Synthetic Chemistry - Science topic

Silyl Protecting groups are fine to temporarily protect primary amines.

Hi Dr., I like your question, and I would love to answer and support you on your research, but I would appreciate it if you could click RECOMMEND for my 6 research papers under my AUTHORSHIP below is my short answer to your question. Click the RECOMMEND word under each of my research papers and follow me. In return for your kind support, I provide you with the answer to your question :

Reductive cleavage of the chromophore under mild conditions would seem the most prudent preliminary synthetic step. The electrophilic reactivity of unprotected thiol moieties at elevated temperature risks engendering non-specific reactions and diminished atom economy.

Phosphorus-based reductants such as (VA-044) furnish the requisite reducing potential under ambient conditions, thus circumventing such issues. Subsequent protection of the resultant thiol moieties, via transient acetal or α-methoxymethyl ethers for example, would insulate their nucleophilic character during downstream processing.

While the elevated temperatures proposed for your aminolysis are conducive to facilitating nucleophile-electrophile conjugate addition, prolonged duration risks isomerization or decomposition pathways. A systematic kinetic study, evaluating conversion as a function of time, would help optimize the reaction parameters to maximize atom transfer with minimal unproductive side reactions.

Cleavage of the resultant thiol protecting groups under bench-stable chemical or enzyme-based reductive protocols would furnish the desired product(s) in their exposed, functional thiol form.

In closing, the strategy outlined adheres to best practices in disulfide activation, functional group manipulation and reaction optimization methodologies.

For the formation of diamine the first method may be some what better and can lead to product but during alkylation with RBr base like NaH or BuLi may be necessary.

The second method may fail. Alpha, beta amides are not good Michal acceptor hence attempt of Michael addition of amine to alpha, beta unsaturated amide may fail or can give very poor yield. Another problem is very natural tendency of polymerization of acryloyl chloride and acrylic acids....it can lead poor yield with impurities.

As an alternate method peptide coupling reagents like DCC (or DCCD) (dicyclohexyl carbodiimide), CDI (Carbo diimidazlole) can be used.

One equivalent of diamine, 2 equivalents of mono carboxylic acid can be coupled in presence of 2 equivalent. of DCC or one equivalent. of CDI on anhydrous THF or DCM solvent at r.t or lower temperature can furnish the desired diamide. It can then be reduced to diamine derivatives with suitable reducing agents like LAH etc.

If One uses a dicarboxylic acid as source of amide carbonyl then one equivalent of dicarboxylic acid 2 equivalents of amine should be allowed to react with 2 equivalent of DCC or 1 equivalent of CDI. Plenty of procedures are available in organic synthesis (collective volumes), proper journals or references may be available in Organic Chemistry portal. Please see Mitsonobu reactions , Peptide Coupling reagents etc. , Application of reagents like DCC, CDI, DEAD etc. If One uses ROH instead of RNH2 esters can also be prepared.

The method is very good and high yielding too.

Show quoted text

May explode on heating

Reactions, which are run for 14 hours, frequently are just sitting on the bench from 6pm to 8am. I would be surprised if it is completed in much shorter time.

Thanks, Adam B Shapiro

I followed their protocol but working AdipoRon became cloudy and precipitated.

Now, I'm try to change the new solvent for AdipoRon.

First protect the aminogroup. For example with t-BOC group.

The computational predication of chemical synthesis of a particular compound by calculating reactivity index using molecular orbital theory .

Some software of quantum mechanics such as Gaussian, Hyperchem, Material Studio, Gamess, and so on could support you to solve well it. Have a good day!!!

Dear Hari,

many thanks for sharing this very interesting technical question with the RG community. We have 40+ years of experience in inorganic and organometallic chemistry. Thus I'm not a proven expert in multi-step organic synthesis, but for our organometallic research we synthesized numerous organic ligands. So I would just like to add a few personal comments in addition to the very valuable expert answers provided by Corentin Lefebvre. I did a quick SciFinder search and found that this molecule has never been reported in the previous literature. When you ask "What are all the different synthetic routes/steps that could be used to synthesis this compound?" my impression is that the answer can perhaps be found in the course of a Master or PhD thesis, but not within an answer on RG. However, in my personal opinion the main question is "Will this compound have any useful applications which justify the efforts of synthesizing it?". If not, it is perhaps not worth spending months to develop a suitable synthesis.

