graphene synthesis research paper

Synthesis of graphene

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• Published: 09 February 2016
• Volume 6 , pages 65–83, ( 2016 )

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• Md. Sajibul Alam Bhuyan 1 ,
• Md. Nizam Uddin 1 ,
• Md. Maksudul Islam 2 ,
• Ferdaushi Alam Bipasha 3 &
• Sayed Shafayat Hossain 1  

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Graphene, a two-dimensional material of sp 2 hybridization carbon atoms, has fascinated much attention in recent years owing to its extraordinary electronic, optical, magnetic, thermal, and mechanical properties as well as large specific surface area. For the tremendous application of graphene in nano-electronics, it is essential to fabricate high-quality graphene in large production. There are different methods of generating graphene. This review summarizes the exfoliation of graphene by mechanical, chemical and thermal reduction and chemical vapor deposition and mentions their advantages and disadvantages. This article also indicates recent advances in controllable synthesis of graphene, illuminates the problems, and prospects the future development in this field.

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Introduction

Carbon is a ubiquitous material that has been ever found whereas the epoch making material graphene is also an allotropy of carbon. Actually graphene is a two-dimensional, single-layer sheet of sp 2 hybridized carbon atoms and has arrested enormous attention and research motives for its versatile properties. In sp 2 hybridized bond, the in-plane σ C–C bond is one of the strongest bonds in materials and the out-of-plane is π bond, which imparts to a delocalized network or array of electrons resulting electron conduction by providing weak interaction among graphene layers or between graphene and substrate. Graphene is a material which has a large theoretical specific surface area (2630 m 2 g −1 ), high intrinsic mobility (200,000 cm 2 v −1 s −1 ), [ 1 , 2 ] high Young’s modulus (∼1.0 TPa) [ 3 ] and thermal conductivity (∼5000 Wm −1 K −1 ), [ 4 ] and its optical transmittance (∼97.7 %) and good electrical conductivity merit attention as well as ability to with stand current density of 108 A/cm 2 [ 5 ], for applications such as for transparent conductive electrodes [ 6 , 7 ] among many other potential applications. However, its applicability cannot be effectively realized unless superficial techniques to synthesize high-quality, large-area graphene are developed in a cost effective way. Besides, a great deal of effort is required to develop techniques for modifying and opening its band structure so as to make it a potential replacement for silicon in future electronics. Graphene has been experimentally studied for over 40 years [ 8 – 14 ] and measurements of transport properties in micromechanically exfoliated layers [ 15 ], of graphene grown on (SiC) [ 16 ], large-area graphene grown on copper (Cu) substrates [ 17 ], as well as a variety of studies involving the use of chemically modified graphene (CMG) to make new materials [ 12 – 21 ].

The basic building blocks of all the carbon nanostructures are a single graphitic layer that is covalently functionalized sp 2 bonded carbon atoms in a hexagonal honeycomb lattice which forms 3D bulk graphite, when the layers of single honeycomb graphitic lattices are stacked and bound by a weak van der Waals force. When the single graphite layer forms a sphere, it is well known as zero-dimensional fullerene; when it is rolled up with respect to its axis, it forms a one-dimensional cylindrical structure called a carbon nanotube; and when it exhibits the planar 2D structure from one to a few layers stacked, it is called graphene. One graphitic layer is well known as monoatomic or single-layer graphene and two and three graphitic layers are known as bilayer and tri-layer graphene, respectively. More than 5 layer up to 10 layer graphene is generally called few layer graphene, and ~20–30 layer graphene is referred to as multilayer graphene, thick graphene, or nanocrystalline thin graphite [ 22 ].

Synthesis of graphene refers to any process for fabricating or extracting graphene, depending on the desired size, purity and efflorescence of the specific product. In the earlier stage various techniques had been found for producing thin graphitic films. Late 1970’s carbon precipitated in the form of thin graphitic layers on transition metal surfaces [ 24 , 25 ]. In 1975, few-layer graphite was synthesized on a single crystal platinum surface via chemical decomposition methods, but was not designated as graphene due to a lack of characterization techniques or perhaps due to its limited possible applications [ 26 ].

In those periods, their electronic properties never were investigated because of the difficulty in isolating and transferring them onto insulating substrates. But in the late 90’s Ruoff and co-workers tried to isolate thin graphitic flakes on SiO 2 substrates by mechanical rubbing of patterned islands on HOPG (Highly Oriented Pyrolytic Graphite) [ 13 ]. However there was no report on their electrical property characterization. Using a similar method this was later achieved in 2005 by Kim and co-workers and the electrical properties were reported [ 27 ]. But the real prompt advancement in graphene research began after Geim and co-workers first published their work of isolating graphene on to SiO 2 substrate and measuring its electrical properties. After discovery of graphene in 2004 various techniques were developed to produce thin graphitic films and few layer graphene. The experimental evidence of 2D crystals came in 2004 [ 15 ] and 2005 [ 28 ] when thin flakes of graphene and other materials molybdenum disulphide, niobium diselenide and hexagonal boron nitride were first exfoliated from their bulk counterparts (Fig.  1 ). But graphene was first obtained in the form of small flakes of the order of several microns through mechanical exfoliation of graphite using scotch tape [ 4 , 9 ]. Although this method gives the highest quality graphene but for mass production, fabrication method is needed that can synthesize wafer scale graphene.

