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Showing posts with label Preparative Organic Chemistry. Show all posts
Showing posts with label Preparative Organic Chemistry. Show all posts

Sunday, 24 November 2013

Recent advances on diversity oriented heterocycle synthesis via multicomponent tandem reactions based on A3 coupling

ARKIVOC 2014 Part (i): Special Issue 'Reviews and Accounts', PG 1-20
Recent advances on diversity oriented heterocycle synthesis via multicomponent tandem reactions based on A3 coupling (14-8183LR) [pp. 1-20]
Yunyun Liu, a,b
a  Key Laboratory of Functional Small Organic Molecule, Ministry of Education, 
Jiangxi Normal University, Nanchang 330022, P. R. China 
b College of Chemistry and Chemical Engineering, Jiangxi Normal University, 

Nanchang 330022, P. R. China 

Full Text: PDF (235K)http://www.arkat-usa.org/get-file/48824/

A3 coupling reactions are the reactions between aldehydes, amines and alkynes, which yield
propargylamine derivatives under various catalyst conditions. By making use of the versatile
reactivity of propargylamines, tandem reactions initiated by the functional group(s) in the in situ
generated propargylamines constitute one of the most important applications of A3
These tandem reactions are especially useful for the synthesis of heterocyclic compounds. In this
review, the progress on multicomponent tandem reactions based on A3
 coupling is summarized.

Conclusions and Outlook

During the last decade, A3
 coupling reaction has evolved to a classical three-component protocol
for accessing various propargylamines. Numerous papers have been published on the
investigation of this synthetic method and spectacular advances on A3
 coupling reactions have
been witnessed in terms of green catalyst system, asymmetric catalysis etc. which also promoted
this coupling protocol as the most preferred option for propargylamine synthesis. From the
perspective of application, the propargylamines possessed broad spectrum of diversity andreactivity, and these compounds could serve as main building blocks in the synthesis of many
organic small molecules. From the perspective of atom economics, devising tandem reactions
based on key transformation of A3
 coupling for the synthesis of more complex and structurally
diverse heterocyclic products in one-pot represent a promising direction in modern organic
synthesis. As introduced in the contents, many elegant results have already been reported on this
area. On the other hand, at current state, this kind of tandem reactions were mainly performed by
using the second functional group in aldehyde, amine or alkyne to initiate subsequent
transformations on propargylamine intermediates, although some reactions using additional
components such as carbon dioxide to design tandem synthesis of heterocyclic products have
also been reported, this kind of examples are still rather rare. Thus, deeper and broader explore is
still demanding since using additional substrates for reactions is theoretically able to provide
considerably higher diversity both in reactions and corresponding products. In addition, versions
of asymmetric catalysis on traditional A3
 coupling have already been accomplished with nice
results, while asymmetric catalysis protocols of A3
 coupling-based tandem synthesis of
heterocycles kept unexplored, more systematic and advanced approaches of asymmetrical
catalysis on these tandem reactions are expected in future.


Some of the thousands of life-sizeTerracotta Warriors of the Qin Dynasty, ca. 210 BCE

The Great Wall of China was built by several dynasties over two thousand years to protect the sedentary agricultural regions of the Chinese interior from incursions by nomadic pastoralists of the northern steppes

Detail from Along the River During the Qingming Festival, a 12th-century painting showing everyday life in the Song Dynasty's capital city, Bianjing (today's Kaifeng)

Shanghai skyline

The Great Hall of the People in Beijing, where the National People's Congress convenes


Friday, 27 September 2013


Systematic name
Other names
1,3-dioxolane, 2-[2,5-bis(3,3-dimethyl-1-butyn-1-yl)-4-[2-(3,5-di-1-pentyn-1-ylphenyl)ethynyl]phenyl]
618904-86-2  cas

NanoPutians are a series of organic molecules whose structural formulae resemble human forms.[1] James Tour et al. (Rice University) designed and synthesized these compounds in 2003 as a part of a sequence of chemical education for young students.[2] The compounds consist of two benzene rings connected via a few carbon atoms as the body, four acetylene units each carrying an alkyl group at their ends which represents the hands and legs, and a 1,3-dioxolane ring as the head. Tour and his team at Rice University used the NanoPutians in their NanoKids educational outreach program. The goal of this program was to educate children in the sciences in an effective and enjoyable manner. They have made several videos featuring the NanoPutians as anthropomorphic animated characters.