As for the possible purification, it is clear to me that the compound will be a solid, so that recrystallization will be the purification method of choice. Since it is a carboxylic acid, chances are that it could also be dissolved in aqueous NaOH and then precipitated again by adding hydrochloric aid.

Good luck with your research and best wishes, Frank Edelmann

Kyle,

You can contact us for consulting services.

Dear Rengwei, thank you for asking this very interesting technical question. I think that Kohei Torikai already provided a good and plausible informatiom why the yields of tertiary alcohols were lower in the case of the 3-aminobenzoate reactions. One way to circumvent this problem could be the protection of the –NH₂ functional group by acetylation. This has been described by Palomo et al. in the artcile entitled "Enantioselective Synthesis of Quaternary D4- and D5- Dehydroprolines Based on a Two-Step Formal [3+2] Cycloaddition of a-Aryl and a-Alkyl Isocyano(thio)acetates with Vinyl Ketones":

The paper has not been posted as public full text on RG, but the Supplementary Information is freely accessible. Please find attached a pdf file. As can be seen in the attched reaction Scheme, the 2 step-reaction of the N-acetylated 3-aminobenzoate with methyl magnesium bromide followed by de-acetylation (described on page S14) provided the tertiary alscohol in fairly good yield.

Good luck with your work and best wishes, Frank Edelmann

I haven't used it but would DeepFrag https://rxivist.org/papers/127442 help you?

Thank you very much for sharing this question

Dear Ehtesham Mohammed many thanks for your very interesting technical question. In fact, one could write an entire book about this. Very good examples have already been provided by Thomas Mayer-Gall, Ekaterina E. Khramtsova and Andy Towns. Benzene is certainly one the most useful building blocks in organic chemistry. Among the more unusual hexa-substitited examples with six equal substituents are hexacyanobenzene and hexanitrobenzene (see attached schematic formula). An intermediate in the synthesis of hexanitrobenzene is 1,3,5-triamino-2,4,6-trinitrobenzene, i.e. a hexa-substituted benzene derivative with 2x3 different substituents:

and

Surprisingly, I also came across an article in which a derivative of hexaphenylbenzene derivative with six different substitunents has been reported (see attached Figure). Please have a look at the article entitled

This is certainly rather unique!

Ester can cleaved by boiling it with aqueous ethanolic solution to form acid salt and alcohol. Neutralization of solution with HCL gives an acid.

Dear all, attached is a book dealing with tips and practices in manipulating air sensitive chemicals. Under the circonstances you want to work, the best option is to work with a continuous lab flow reactor. Please check the link below. My Regards

How soft has been your gel? I am working on soft gels that are difficult to be purified. I have to purify them by membrane dialysis, which creates another issue that is the low concentration of my gel due to the osmosis phenomenon.

0.5 ml is a fairly small volume of solvent, however, if it's reported that way in literature, it sugests that your Ar-Cl would have very high solubility in DMSO and hence 200 ml should dissolve.

I imagine like most people have commented, that the reason for such low volumes is to aid isolation of product, given the difficulty that comes with using DMSO.

I expect that your amine is either liquid or dissolves in a separate volume of solvent??? I also imagine the reaction does not require stirring with would be inefficient in such low volumes.

You have answered your own question. Proper chromatography methods require detection methods which are applicable to the samples under analysis. You may want to review the types of instruments, detectors, columns and materials available at your school before deciding on a final approach. Have someone in the school's analytical instrument lab assist you.

For HPLC samples with weak or no chromaphore, you will need to use a detector that does not rely on wavelength based light absorbance such as an RID, ELSD, CAD or MS, to name a few. Put a little time into researching this basic question so you will better understand the uses and limitations of these methods and detectors. I often suggest my students start with a keyword search on the web (GOOGLE or BING) to find examples and articles to review. This is one of the best ways to learn. Once you have familiarized yourself with the basics, be sure to ask your teacher for help in setting up and running some example methods.