Mother of all graphene forms. Graphene is a 2D building material for carbon material of all other dimensionalities. It can be wrapped up into 0D buckyballs, rolled into 1D nanotubes or stacked into 3D graphite [ 23 ]

In recent years, various techniques have been established for graphene synthesis. However, mechanical cleaving (exfoliation) [ 15 ], chemical exfoliation [ 29 , 30 ], chemical synthesis [ 21 ], and thermal chemical vapor deposition (CVD) [ 31 ] synthesis are the most commonly used methods today. Some other techniques are also reported such as unzipping nanotube [ 32 – 34 ] and microwave synthesis [ 35 ]. Although mechanical exfoliation using AFM cantilever was found capable of fabricating few-layer graphene, the process limitation was thickness of graphene varies to ~10 nm, which is comparable to 30-layer graphene.

In chemical exfoliation method, solution dispersed graphite is exfoliated by inserting large alkali ions between the graphite layers. Chemical synthesis is the similar process which consists of the synthesis of graphite oxide, dispersion in a solution, followed by reduction with hydrazine. Similarly for carbon nanotube synthesis, catalytic thermal CVD has proved most significant process for large-scale graphene fabrication. When the thermal CVD process is carried out in a resistive heating furnace, it is known as thermal CVD, and when the process consists of plasma-assisted growth, it is called plasma enhanced CVD or PECVD. In this world as nothing is unmixed blessing, all synthesis methods have some drawbacks too depending upon the final application of graphene. For instance, the mechanical exfoliation method is capable of fabricating monolayer to few-layers of graphene, but the reliability of obtaining a similar structure using this technique is quite insignificant. Furthermore, chemical synthesis processes are low temperature processes that make it more comfortable to fabricate graphene on multi-types of substrates at ambient temperature, particularly on polymeric substrate. But, large-area synthesized graphene produced in this process are non-uniform and dispersed. Again, graphene synthesized from reduced graphene oxides (RGOs) usually causes incomplete reduction of graphite oxide that results in the successive debasement of electrical properties depending on its degree of reduction. In contrast, thermal CVD methods are more advantageous for large-area device fabrication and favorable for future complementary metal-oxide semiconductor (CMOS) technology by replacing Si [ 36 ]. Epitaxial graphene means thermal graphitization of a SiC surface which is another method of graphene synthesis, but the limitation of this method are high process temperature and inability to transfer on any other substrates. So, the thermal CVD method is unique because of producing uniform layer of thermally chemically catalyzed carbon atoms and that can be deposited onto metal surfaces and also can be transferred over a wide range of substrates.

An overview of graphene synthesis techniques is shown in the flow chart in Fig.  2 .

A process flow chart of Graphene synthesis

Bottom-up graphene

The nature, average size, and thickness of the graphene sheets produced by different bottom-up methods as well as the advantages and disadvantages of each method are summarized in Table  1 .

Top-down graphene

In top-down process, graphene or modified graphene sheets are produced by separation/exfoliation of graphite or graphite derivatives (such as graphite oxide (GO) and graphite fluoride. Table  2 may surmise some researcher’s contribution.

