How to Create Your Own Lilliputians?

Chemical synthesis has become a great tool in exploring interesting structures such as natural products. However, this is not only limited into the natural products, the ultimate designed in miniaturisation can also be attained such as nanocar. Researchers from Houston, USA successfully created a new class of 2 nm-tall human-like, anthromorphic, compounds. This class of compound is dubbed as NanoPutians, after Liliputians from Jonathan Swift's classic Gulliver's Travel.

The first edition of Jonathan Swift's Gulliver's Travel 

The first compound that was firstly prepared from NanoPutians family was NanoKid. The synthesis of the NanoKid serves as template to construct the rest of the family of NanoPutians. In general, the synthesis of NanoPutians can be divided into two assemblies; construction of upper and lower bodies, and joining both parts.

Synthesis of a NanoPutian's upper body

The upper body portion was synthesised from 1,4-dibromobenzene 1 which then iodinated to give the point of attachment for the arms. The Sonogashira-type coupling reaction featured heavily in this synthesis for C-C bond formation. The NanoKid's head was formed from lithium-halogen exchange followed by reaction with N,N-dimethylformamide (DMF) to form aldehyde functionality which then can transformed into acetal group which serves as its head. The last step of the formation of the upper body is halogen exchange from Br to I to give more reactive point of attachment to the lower body.

Synthesis of NanoPutian's lower body

The lower part of NanoPutians was synthesised from 4-nitroaniline which then brominated in acidic condition to give 9. Interestingly, the amino group in 9 serves as protecting agent of the 4-position which then removed using acidic sodium nitrite to give 10; it also acts as ortho-directing groups. Then, 10 is reduced using Sn(II) to give amino group which can be converted into iodidie group via diazonium salt. This iodide group serves as the attachment to the stomach to give 13. The attachment of legs was done by using Sonogashira-type coupling reaction to give 15 which then underwent TMS-protecting group removal. After both the upper and lower body parts had been synthesised, the final step would be coupling both parts to give NanoKid 17 and it was done under Pd-Cu catalysed Sonogashira coupling reaction.

Coupling the upper and lower body segments to complete the synthesis of NanoPutian, NanoKid 17 with its structure in its energy-minimised conformation, determined using molecular mechanics (Spartan), and the synthesis of some examples of NanoProfessionals 21-23.

Interestingly, NanoKid can be easily transformed into a new series of NanoPutians, dubbed as NanoProfessionals, by reacting NanoKid with corresponding diols under microwave irradiation for 1-16 minutes.

Besides its head, modification can also be done on NanoKid's feet, such as using shorter "feet segment". Hence, another member of NanoPutians, called as NanoToddler, can be formed.

The formation of NanoToddler

Another modification on the NanoKid's feet is installing thiol functional group and this modification would lead to the attachment of NanoKids on the surface, such as gold surface.

The synthesis of the NanoKid with thiol feet and the formation of self-assembled monolayer of NanoKid on gold surface.

The formation of the self-assembled monolayer 32 was confirmed by thickness measurement which gave thickness of 1.97 nm, slightly shorter than NanoKid's height (2.11 nm). This small difference might indicate the sp³-sulphur hybridisation  and intermolecular interaction-induced tilt angle from the surface normal.

Up to this point, all the NanoPutians we have seen have "straight" stomach section, but this connector group can also be modified. Replacing alkyne connector with CH₂ connector would lead to the formation of another NanoPutians known as NanoBalletDancers.

The formation of NanoBalletDancer

The upper body of NanoBalletDancer was synthesised from 32 which then diiodinated followed by removal of amine group using isoamyl nitrite 34 to give 35. Then, the arms were attached using Sonogashira-type coupling reaction followed by installation of aldehyde which would form the head. Meanwhile, the lower part was synthesised from 39 which underwent lithium-halogen exchange and reaction with DMF to give aldehyde, this group would act as the connector. The synthesis of the lower part was completed by installation of the legs. Both parts were adjoined using t-BuLi and the resulted hydroxyl group was removed in three steps.

The final member of NanoPutians is the NanoPutians chain where they were joined as an extended polymer. In this polymer, AB-copolymer was assigned as the target.

The key step in the formation of NanoPutians chain is the modification of the arms which acts as the connecting group between NanoPutians units. Instead of using alkyne 3 as the arm unit, TBS protected 45 was used as the hands.

The synthesis of the NanoPutian monomers

After the completion of the upper part 47, then it was connected with the lower part to give the body of the NanoPutian monomeric unit 48. To finish off the synthesis of the monomer, two different diols were used to give monomer 49 and 50.

The formation of the AB NanoPutians copolymer was started by installing the carbonate connector group to 50  which then reacted with another monomer 49 to give the AB copolymer. Furthermore, the isolated oligomers of and polymers 53 were shown to have a range of mass centered around 47500 which corresponds to 42 units; size-exclusion chromatography showed 53 has M_n of 23 500 and M_w of 36 600, relative to polystyrene (click here for more about M_n and M_w).

Reaction of the formation the copolymeric 53 and hetero-dimer 54 and 55.

Besides the AB copolymer, cyclic dimer 52 and 53 were isolated as well.

In conclusion, this study showed a series of monomeric, dimeric, and polymeric anthromorphic molecules have been synthesised. This shows how powerful the synthetic chemistry as a tool to explore different structure and these syntheses represent the ultimate in anthromorphic design miniaturisation.

Reference
S. H. Chanteau and J. M. Tour, J. Org. Chem., 2003, 68, 8750-8766.