BTW: You may also be able to derivatize some of your samples and use GC/FID or GC/MSD as an alternative to HPLC (only if the samples are appropriate).

I prefer to deal with free amines, convert to free amine then try to protect 2ry amine using 1:1 mole then check it's TLC , if their is more than one product separate by chromatography, after drying take IR, if the peak at around 3300 cm-1

disappeared and appearance of signals for Boc indicates the protection of 2ry amine

dear

this article us good for your question

best regards

The nitrile group is also in resonance with the carbanion

Depending on the reaction rate you can lower the temperature to capture the intermediate and fraction collect it. You need to know the reaction mechanism to avoid conditions that might lead to decomposition. An other alternative is to make the synthesis if you know the structure, again, controlling the temperature.

Cyclopropene could be of interest

Curcumin. Dissolve Excess household tumeric in EtOH and you have your stain. Boronic acids/ esters stain orange against yellow background

May be you can useful from the following article

K.A.Shaikh, V.A.Patil, A.M.Zamir ‘‘Solid phase promoted greener synthesis andantibacterial activity of novel Schiff base under catalytically free condition’’ Elixir Org. Chem., 43, 6960-6963(2012

Dear T. G. Hwang,

No doubt Pd(PPd3)4 in THF/Water is a good condition for SM reaction towards synthesis of several similar compounds. But at some cases that may not give fruitful results even on maintaining inert conditions due to several factors like solubility, molecular stability to temperature, column purification etc., So, I would like to suggest you to have a trial with Pd(PPh3)2Cl2 in Toluene:EtOH:Water which may give you better result. And also I would like to recommend F.Nahra where Pd-NHCs are now playing a crucial role in SM couplings.

Well, if EDC stands for the coupling agent (carbodiimide), you need at least 1 equivalent of it. DMAP can be used in catalytic amount provided that another base (like Et3N) is present in 1-1.2 equivalent.

Good idea will be to read the review recommended by Petr in the first post. Good luck.

Using anhydrous THF and fresh DIAD is important to speed up the reaction.

I have found that a mixture THF/toluene 1:1is also a nice trick to reduce your reaction time

Regards

I found this web page is very useful. I'd encourage you to take a look.

Pratik

This chemistry work fine, almost as described in patent you were referring, but workup and purification is not straightforward, but works well according to this patent. Making NHS ester and its purification is more troublesome compared to making Alexa Fluor 488, it just hydrolyzes much faster compared to other NHS esters I worked with. Nowadays you can buy Alexa Flour 488 NHS ester and most of other Alexa Flours (kind of generic Alexa Fluors) at very reasonable price. Here is a link to one supplier.

Alexa Flour 488 NHS ester https://fluoroprobes.com/product/af-488-nhs-ester/

Alexa Flour 594 NHS Ester https://fluoroprobes.com/product/alexa-fluor-594-nhs-ester/

Many other Alexa Dyes are available from

https://fluoroprobes.com/

1. Based on your data, the catalyst seems to be heterogeneous. Increasing the catalyst amount does not increase the concentration of the catalyst in solution. "Hot filtration method shows reaction stopped after removing catalyst by filtration" indicates that the true catalyst is not in solution.

2. You have already conducted the "specific test"

3. I don't know, but why not.

Use KSCN in the presence of dry acetone at room temperature stirring. Toluene can also be used to prepare isothiocyanate.

Ideally there shouldn't be a residue (Kindly check the quality, proportion of polymer and curing agent and thorough mixing, plus use a glass substrate). IsoPropyl alcohol is the best way to remove the remaining uncured PDMS. The alternative is: Using Piranha solution (Hydrogen peroxide and Sulphuric acid in the ratio of 2:3 by volume). However, it's a highly corrosive acid which needs extreme caution while handling.

There's an odd esterification method involving CBr₄ that's fairly selective, but might work, depending on the structures of your substrates:

Hello Rashid, here is a really good paper on the stability of boronic esters with various diol ligands and the rates of transesterification from one diol ligand to another.

The paper is on research gate and sciencdirect.