• Mechanical exfoliation

Mechanical exfoliation is may be the rarest and eminent process for extracting single layer graphene flakes on preferred substrates. It is the first recognized method of graphene synthesis. This is a top-down technique in nanotechnology, by which a longitudinal or transverse stress is created on the surface of the layered structure materials. Graphite is formed when mono-atomic graphene layers are stacked together by weak van der Waals forces. The interlayer distance and interlayer bond energy is 3.34 Å and 2 eV/nm 2 , respectively. For mechanical cleaving, ~300 nN/μm 2 external force is required to separate one mono-atomic layer from graphite [ 27 ]. Stacking of sheets in graphite is the result of overlap of partially filled π orbital perpendicular to the plane of the sheet (involving van der Waals forces). Exfoliation is the reverse of stacking; owing to the weak bonding and large lattice spacing in the perpendicular direction compared to the small lattice spacing and stronger bonding in the hexagonal lattice plane [ 58 ]. Graphene sheets of different thickness can indeed be obtained through mechanical exfoliation or by peeling off layers from graphitic materials such as highly ordered pyrolytic graphite (HOPG), single-crystal graphite, or natural graphite [ 59 – 63 ]. This peeling/exfoliation can be done using a variety of agents like scotch tape [ 15 ], ultrasonication, [ 64 ] electric field [ 65 ] and even by transfer printing technique [ 66 , 67 ], etc. In certain studies the HOPG has also been bonded to the substrate either by regular adhesives like epoxy resin [ 64 , 68 ] or even by SAMs [ 69 ] to improve the yield of single and few layer graphene flakes. A recent study also demonstrates transfer printing of macroscopic graphene patterns from patterned HOPG using gold films [ 70 ]. It is by far the cheapest method to produce high-quality graphene. Graphene flakes obtained by mechanical exfoliation methods are usually characterized by optical microscopy, Raman spectroscopy and AFM. AFM analysis is carried out on exfoliated graphene to assess its thickness and number of layers. Finding a single layer flake is a fact of chance plus the yield of single and few layer graphene obtained by this method is more weaker and the flakes are randomly diffused on the substrate. Optical microscopy is another popular method of identifying single layer graphene. Depending on thickness graphene flakes give a characteristic color contrast on a thermally grown SiO 2 layer of 300 nm thickness on top of Si wafers [ 71 ]. Raman spectroscopy is also carried out on graphene acquiring by mechanical exfoliation. It is the quickest and most precise method of identifying the thickness of graphene flakes and estimating its crystalline quality. This is because graphene exhibits characteristic Raman spectra based on number of layers present [ 72 – 74 ]. In this micromechanical exfoliation method, graphene is separated from a graphite crystal using adhesive tape. After peeling it off the graphite, multiple-layer graphene remains on the tape. By repeated peeling the multiple-layer graphene is cleaved into several flakes of few-layer graphene. Subsequently the tape is attached to the acetone substrate for detaching the tape. Finally one last peeling with an unused tape is performed. The obtained flakes vary substantially in size and thickness, where the sizes range from nanometers to several tens of micrometers for single-layer graphene, based on wafer. Single-layer graphene has an absorption rate of 2 %, nevertheless it is possible to see it under a light microscope on SiO 2 /Si, due to interference effects [ 75 ].

Actually it is not easy to obtain larger amounts of graphene by this exfoliation method, not even taking into account the lack of sustainable flakes. The difficulty of this method is really low, nevertheless the graphene flakes require to be found on the substrate surface, which is labor exhaustive. The quality of the prepared graphene is very high with almost no defects. The graphene formed by these mechanical exfoliation methods was used for production of FET devices (Fig.  3 ). Still, the mechanical exfoliation method needs to be enhanced further for large-scale, defect-free, high-purity graphene for mass production in the field of nanotechnology.

Graphene films. a Photograph (in normal white light) of a relatively large multilayer graphene flake with thickness ~3 nm on top of an oxidized Si wafer. b Atomic force microscope (AFM) image of 2 µm by 2 µm area of this flake near its edge. Colors: dark brown , SiO 2 surface; orange , 3 nm height above the SiO 2 surface. c AFM image of single-layer graphene. Colors: dark brown , SiO 2 surface; brown–red ( central area ), 0.8 nm height; yellow–brown ( bottom left ), 1.2 nm; orange (top left ), 2.5 nm. d Scanning electron microscope image of FLG (Few layer graphene). e Schematic view of the device in ( D ) with permission of [ 15 ]

Chemical exfoliation

Chemical method is one of the best appropriate method for synthesis of graphene. In chemical method producing colloidal suspension which modify graphene from graphite and graphite intercalation compound. Different types of paper like material [ 20 ], [ 76 – 80 ] polymer composites [ 18 ], energy storage materials [ 81 ] and transparent conductive electrodes [ 82 ] have already used chemical method for production of graphene. In 1860 graphene oxide was first manufactured Brodie [ 83 ], Hummers [ 84 ] and Staudenmaier [ 85 ] methods. Chemical exfoliation is a two-step process. At first reduces the interlayer van der Waals forces to increase the interlayer spacing. Thus it forms graphene-intercalated compounds (GICs) [ 86 ]. Then it exfoliates graphene with single to few layers by rapid heating or sonication. For single-layer graphene oxide (SGO) uses ultrasonication [ 84 , 87 – 91 ] and various layer thickness using Density Gradient Ultracentrifugation [ 92 , 93 ]. Graphene oxide (GO) is readily prepared by the Hummers method involving the oxidation of graphite with strong oxidizing agents such as KMnO 4 and NaNO 3 inH 2 SO 4 /H 3 PO 4 [ 84 , 94 ]. Ultrasonication in a DMF/water (9:1) (dimethyl formamide) mixture used and produced single layer graphene. For this reason interlayer spacing increases from 3.7 to 9.5 Å. For oxidization high density of functional groups, and reduction needs to be carried out to obtain graphene-like properties. Single layer graphene sheets are dispersed by chemical reduction with hydrazine monohydrate [ 88 , 90 ]. Polycyclic aromatic hydrocarbons (PAHs) [ 94 – 96 ], has used for synthesis of graphene. Using a dendrict precursor transformed by cyclodehydrogenation and planarization [ 97 ].produce small domains of graphene. Poly-dispersed hyper branched polyphenylene, precursor give larger flakes [ 97 ]. The first were synthesized through oxidative cyclodehydrogenation with FeCl 3 [ 97 ]. Variety of solvents are used to disperse graphene in perfluorinated aromatic solvents [ 54 ], orthodichloro benzene [ 98 ], and even in low-boiling solvents such as chloroform and isopropanol [ 99 , 100 ]. Electrostatic force of attraction between HOPG and the Si substrate use in graphene on SiO 2 /Si substrates [ 65 ]. Laser exfoliation of HOPG has also been used to prepare FG, using a pulsed neodymium-doped yttrium aluminum garnet (Nd:YAG) laser [ 42 , 101 ]. Thermal exfoliation and reduction of graphite oxide also produce good-quality graphene, generally referred to as reduced graphene oxide (RGO).