Construction of the structures depends on Sonogashira coupling and other synthetic techniques. By replacing the 1,3-dioxolane group with an appropriate ring structure, various other types of putians have been synthesized, e.g. NanoAthlete, NanoPilgrim, and NanoGreenBeret. Placing thiol functional groups at the leg enables them to "stand" on a gold surface.
"NanoPutian" is a portmanteau of nanometer, a unit of length commonly used to measure chemical compounds, and lilliputian, a fictional population of humans in the novel Gulliver's Travels.


NanoKids Educational Outreach Program]

While there are no chemical uses for the NanoKid or any of its subsidiaries, James Tour has turned the NanoKid into a lifelike character to educate children in the sciences. The goals of the outreach program, as described on the NanoKids website, are:
  • “To significantly increase students’ comprehension of chemistry, physics, biology, and materials science at the molecular level."
  • "To provide teachers with conceptual tools to teach nanoscale science and emerging molecular technology."
  • "To demonstrate that art and science can combine to facilitate learning for students with diverse learning styles and interests."
  • "To generate informed interest in nanotechnology that encourages participation in and funding for research in the field.”[3]
To accomplish these goals, several video clips, CDs, as well as interactive computer programs were created. Tour and his team invested over $250,000 into their project. In order to raise the funds for this endeavor, Tour used unrestricted funds from his professorship and small grants from Rice University, the Welch Foundation, the nanotech firm Zyvex, and Texas A&M University. Tour also received $100,000 in 2002 from the Small Grants for Exploratory Research program, a division of the National Science Foundation.[4]
The main characters in the videos are animated versions of the NanoKid. They star in several videos and explain various scientific concepts, such as the periodic tableDNA, and covalent bonding.
Rice conducted several studies into the effectiveness of using the NanoKids materials. These studies found mostly positive results for the use of the NanoKids in the classroom. A 2004-2005 study in two schools districts in Ohio and Kentucky found that using NanoKids led to a 10-59% increase in understanding of the material presented. Additionally, it was found that 82% of students found that NanoKids made learning science more interesting.[5]

ChemSpider 2D Image | Nanokid | C39H42O2

Synthesis of NanoKid

Upperbody of NanoKid

To create the first NanoPutian, dubbed the NanoKid, 1,4-dibromobenzene was iodinated in sulfuric acid. To this product, “arms”, or 3,3-Dimethylbutyne, were then added through Sonogashira coupling. Formylation of this structure was then achieved through using the organolithium reagent n-butyllithium followed by quenching with N,N-dimethylformamide (DMF) to create the aldehyde. 1,2-Ethanediol was added to this structure to protect the aldehyde using p-toluenesulfonic acid as a catalyst. Originally, Chanteau and Tour aimed to couple this structure with alkynes, but this resulted in very low yields of the desired products. To remedy this, the bromide was replaced withiodide through lithium-halogen exchange and quenching by using 1,2-diiodoethane. This created the final structure of the upper body for the NanoKid.[1]

Lowerbody of NanoKid

The synthesis of NanoPutian’s lower body begins with nitroaniline as a starting material. Addition of Br2 in acetic acid places two equivalents of bromine on the benzene ring. NH2 is an electron donating group, and NO2 is an electron withdrawing group, which both direct bromination to the meta position relative to the NO2 substituent. Addition of [[NaNO2]], [[H2SO4]], and EtOH removes the NH2¬ substituent. The Lewis acid SnCl2, a reducing agent in THF/EtOH solvent, replaces NO2 with NH2, which is subsequently replaced by iodine upon the addition of NaNO2, H2SO4, and KI to yield 3,5-dibromoiodobenzene. In this step, the Sandmeyer reaction converts the primary amino group (NH2) to a diazonium leaving group (N2), which is subsequently replaced by iodine. Iodine serves as an excellent coupling partner for the attachment of the stomach, which is executed through Sonogashira coupling with trimethylsilylacetylene to yield 3,5-dibromo(trimethylsilylethynyl)benzene. Attachment of the legs replaces the Br substituents with 1-pentyne through another Sonogashira coupling to produce 3,5-(1′-Pentynyl)-1-(trimethylsilylethynyl) benzene. To complete the synthesis of the lower body, the TMS protecting group is removed by selective deprotection through the addition of K2CO3, MeOH, and CH2Cl2 to yield 3,5-(1′-Pentynyl)-1-ethynylbenzene.[1]