In general mixing a boronic esters and a diol in pentane for several hours, removing the water layer that forms, reducing the solvent volume and passing the concentrated reaction solution through a plug of silica gel with DCM as the eluent is a very effective way of esterefying and purifying a boronic ester. This is the method we often use in our lab. You can find the actual procedure in the SI of the Science paper on my researchgate profile. Here is the link to the paper http://science.sciencemag.org/content/351/6268/70

If you don't have access to Science Journal just let me know and I can upload the SI to my profile. Another common method that is used involves mixing boronic acids and diols in dichloromethane for several hours with a desiccants such as 4 angstrom molecular sieves (the method used in the first paper I mentioned).

I am trying to protect two OH with Boron, through its condensation with ethylene glycol. this picture with give you an idea.

Haroon

Your question is not clear to me. Please, use equation then you may send me on my e-mail and I 'd be glad to help.

Good luck

you can protect the diol by carboyl group, and you can also protect the PBA pinacol. the later one is always supplied commercially.

Dear Dr. Rashid,

There is a tailored interplay between a hydrophobic skeleton and hydrophilic spacers (crosslinking agents) in hydrogels that is regulated with concentration and molecular nature of both components. Besides, you have to take into account the segmental or/and molecular mobilities which may be constrained. So, I would like to emphasis two principal aspects (structural and dynamic) affected your balance in the polymer network. For each individual pair "polymer-c.agent" it is worth to elaborate the proper set of instruments which could give information on structure-dynamic behavior of gels.

Happy New Year

@ Salvador Ramirez-Flandes: ok, I retract "absurd" and replace it by "improbable" or "costly to such an extent that it seems improbable to me unless we have access to so much energy that is is reduced to a secondary question".  

There are different reactive sides in the two reactions

the it is difficult to precise the reactions products

But I think that they can produce 1,2,3-triazoe and thiazolone respectively 

I guess alpha pinene was isolated first, and later when its isomer was discovered, it was named beta-pinene, thus the initially isolated pinene has become alpha. 

By the way, alpha and beta descriptors in this case have nothing to do with traditional stereochemistry notation (down/up). Anyway, it is not always easy to find logic in the naming of natural products.

I have worked with liter quantities of liquid HCN, which requires elbow-length heavy gloves and a rubber apron.  I did not use a respirator, but worked in an efficient hood with the sash as low as practicable, and the apparatus mounted in a plastic tray or bucket large enough to contain a spill.  An emergency kit (syringe w/ thiosulfate solution) was kept at hand. 

I would recommend the same if dealing with large quantities of KCN, and as Veronika notes, would not work without a well-operating hood.  With appropriate equipment and precautions, a respirator is not necessary.

Why you go for a costly reagent when when a mineral acid will be able to remove tosyl group. 

I agree with Nadeem A. Lodhi.

BuLi decomposes above 50oC.

Ziegler, K.; Gellert, H. G. Liebigs Ann. Chem. 1950, 567, 179.

Hi. Sorry but the first thing I would do was to register the optical purity of your sample, the optical rotation. After that you and we may start to discuss or theorize concerning conditions, base, time of reaction and eventual implications and ways to tackle the EVENTUAL problem.

Sometimes Mitsunobu reactions can be a pain. TPP=O is relatively easy to remove if your material is soluble in ether. If so, make a conc solution in ether (with an ice bath) and add hexane or pentane dropwise (quite slowly .. a drop ~ every 10 seconds, to avoid losing product)  until the TPP=O crashes out, then load it directly onto a column or filter. the DIAD byproduct can be tough to get shot of. I have had luck changing mobile phase from Hexane/ethyl acetate to Hexane/diethy ether. Basifying your column or switching to alumina can also work. If all else fails you could try a DIAD alternative, the Brimble group put this out a few years ago, its a shorter prep than other alternatives and I'm told its the shiz  10.1002/ejoc.201403152. On a side note, I  have found that DCM is a really good solvent for Mitzy's and it doesn't require drying or inert atmosphere. Doing it in a sonic bath (the same type used for cleaning glassware) really speeds the process up and in some cases improves the yield.  

Thanks a lot everyone, I will look into this!