Reduction graphene oxide

Chemical reduction of graphite oxide is one of the conventional procedures to prepare graphene in large quantities [ 84 ]. Graphite oxide (GO) is usually synthesized through the oxidation of graphite using oxidants including concentrated sulfuric acid, nitric acid and potassium permanganate based on Brodie method [ 83 ], Staudenmaier method [ 85 ], Hummers method [ 84 ]. Another approach to the production of graphene is sonication and reduction of graphene oxide (GO). Addition of H 2 occurs across the alkenes, coupled with the extrusion of nitrogen gas, large excess of NaBH 4 have been used as a reducing agent [ 102 ]. Other reducing agents used include phenyl hydrazine [ 103 ], hydroxylamine [ 104 ], glucose, [ 105 ] ascorbic acid [ 106 ], hydroquinone [ 107 ], alkaline solutions [ 108 ], and pyrrole [ 109 ]. GO was formed by the chemical reaction between organic isocyanates and the hydroxyl is shown in Fig.  4 also mention the FT-IR spectra of GO.

a Proposed reactions during the isocyanate treatment of GO where organic isocyanates react with the hydroxyl ( left oval ) of graphene oxide sheets to form carbamate and amide functionalities, respectively. b FT-IR spectra of GO and isocyanate-treated GO. With permission of [ 110 ]

Electrochemical reduction is another means to synthesize graphene in large scale [ 111 – 113 ]. In 1962, first established monolayer flakes of reduced graphene oxide. The graphite oxide solution can then be sonicated in order to form GO nanoplatelets. The oxygen groups can then be removed by using a hydrazine reducing agent, but the reduction process was found to be incomplete, leaving some oxygen remaining. GO is useful because its individual layers are hydrophilic, in contrast to graphite. GO is suspended in water by sonication [ 114 , 115 ] then deposited on to surfaces by spin coating or filtration to make single- or double-layer graphene oxide. Graphene films are then made by reducing the graphene oxide either thermally or chemically [ 87 ] a simple one-step, solvo thermal reduction method to produce reduced graphene oxide dispersion in organic solvent [ 116 ]. The colloidal suspensions of chemically modified graphene (CMG) ornamented with small organic molecules [ 117 ]. Graphene functionalization with poly ( m -phenylenevinylene-co-2, 5-dioctoxy- p -phenylenevinylene) (PmPV) [ 118 ], 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- N [methoxy (polyethyleneglycol)-5000] (DSPE-mPEG) [ 119 ], poly (tert-butyl acrylate). Here two cross-sectional FE-SEM and TEM pictures are shown in Fig.  5 for distinguishing GO and RGO.

Cross-sectional FE-SEM images of ( a ) graphene oxide (GO) ( b ) Reduced graphene oxide (RGO) with permission of [ 120 ]. Cross-sectional TEM images of ( c ) graphene oxide (GO) [ 121 ] ( b ) Reduced graphene oxide (RGO) with permission of [ 122 ]

Pyrolysis of graphene

Solvo thermal method was used as a chemical synthesis of graphene in bottom up process. In this thermal reaction the molar ratio of sodium and ethanol was 1:1 in closed vessel. Graphene sheets could be smoothly detached by pyrolization of sodium ethoxide using sonication. This produced graphene sheets with dimensions of up to 10 μm. The crystalline structure, different layers, graphitic nature, band structure were inveterate by SAED, TEM and Raman spectroscopy [ 123 ]. Raman spectroscopy of the resultant sheet showed a broad D-band, G-band, and the intensity ratio of IG/ID ~1.16, representative of defective graphene. The benefits of this process were low-cost and easily fabricated of high-purity, functionalized graphene in low temperature. Yet, the quality of graphene was still not suitable because it comprised a large number of defects.

• Chemical vapor deposition (CVD)

