium salts and iodoalkanes, developed by Professor Daniele Leonori of the Technical University of Aachen, Germany. The Fischer indole synthesis requires the preparation of arylhydrazines, which limits substrate generality and functional group acceptability. However, if indole synthesis from aryl diazonium salts becomes possible, this would allow for the use of a wider range of substrates. Aryl diazonium salts can be prepared from aniline using sodium nitrite and an appropriate acid, which greatly expands substrate generality. Aniline derivatives are readily available in the market, making this method potentially useful for a variety of applications.
In the optimization of conditions, tertiary amines were initially considered as reductants. However, a large amount of byproducts resulting from the side reaction of 1 with amines required the use of excess reductants. The authors speculated that some side reaction might have occurred in a Gomberg-Bachmann type mechanism. Due to the possibility of side reactions and the cost-effectiveness of the reductants, the authors ultimately chose to use iron sulfate instead of sodium triacetoxyborohydride.
In my experience, when reactions involving radicals with amines were attempted, they encountered some difficulties. When radicals were involved, the reaction was not as straightforward as anticipated. NMR cannot be used to study radical reactions involving amines. If there is an opportunity, it would be interesting to elucidate the whole picture of radical reactions using amines, making full use of EPR and resonance Raman, among other techniques. This could be tied into a project at the author's company, or the author could return to academia to pursue this topic further.
Iodo-alkanes and iodoarenes are commonly used for SET reactions, but iodine-based substrates have some disadvantages, such as substrate generality and susceptibility to degradation by light. In my opinion, finding a highly generalized methodology that solves these problems would be a significant breakthrough in the field.
Dihydroxylation of olefins using nitroarenes as photoresponsive oxidants
Next, I would like to discuss another method for dihydroxylation of olefins using nitroarenes as photoresponsive oxidants, developed by Professor Daniele Leonori of the Technical University of Aachen, Germany. This study is a derivative of a paper previously reported in Nature, where an ozone decomposition-type reaction of olefins using nitroarene as a photoresponsive oxidant was performed. In this study, diol synthesis was successfully achieved by controlling the reactivity and reducing it without cleavage. This reaction is not only interesting but also attractive because it can replace a reaction that previously required the use of osmium tetroxide, which is extremely poisonous.
In the reaction mechanism section, valuable insight into the photocycloaddition reaction was given, as the syn isomer was obtained as the main product from the dihydroxylation of both (E)- and (Z)-olefins. It is easy to imagine that the reaction of the excited nitroarene triplet biradical is stepwise rather than concerted, as there would be a fast bond rotation that equilibrates to an intermediate with less steric hindrance.
Since the syn diol is preferentially obtained, it would be interesting to utilize the conditions for dynamic epimerization from trans to cis diols reported by David W. C. MacMillan to synthesize diastereodivergent syn and anti diols from olefins in a one-pot reaction. It would be intriguing to synthesize diols with syn and anti diastereodivergent diols in one pot from olefins.
Halogenation of pyridines at the 3-position via a Zincke imine intermediate
The last paper is by Professor Andrew McNally of Colorado State University on the halogenation of pyridines at the 3-position via a Zincke imine intermediate.
To put it simply, this is an awesome reaction. Pyridines are electron-deficient aromatic rings, so halogenation by electrophilic aromatic substitution (EAS) requires harsh conditions. Although the reaction can proceed at high temperatures with strong Brønsted or Lewis acids, it is not practical due to substrate generality and functional group acceptability issues. Another problem is that regioselective isomers are not always obtained selectively, resulting in a mixture. The metalation-halogenation reaction using a strong base is another approach, but this also requires an oriented group to access the 3-position. Consequently, as a practical solution, researchers have developed iridium-catalyzed 3-position selective borylation and silylation through steric hindrance and structural control of the ligand, albeit indirectly via other versatile functional groups. I may have gotten a little carried away and talked too much about my research background.
Against this background, an alternative approach to 3-position-selective halogenation of pyridines has been developed using a ring-opening → halogenation → ring-closing strategy. This reaction is a modification of the classical Zincke ring-opening reaction that converts pyridines to azatriene intermediates (Zincke imines) in a one-pot procedure. The idea of halogenating the aromatic ring while opening and closing it, even with pyridine, is fascinating.