I am sorry I got here late (a random google search on similar items brought me here). This is (very likely) same as what happened to me when I was mixing mPEG-NHS and phosphatidylethanolamine well back into last century (see PMID: 2384160 in pubmed for details). First time I tried this synthesis, it did not work. Turned out, NHS ester was hydrolyzed almost completely when it was shipped to me by the manufacturer. They have replaced it with the new material, and it worked fine, so that paper was published and still cited. NHS ester degradation can be tested by a simple UV experiment: the active ester does not absorb at 260 nm, but hydrolyzed free NHS does (in mild alkaline conditions, eg PBS, HEPES or borate - the higher the pH the faster the hydrolysis - so you can get the whole hydrolysis kinetic curve and find out how much NHS was there in free form or as an ester). Molar extinction coefficient is ~8200, if I remember correctly, so you only need a fraction of a milligram to test. I teach this analysis technique to UVA BME undergraduates as a part of my liposome module in their lab class. Take some in methanol or DMSO solution of your NHS ester and squirt into PBS that is already in the spectrophotometer cuvette and zeroed. Mix very well, and start measuring.  So you do not even need NMR...

I am sure there should be a difference - after all, cis/trans isomers may behave differently in chemical reactions (and chemical ionization is a chemical reaction !). One can speculate that certain cyclization or fragmentation reaction would be possible for only one of cis/trans isomers. However I cannot give examples; also I don't know how big could be the difference and under which conditions it would be really noticeable. It would be good to hear the opinion of experts in mass-spectrometry.

It sounds as though your crystals may also be absorbing water from the air and then dissolving in it. If may be worth filtering through a Schlenk flask with a frit, so that you can keep the atmospheric water out, and storing the solid under nitrogen or dry air.

I've done nitrations using fuming sulfuric acid (oleum) and solid sodium nitrate.  Dissolving the nitrate salt first is a good idea, as you can do that at room temperature, then cool to 0ºC.  The nitrating strength is a function of the water content, and you can "tune" the reagent by adding water to moderate it, or SO₃ to boost it.

By reacting a soluble zinc salt such as zinc sulphate with a solution of sodium carbonate. The products are zinc carbonate (which is insoluble and forms a white precipitate) and sodium sulphate which is very soluble and so remains in solution;-

ZnSO4(aq) + Na2CO3(aq) → Na2SO4(aq) + ZnCO3(s)

Thanks for the answer. I have already contacted LGC, and they said that the product is no longer available.

I assume that you are trying to oxidize the attached chiral auxiliary into the corresponding benzaldimine for subsequent hydrolysis into the free amine. 

Have you considered sodium metaperiodate (NaIO₄) or a related reagent? Please see the references below. NOTE: Be careful when handling reactions that require or generate large amounts of periodic acid. It is a strong oxidizer and highly corrosive. 

"Asymmetric Synthesis of 1-(2-Pyrrolyl)alkylamines by the Addition of Organometallic Reagents to Chiral 2-Pyrroleimines"

Admittedly, I have only cleaved similar auxiliaries by hydrogenation. Hope this helps!  

cross metathesis is possible too but the reagents needed may not be readily available.

I think the Wittig or HWE reactions will be problematic as there are several sites e.g. ester or phosphonium/phosphonate and aldehye/bromo/ester. It looks like a lot of optimisation is needed to find the right conditions.

should consider using temporary protecting groups instead of the bromo or ester

Jae Jun Lee:

                         The electrophillic substitution reactions such as nitration on the aromatic hydrocarbons phenanthrene and1,10- phenanthroline are generally difficult/complicated. That is due to the higher reactivity of the functional unit (that may not be real part of aromatic system as shown in attached file) toward addition reactions. Due to its typical reactivity, this structural unit generally behaves like alkene in few reactions and is more prone to give addition reactions rather than substitutions. In your experiment, you have used two oxidizing agents such as nitric acid acid and sulphuric acid. There may be many complicated processes involving in the oxidation. The most reasonable is given in the attachment.