Chemical vapor deposition comprises chemical reaction on which process molecules are heated and changed to a gaseous state and that is called precursor. In this CVD process a substrate is diffused on thermally disintegrated precursors in high temperature. It deposits on thin films, crystalline, solid, liquid or gaseous precursors on the surface of the substrate. The deposition of high-quality graphene from CVD process is usually done onto various transition-metal substrates like as Ni [ 124 ] Pd [ 123 ], Ru [ 49 ], Ir [ 126 ], and Cu [ 31 ]. CVD growth of graphene has been mainly practiced on copper [ 31 , 127 ] and nickel [ 31 , 124 , 128 ] substrates. Nickel was the first substrate on which CVD growth of large area graphene was attempted. These efforts had begun right from 2008. [ 129 ].In 1966 [ 130 ] Ni exposed to methane at T  = 900 °C to form thin graphite, to be used as sample support for electron microscopy. In 1971, they [ 131 ] observed the formation of FLGs via evaporation of C from a graphite rod [ 131 ]. Deposition of mono-layer graphitic materials on Pt by thermal CVD was first reported in 1975 [ 26 ]. Later, Eizenberg and Blakely [ 24 ] reported graphite layer formation on Ni (111). In 1984 researcher [ 132 ] performed what may be the first CVD graphene growth on a metal surface, Ir, to study the catalytic and thermionic properties of Ir in the presence of carbon [ 133 ]. The physical and chemical properties of graphene have been precisely analyzed to open a new area of graphene-based electronics [ 15 , 134 – 136 ]. In 2006, the first attempt at graphene synthesis on Ni foil using CVD was done using camphor (terpinoid, a white transparent solid of chemical formula C 10 H 16 O) as the precursor material [ 137 ]. Different hydrocarbons such as methane, ethylene, acetylene, and benzene were decomposed on various transition-metal substrates such as Ni, Cu, Co, Au, and Ru [ 31 ]. Single crystals using an ethylene precursor was found to yield graphene structurally coherent even over the Ir step edges [ 126 ]. Using methane as a hydrocarbon Table  3 can emblem a summary of significant researcher’s contribution.

Classification of CVD process

Depending on the material quality, precursors, the width, and the structure required; there are many various types of CVD processes: thermal, plasma enhanced (PECVD), cold wall, hot wall, reactive, and so on.

In CVD process reactors like hot wall reactor, there temperature is relatively constant everywhere and these walls never get heated in cold wall system. Graphene is formed on Cu thin film mostly by cold wall system.

Growth on Cu

Graphene growth on copper shows that it may emerge as alternate route towards scalable growth of graphene with higher monolayer coverage [ 17 , 140 ]. In 2009, the first CVD growth of uniform as well as large area (~cm 2 ) graphene on a metal surface was done on polycrystalline Cu foils by exploiting thermal catalytic decomposition of methane [ 17 ]. Copper foil was an even superior substrate for growing single layer graphene films [ 17 ]. Although copper is an inexpensive substitute in contrast to other metals that is also simply extractable by etchants without chemically affecting graphene. For a very small solubility of carbon in copper, the carbon deposition process was found to be largely self-limiting [ 17 ]. The solubility of carbon in copper is negligible of the perspective of ppm even at 1000 °C [ 141 ] so the carbon precursor forms graphene directly on copper surface through growth step [ 17 ]. Cu surface is fully enclosed with graphene, save around 5 % of the comprising of BLG and 3LG [ 17 , 142 ] area (Fig.  6 ). Surface roughness is known to produce graphene thickness variation on copper [ 143 , 144 ]. Since graphene growth on copper is surface limited, so smoothness of copper surface imparts very significant role in receiving monolayer coverage across the whole surface of the substrate [ 145 ].

a Optical image of as grown graphene on copper, the corrugations on metal foil are indicated by black arrows . b Same graphene when shifted to 300 nm SiO 2 . Here dark purple areas highlighted by black arrows displays that even on low carbon solubility metal like copper, corrugations on starting substrate can result in formation of significant multilayer regions along with monolayer graphene [ 45 ]. Li et al. used CVD process to produce large-scale monolayer graphene on copper foils. 25 μm thick copper foils were first heated to 1000 ◦ C in a flow of 2 sccm (standard cubic centimeters per minute) hydrogen at low pressure and then exposed to methane flow of 35 sccm and pressure of 500mTorr and acquired sheet resistances of 125Ω/W for a single layer. Using a repeated transfer method, doped 4-layer graphene sheets were formed with sheet resistances as low as 30Ω/W and optical transmittance greater than 90 %. These 4-layer graphene sheets are better to commercially accessible indium tin oxide (ITO). Permission from [ 146 ]

Again Li et al. have shown at 1035 °C with methane flow of 7 sccm and pressure 160 m Torr led to the largest graphene domains with average areas of 142 μm 2 . Using this technique, they were able to produce samples with carrier mobility of up to 16,000 cm 2 V −1  s −1 [ 147 ]. Usually, the graphene layer is slightly strained on the copper foil because of the high-temperature growth [ 148 ] (Fig.  7 ). Formation of graphene on Cu by LPCVD was then scaled up in 2010 where, growing the Cu foil size (30 inches), generating films with μ ~ 7350 cm 2 V −1  s −1 at 6 K. Large grain, ~20–500 μm, graphene on Cu with μ ranging from ~16,400 to ~25,000 cm 2 V −1  s −1 at RT after transfer to SiO 2 was reported in references [ 147 , 149 ] and from ~27,000 to ~45,000 cm 2 V −1  s −1 on h-BN at RT [ 149 ]. Graphene was also formed on Cu by exposing it to liquids or solid hydrocarbons [ 150 , 151 ] reported growth using benzene in the T range 300–500 °C. However based on recent studies on CVD growth on copper have demonstrated copper to be a more auspicious substrate [ 17 ].