Attachment of Upperbody to Lowerbody of NanoKid

To attach the upper body of the NanoKid to the lower body, the two components were added to a solution of bis(triphenylphosphine)palladium(II) dichloridecopper(I) iodide,TEA, and THF. This resulted in the final structure of the NanoKid.[1]

Derivatives of NanoKid

Synthesis of NanoProfessionals[]

The series of NanoProfessionals were created using the NanoKid as the starting material. This was done by adding an excess amount of a 1,2- or 1,3- diol to the NanoKid in the presence of a catalytic amount of p-toluenesulfonic acid and microwave oven-irradiation. The use of microwave irradiation reduced the reaction times. These reactions resulted in an acetal exchange, which changed the structure of the head of the NanoKid to create the different head structures of the NanoProfessionals, which include: NanoAthlete, NanoPilgrim, NanoGreenBeret, NanoJester, NanoMonarch, NanoTexan, NanoScholar, NanoBaker, and NanoChef. By creating a series of different figures, the ultimate product was a recognizably diverse population of NanoPutians.[2]
Although the majority of the figures are depicted in their equilibrium conformations, some of the NanoPutians include nonequilibrium conformations in order to make them more recognizable to nonchemists. Many liberties were taken in the visual depiction of the head dressings of the NanoPutians.[2]
The entire population of NanoPutians (with the exception of the NanoChef) were generated in one microwave oven reaction and confirmed by mass spectrometry and 1HNMR.[1]
Below is a table listing the diols needed to convert the NanoKid into various NanoProfessionals. The diols used to create NanoPilgrim and NanoTexan were made through reductive pinacol coupling of the 1,4- and 1,5-diketones with SmI2 and Mg/TiCl4. To create the diols used to make the NanoMonarch and the NanoScholar, catalytic OsO4 was used to dihydroxylate the respective cycloalkenes. The diastereomeric ratios were determined through 1H NMR using the diastereotopic acetal protons.[1]

Synthesis of the NanoKid in Upright Form]

Stick Figure NanoPutian in its Energy Minimized Conformation. Determined Using Spartan.
3-Butyn-1-ol was reacted with methanesulfonyl chloride and triethanolamine to produce its mesylate. The mesylate was displaced to make thiolacetate. The thiol was coupled with 3,5-dibromo(trimethylsilylethynyl)benzene to create a free alkyne. The resulting product, 3,5-(4’-thiolacetyl-1’-butynyl)-1-(trimethylsilylethynyl)-benzene, had its trimethylsilyl group removed using tetra-n-butylammonium fluoride (TBAF) and AcOH/Ac2O in THF. The free alkyne was then coupled with the upper body product from the earlier synthesis. This resulted in a NanoKid with protected thiol feet.[1]
To make the NanoKid “stand’, the acetyl protecting groups were removed through the use of ammonium hydroxide in THF to create the free thiols. A gold-plated substrate was then dipped into the solution and incubated for four days. Ellipsometry was used to determine the resulting thickness of the compound, and it was determined that the NanoKid was upright on the substrate.[1]

Synthesis of NanoPutian Chain

Synthesis of the upper part of the NanoPutian chain begins with 1,3-dibromo-2,4-diiodobenzene as the starting material. Sonogashira coupling with 4-oxytrimethylsilylbut-1-yne produces 2,5-bis(4-tert-butyldimethylsiloxy-1′-butynyl)-1,4-di-bromobenzene. One of the bromine substituents is converted to an aldehyde through an SN2 reaction with the strong base, n-BuLi, and THF in the aprotic polar solvent, DMF to produce 2,5-bis(4-tert-butyldimethylsiloxy-1′-butynyl)-4-bromobenzaldehyde. Another Sonogashira coupling with 3,5-(1′-Pentynyl)-1-ethynylbenzene attaches the lower body of the NanoPutian. The conversion of the aldehyde group to a diether “head” occurs in two steps. The first step involves addition of ethylene glycol and trimethylsilyl chloride (TMSCl) in CH2Cl2 solvent. Addition of TBAF in THF solvent removes the silyl protecting group.[1]