Ian, the direct reaction you are using should be fine.  We use that method to form amino acid complexes of palladium, although we tend to use a methanol/water mixture.  I can guess that the product is not going to be an easy one to crystallize.  Pd(OAc)2 is a trimer and it is not certain to me that the fluoroethanol analog will be.  We also find that many of our amino acid  complexes hold on to various amounts of water in making suitable crystals and you may need some suitable solvent there as well.  If NMR spectroscopy leads you to believe you have the desired material, experiment with different solvents and mixtures to try for crystals.  Do you have MS analysis?

I would say heat it higher until it either reacts or begins to decompose.

 during your synthesis,  dissolve your 7-HC first in DMF+ K2CO3 (Make sure that k2CO3 must be in dry form). stir it for few min and add N-Boc-3-bromopropylamine drop wise. Maintain temp as mention by Syeda Aaliya Shehzadi in previous reply.

After completion of reaction, Pour whole mix in Crushed ice for overnight. Filter the product and Check in TLC.

All the best 

If you want to isolate tryptamine as a free base from tryptamine.HCl it is better to stir the salt with little more than equimolar sodium carbonate in methanol/acetone for 1-2 hr and then filter the inorganic material . Now you have free base in filtrate and use it for onward reaction.I hope it will work nicely.

It could be due to conjugate addition etc.  We have had a lot of success using either CeCl3 in the reaction to promote 1,2-addition, or LaCl3.2LiCl solution. In either case just stir the ketone with the lewis acid for about 30 mins, then add the organometallic over a few minutes.

best of luck

It deepens on the substance and the substance to silica ratio, dissolve your substance in a solvent, such as DCM or MeOH add the silica and evaporate slowly under mixing. If still sticky, add solvent and increase the amount of silica.

I assume that you are trying to generate the lactone enolate anion.  For various reasons, including reactivity,  NaNH2  would not be a good choice for a base.  The bases suggested should work depending on the solvent being used  and how much the alpha methylene to the  carbonyl may be sterically "sequestered" by folding of the ring.  I would suggest KH in THF as an alternative as KH possesses very high reactivity and cleanly forms enolate anions in THF. 

I think in these papers they correlate the capacity for a solute in an ionic liquid to the infinite dilution activity coefficient (IDAC). IDACs are calculated with any COSMO-RS implementation for your solute + solvent combination from the sigma profiles. Tamal Bannerjee (IIT Guwahati) has also quite a few papers on this specific subject (desulfurization with ionic liquids) 

Dear Sir

Please, find in attch, an Instructions 56-1190-97 AD Gel Filtration for Sephadex LH-20. It might be useful for you.

Best wishes

Thanks Dr. Madhukar Baburao Deshmukh, would you be kind enough to elaborate the ratio which you mentioned as 1:10? Is it 1g or 1mg to 10mL?

Pentafluorophenol esters used to be common active esters in peptide chemistry. They are easily prepared from the acid, pentafluorophenol, and DCC or DIC (1 eq each) in e.g. dichloromethane. Mix, stir, work up after a while (check w/ TLC).

No need for activating the acid in a separate step (acyl chloride or anhydride) or activating the alcohol as Pratik ended up doing.  

I would suggest reaction of an aqueous solution of thioglycolic acid with Ca(OH)₂, which is slightly soluble in water. The only byproduct will be water, as the hydroxide ions are protonated.

Alternatively, calcium oxide and calcium carbonate could be used, but I think both are less desireable than calcium hydroxide. Calcium oxide will react exothermically with water to form the hydroxide, and the carbonate will produce carbon dioxide as a byproduct in addition to water--vigorous bubbling is likely undesirable given the stench of thioglycolic acid...

More soluble calcium salts like calcium chloride are also an option, but the extra ions might complicate isolation and purification of the desired product.

You can use Ca(OH)_{2. Please see files:}

What do you mean by "3 hydroxy group" ?

In chemistry, and especially in the chemistry of azides which are high energy compounds, it is important to know exactly what you need to accomplish. Otherwise it is hard to suggest/predict what may happen. If you meant a tertiary hydroxyl group, then it may be particularly difficult. I would try DPPA/toluene at 80 degC and hope that the reactivity of your molecule allows for the desired process to occur.