Raman spectroscopy and SEM imaging of single layer graphene grown on copper (With Permission) [ 17 ]

Growth on Ni

Due to few disturbing properties of Cu like surface roughening and sublimation; the researcher had to search for new substrates that was Ni substituting the Cu. Graphene was synthesized by Ni foil, polycrystalline nickel thin film, patterned Ni thin film [ 152 ].

The foils were first annealed in hydrogen and then bare to a CH 4 –Ar–H 2 environment at atmospheric pressure for 20 min at a temperature of 1000 °C [ 128 ].The thickness of the graphene layers was found to be reliant on the cooling rate, with few layer graphene. Faster cooling rates consequence in thicker graphite layers, whereas slower cooling avoids carbon from separating to the surface of the Ni foil [ 128 ]. Still, the T range within which graphene can be grown on Ni is very thin, 100 °C [ 153 ], and could end in a Ni 2C phase [ 153 ], which can give rise to defects within the Ni crystal. In a nutshell any graphene grown on the surface could be non-uniform through the Ni–Ni2C regions (Fig.  8 ). The problems of Ni synthesis were time-consuming exposure to the carbon precursor, not self-limiting, catalyzed growth with large number of wrinkles and folds.

SEM images of sample by CVD growth method on Ni film at 900–1000 °C at various H 2 :CH 4 ratios with permission of [ 154 ]

Plasma-enhanced chemical vapor deposition

Plasma-enhanced chemical vapor deposition (PECVD) generates plasma in void chamber which deposits thin flim on the substrate surface. It comprises with chemical reaction of the reacting gases.IN PECVD system uses RF (AC frequency), microwave, and inductive coupling (electrical currents produced by electromagnetic induction). It can be done at relatively low temperature, more feasible for large-scale industrial application and also catalyst free graphene fabrication [ 155 ]. Though it is costly and gas-phase precursor materials are used. The first synthesis of graphene sheets was established [ 156 ]. The production of mono- and few layer of graphene by PECVD on different substrates like Si, SiO 2 , Al 2 O 3 , Mo, Zr, Ti, Hf, Nb, W, Ta, Cu, and 304 stainless steel. Using 900-watt RF power, 10 sccm total gas flow, and inside chamber pressure of ~12 Pa, gas mixture 5–100 % CH 4 in H 2 and 600–900 substrate temperature [ 157 ]. The plasma was deposited within 5–40 min. For complementary metal-oxide semiconductor (CMOS) devices it is need to reduce the temperature. PECVD reduces temperature during deposition was widely exploited in the growth of nanotubes and amorphous carbon [ 158 – 163 ]. When at T  = 317 °C to make TCs with Rs ~ 2 kΩ/at 78 % transmittance. Inductively coupled plasma (ICP) CVD, was used to grow graphene on 150 mm Si wafers [ 164 ], reaching uniform films and good transport properties (i.e., μ up to ~9000 cm 2 V −1  s −1 ).

Epitaxial growth of graphene

Epitaxial thermal growth on a single crystalline silicon carbide (SiC) surface is one of the most praised methods of graphene synthesis. The term “epitaxy” derives from the Greek, the prefix epi means “over” or “upon” and taxis means “order” or “arrangement”. When the deposition of a single crystalline film on a single crystalline substrate produces epitaxial film and the process is known as epitaxial growth. It fabricates high-crystalline graphene onto single-crystalline SiC substrates. There are two general epitaxial growth processes depending on the substrate, homo-epitaxial and hetero-epitaxial growth. When the film deposited on a substrate is of the same material it is known as a homo-epitaxial layer, and if the film and substrate are different materials it is called a hetero-epitaxial layer. Sic first used as on electrical measurements on patterned epitaxial graphene on electrical measurements on patterned epitaxial graphene. In 2004 [ 16 ] SiC is a wide band gap semiconductor (3 eV) and thus electrical measurements can be carried out using it as the substrate. In 1975, Bommel et al. [ 165 ] first reported graphite formation on both the 6H–SiC (0001) surfaces. The heat treatment in the range of 1000–1500 °C in an ultrahigh vacuum (~10–10 m bar) manufactured graphite on both of the SiC polar planes (0001). In 2004, de Heer’s [ 166 ] group reported the fabrication of ultrathin graphite consisting of 1–3 mono-atomic graphene layers on the Si completed (0001) face of single-crystal 6H-SiC and explored its electronic properties [ 167 ]. The growth rate of graphene on SiC depends on the specific polar SiC crystal face [ 166 , 167 ]. Graphene forms much faster on the C- than on the Si-face [ 166 , 167 ]. On the C-face, larger domains (~200 nm) of multilayered, rotationally disordered graphene are produced [ 167 , 168 ]. On the Si-face, UHV annealing leads to small domains, ~30–100 nm [ 168 , 169 ]. (Si (0001)- and C (000-1)-terminated) annealed at high T (>1000 °C) under ultra-high vacuum (UHV) graphitize due to the evaporation of Si [ 170 , 171 ]. Graphene films by thermal decomposition of SiC above1000 °C, graphene grows on a C-rich 6√3 × 6√3R30° rebuilding with respect to the SiC surface [ 172 , 181 ]. Epitaxial graphene growth on SiC has been visualized as a very promising method for large-scale production and commercialization of graphene for applications into electronics. Graphene on SiC produces high-frequency electronics [ 173 ], light emitting devices [ 173 ], and radiation hard devices [ 173 ]. Top gated transistors have been fabricated from graphene on SiC on a wafer scale [ 174 ]. High-frequency transistors have also been revealed with 100 GHz cut-off frequency208 [ 175 ], higher than state of the art Si transistors of the same gate length [ 176 ]. Graphene on SiC has been established as a novel resistance standard based on the quantum Hall effect (QHE) [ 177 ]. Though this process is very expensive.