The authors first worked to improve the conventional Zincke ring-opening chemistry by removing the limitations that the pyridine N-activation step required strong reaction conditions and often failed in the presence of a substituent at position 2, and by expanding the generality of substrates for substituted pyridines. A specific solution is the ring-opening of NTf-pyridinium salts, which are readily formed from pyridine and anhydrous triflate (Tf2O) at low temperatures. Toscano et al. also reported ring-opening with Tf2O, but they did not extend this process beyond pyridine and stopped when they observed a mixture of ring-opening products. Using 2-phenylpyridine and a series of aliphatic amines as nucleophiles for ring-opening, they obtained moderate yields of ring-opening products from pyrrolidine, piperidine, and morpholine, as well as diisobutylamine, but ultimately found that dibenzylamine was optimal, yielding the ring-opening products in high yield. By coincidence, dibenzylamine was also optimal in the Ugi-type four-component coupling reaction described earlier.
This Zincke ring-opening chemistry is indeed interesting. When a nucleophile attacks a pyridine, an aromatic nucleophilic substitution reaction typically proceeds, as in the Chichibabin reaction. However, the product is more stable than the intermediate after addition due to the "advantage of recovering aromaticity," which is a characteristic of aromatic reactions. In this case, due to the electron-withdrawing nature of the Tf group, the noncovalent electron pair on the nitrogen of the post-adduct intermediate may not be strong enough to restore aromaticity. Additionally, the use of colidine, which has three methyl groups, as a base is probably a perfect balance between preventing the transfer of Tf groups to the colidine side and the addition of nucleophiles, while not being too strong. The intermediate after the addition has a locally amidine-like skeleton, and if we consider NTf as a leaving group, we can propose a natural reaction mechanism.
After the ring-opening step, iodination and bromination proceed smoothly using halosuccinimide (NXS). The combination of ring-opening and halogenation in one pot, in the presence of TFA, suggests a delicate balance between acidity and basicity is needed to establish ring-opening and ring-closing or further decomposition.
The authors used DFT calculations to investigate the mechanism and regioselectivity of Zincke imine halogenation by NXS. I am curious about the factors that determine regioselectivity. The authors used B3LYP-D3(BJ)/def2-TZVP///ωB97X-D/6-31+G(d,p) level of theory, including solvent correction by SMD of CH2Cl2. ωB97X is a better function that has been recently used in place of B3LYP and M06 because of its high accuracy in structural optimization. In the structural optimization, ωB97X-D was used, while B3LYP-D3 (BJ) with a long-range correction was used in the energy calculation. It does not seem to be a system where weak interactions are likely to be effective, but it is probably just a precaution. The long-range correction in D is small compared to the computational cost of changing from B3LYP to ωB97X. The pathway for halogenation appears to involve a general electrophilic addition followed by deprotonation, while the pathway assuming an outer-shell electron transfer process has a much higher activation barrier of 34 kcal/mol. As an aside, using Boltzmann's constant to roughly estimate the energy of 34 kcal/mol, we can say that heating at 200°C for 1 hour and at 160°C for 24 hours is required to consume 99% of the raw material.
Regioselectivity in halogenation reactions is often explained in terms of differences in frontier orbital coefficients, atomic charges, or nucleophilic parameters. However, in the current study, the electronic environments at the C3 and C5 positions of Zincke imines did not show significant differences in Fukui f-factor (0.24 vs. 0.25), natural charge (-0.20 vs. -0.22), and HOMO coefficients (both 0.26). Therefore, a different rationale for the high C3 selectivity is needed. The results suggest an irreversible overall reaction with kinetically controlled regioselectivity in all cases of reactions with NCS, NBS, and NIS, with activation barrier energies around 19-22 kcal/mol that are in quantitative agreement with experimental results.
Without going into details, there are two distinct regions that ultimately determine the selectivity. The irreversible C-Hal bond formation step determines the regioselectivity of chlorination and bromination, while the C-I bond formation is reversible, and the second deprotonation step determines the regioselectivity. This means that the second deprotonation step is crucial in determining the regioselectivity.
This is the second in-depth analysis of the OPR&D paper. This time, we did not focus much on the synthesis of SI, but rather on the concept of reaction energies and mechanisms in the paper. It would be a good idea for you to read the paper from your own perspective and try to incorporate various ideas and points of view into your reading.
I'll be happy to help you again soon.