  1. a b c d e f g h i Chanteau, S. H.; Tour, J. M. (2003). "Synthesis of Anthropomorphic Molecules:  The NanoPutians"The Journal of Organic Chemistry 68 (23): 8750–8766.doi:10.1021/jo0349227PMID 14604341. edit
  2. a b c Chanteau, S. H.; Ruths, T.; Tour, J. M. (2003). "Arts and Sciences Reunite in Nanoput: Communicating Synthesis and the Nanoscale to the Layperson"Journal of Chemical Education 80 (4): 395. doi:10.1021/ed080p395. edit
  3. ^ “Welcome to Nanokids.” Accessed May 6, 2013. http://nanokids.rice.edu/.
  4. ^ “C&EN: EDUCATION - ‘NANOKIDS’ TRY TO GET INTO MIDDLE SCHOOL.” Accessed May 10, 2013. http://pubs.acs.org/cen/education/8214/8214nanokids.html.
  5. ^ “NanoKids - Mission.” Accessed May 6, 2013. http://cohesion.rice.edu/naturalsciences/nanokids/mission.cfm?doc_id=3039.

External link


In 2003, there was a paper published which looked like it was going to be a good candidate for the Ig Nobel Prize. It was “Synthesis of Anthropomorphic Molecules: The NanoPutians” by Professor James Tour, a chemistry professor at Rice University’s Institute for Nanoscale Science and Technology. The word “NanoPutian” is a portmanteau of “nano”, which means a billionth and the “Lilliputian” from the novel Gulliver’s Travels.
The Tour group designed and synthesized a number of human-shaped organic molecules in this paper. Shown in Figure 1 is a molecule named NanoKid, which was chosen by the group as a basic skeleton. The 3-D model looks like the figure on the right and the structural formula used by chemists is shown on the left. The structural formula might look more human, since the oxygen atoms look kind of like the eyes.

Fig 1 NanoKid
The functional group used for the head part of NanoKid is called acetal. This group is easily exchangeable to make NanoPutians of various occupations (Figure 2). Let’s not be too picky about the bond angles of NanoMonarch and NanoTexan.

Fig 2 various NanoPutians
Unfortunately, NanoBalletDancer seems to be the only one having a different posture (Figure 3). Personally, I would be interested in making NanoPitcher or NanoGermanSuplex!

Fig 3 NanoBalletDancer
The Tour Group also synthesized NanoPutians standing on gold surface with thiol functional groups on their feet, a NanoPutian couple dancing (Figure 4), and even a polymer of NanoPutians (Figure 5).

Fig 4 NanoPutian Couple

Fog 5 NanoPutian polymer
NanoPutians aren’t actually the first example of human-shaped molecule. For example, the molecule shown in Figure 6 has appeared as a joke in a journal published on April Fool’s Day. The molecule shown in Figure 7 has been introduced once as Buddha molecule. Nevertheless, NanoPutians were probably the first case where human-shaped molecules were synthesized systematically(?) to be published as a full paper.

Fig 6 human-shaped molecule Fig 7 molecular Buddha
The Role of NanoPutians
Besides being human-shaped, the NanoPutian molecules have neither notable properties nor potential usefulness for future. The synthesis is also too straightforward to make any significant methodological contribution to chemical science.
Then how did this research get funded and get to be published on Journal of Organic Chemistry? It turns out that the synthesis was a part of the chemistry education program at Rice University aimed at introducing nanotechnology to young students. In fact, it has also been on the cover page of Journal of Chemical Education too. It’s funny though, to imagine the faces of the journal editors when they first read the paper.
But come to think of it, molecules like dodecahedrane and kekulene might not be so different in terms of not having much to appeal other than their structural beauty. Even “total synthesis of biologically active natural products”, the most respected subfield of organic chemistry, has been criticized on its meaning recently. In a way, the NanoPutian research seems to me as a voice saying “synthetic targets should be selected more freely” and almost as an antithesis against the state of organic chemistry today.

Anyway, this paper was introduced by general media and was also one of the topics that received most feedbacks on my homepage. There were those who dismissed it as a meaningless play by chemists, but in terms of directing public interest toward organic chemistry wasn’t it a hundred times more effective than ordinary researches? I think it was an excellent work for the education of young chemists as well.
Professor Tour’s playful sense of molecular design can be seen in his research of NanoCars too, which I will introduce in a separate column. This is a wonderful work which can impress both serious scientists and general public.