• Unzipping method

Chemical and plasma-etched method uses in unzipping a carbon nanotube (CNT). Graphene nano ribbon (GNR) defines a thin elongated strip of graphene which demonstrates straight edges. Transformation of electronic state from semimetal to semiconductor depends on the width of nanaotube [ 178 ]. Multi-layer graphene or single-layer graphene produces if the starting nanotube is multi-walled or single walled. The width of the nanoribbons thus produced depends on the diameter of the precursor nanotubes. Multi-walled carbon nanotubes (MWNTs) established by lithium (Li) and ammonia (NH 3 ). Conversion of graphene nanoribbon from (MWNTs) are shown in Fig.  9 .

The Images of graphene nanoribbons (GNRs) converted from Multi–wall carbon nanaotubes (MWCNTs) with permission of [ 34 ]

Liquid NH 3 (99.95 %) and dry tetrahydrofuran (THF) used in growth of (MWNTs) retaining the dry ice bath temperature of −77 °C [ 179 ]. It was found that ~60 % fully exfoliated and (0–5 %) unexfoliated or partially exfoliated nanotubes of (MWNTs). For Oxidation of CNT’s side wall used H 2 SO 4 , KMnO 4 , and H 2 O 2 in step by step process [ 32 ]. At the beginning they reported that the MWNT diameter was 40–80 nm and increased up to 100 nm. The step-by-step fabrication process from nanotube to nanoribbon is shown in Fig.  10 .

A process flow chart of graphene nanoribbon fabrication from a carbon nanotube (CNT) by the plasma etching process with permission of [ 34 ]

In controlled unzipping technique a pristine MWNT (dia. ~4–18 nm) suspension was put on to a Si substrate pretreated with 3-aminopropyltriethoxysilane. A polymethylmethacrylate (PMMA) solution [ 34 ]. They established high quality of MWNTs which diameter were ~6–12 nm and step height GNRs were 0.8–2.0 nm. Again single- to few-layer GNRs also depends on the plasma etching time.

Another method for unzipping MWCNTs to GNRs used electric field. An electric field was applied to a single MWNT using a tungsten electrode and perceived that the noncontact end of the MWCNT started unwrapping and forming graphene nanoribbon. The fabrication process of GNRs achieve a high-purity, defect-free controlled synthesis process for scalable device in modern electronics.

Others method

There are several other ways to produce graphene such as electron beam irradiation of PMMA nanofibres [ 180 ], arc discharge of graphite [ 181 ], thermal fusion of PAHs [ 182 ], and conversion of nano diamond [ 183 ]. Graphene can synthesis by arc discharge method in the presence of H 2 atmosphere with two to three layers having flake size of 100–200 nm [ 180 , 184 ]. By rapid heating process Arc discharge in an air atmosphere resulted in graphene nano sheets that are ~100–200 nm wide predominantly with two layers [ 182 ]. The conditions that are favorable for obtaining graphene in the inner walls are high current (above 100 A), high voltage (>50 V), and high pressure of hydrogen (above 200 Torr). The vintage of graphene layer depends strongly on the initial air pressure [ 185 ]. He and NH 3 atmosphere are also used as arc discharge method [ 43 ]. In He atmosphere has considered gas pressure and currents to obtain different number of graphene sheets. In molecular beam deposition technique used ethylene gas source which deposited on a nickel substrate. Large-area, high-quality graphene layers were produced dependent on cooling rate.

Applications

In the field of application, the novel 2D material graphene plays a vanguard and outstanding role in this twenty-first century. The applications and applied areas of graphene are so vast that it is too many to describe here. The recent advances in the unique electronics, optical, magnetic, surface area, and mechanical properties of functionalized graphene have emerged new approach of green technology and innovative solution of existing problems like as electronic and photonic applications for ultrahigh-frequency graphene-based devices, nanosized graphene in material science, in ceramics, anode for li-ion battery, supercapacitor, lightweight natural gas tanks, sensors to diagnose diseases and solar cell [ 186 ]. In October 2014, international wheel producer Vittoria released a new range of bicycle race wheels built from graphene-enhanced composite materials. The new wheels (called Quarno) are the best wheels offered by Vittoria, and are said to be the fastest in the world [ 187 ]. In September 15th, 2015; the first flight of a UAV part-constructed with graphene have brought a new nano-material that the thinnest material on Earth [ 188 ]. Recently a group of researcher have developed a range of membrane assemblies for advanced water treatment, including crumpled graphene oxide nanocomposites, which are highly water-permeable, photo reactive and antimicrobial. In future there will be myriad scope for disseminating this research concept [ 189 ].

Recently graphene the noble material has brought a revolutionary change in the field of nanoelectronics. Its outstanding contribution is not only limited in nanoelectronics but also expanding in medical science, nanorobotics, commercial manufacturing of graphene synthesized products and so on.

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Acknowledgments

We express deep sense of gratitude and indebtedness to our project supervisor Md. Nizam Uddin, Assistant Professor, Department of Mechanical Engineering for providing precious guidance, inspiring discussions and constant supervision throughout the course of this work. His help, constructive criticism, and conscientious efforts made it possible to present the work contained in this project. It’s our goodness that in spite of having a tight and busy schedule supervisor has found time to help and guided us. For this, we again express our greatness to him. We are also grateful to those staff who help us directly or indirectly which was very essential to accelerate our work.

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Md. Sajibul Alam Bhuyan, Md. Nizam Uddin & Sayed Shafayat Hossain

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Bhuyan, M.S.A., Uddin, M.N., Islam, M.M. et al. Synthesis of graphene. Int Nano Lett 6 , 65–83 (2016). https://doi.org/10.1007/s40089-015-0176-1

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• Molecular capsules
• Self-assembly

Here we report a two-step, hierarchical synthesis that assembles a trigonal prismatic organic cage into a more symmetric, higher-order tetrahedral cage, or ‘cage of cages’. Both the preformed [2+3] trigonal prismatic cage building blocks and the resultant tetrahedral [4[2+3]+6]cage molecule are constructed using ether bridges. This strategy affords the [4[2+3]+6]cage molecule excellent hydrolytic stability that is not a feature of more common dynamic cage linkers, such as imines. Despite its relatively high molar mass (3,001 g mol −1 ), [4[2+3]+6]cage exhibits good solubility and crystallizes into a porous superstructure with a surface area of 1,056 m 2  g −1 . By contrast, the [2+3] building block is not porous. The [4[2+3]+6]cage molecule shows high CO 2 and SF 6 uptakes due to its polar skeleton. The preference for the [4[2+3]+6]cage molecule over other cage products can be predicted by computational modelling, as can its porous crystal packing, suggesting a broader design strategy for the hierarchical assembly of organic cages with synthetically engineered functions.

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A class of organic cages featuring twin cavities

Self-assembled conjoined-cages

Non-statistical assembly of multicomponent [Pd2ABCD] cages

The chemical synthesis of complex organic molecules is part of our toolkit to access materials with unique structures and functions 1 , 2 , 3 , 4 , 5 . Supramolecular self-assembly is a powerful strategy to synthesize molecules comprising a number of separate precursors 6 , 7 , 8 ; these assemblies can also be nanometres in size 9 , 10 or chemically interlocked 11 , 12 . However, obtaining the desired self-assembly outcomes for more complex molecules quickly becomes synthetically challenging, particularly when the bond-forming chemistry has low reversibility. This creates a dichotomy: the more successful supramolecular reactions often lead to labile, unstable products, and this can limit the scope for applications. This challenge can be tackled by careful tuning of precursor structure and functionality, such as molecular geometry, or by iterative optimization of the synthetic procedures, but the best reaction conditions are often not intuitively obvious.

Some of the earliest supramolecular systems were synthesized by condensing simple bidentate building blocks, such as ethylenediamine and triethylene glycol, to form cryptands and crown ethers, respectively 13 . These molecules inspired the synthesis of larger and more complex architectures. For example, Fujita and co-workers introduced the concept of emergent behaviour in the assembly of large self-assembled macrocyclic products using carefully designed precursors 14 . Such supramolecular design strategies have allowed us to synthesize more complex self-assembled structures and, hence, to unlock new applications 2 , 15 , 16 . However, high structural complexity is often accompanied by increased synthetic challenges and lower predictability because of sensitivity to parameters such as the precise bond angles in the precursors 9 , 14 , 17 .

Postsynthetic modifications have been used previously to enhance the porosity of organic cages 18 , 19 , such as by hooping parts of the cage together 20 . More recently, we and others have used hierarchical assembly strategies to form topologically complex hydrogen-bonded organic frameworks 21 , 22 and covalently bonded materials, such as covalent organic frameworks 23 , 24 , 25 , 26 , using three-dimensional organic cages as the building blocks 27 . These studies have shown that cage-based building blocks can assemble into higher-order structures and increase the complexity of the resulting materials, for instance, by controlling network topology and interpenetration, while still offering a degree of structural predictability. In turn, this has afforded cage-based hydrogen-bonded organic frameworks and three-dimensional cage-based covalent organic frameworks with properties such as guest-responsive structural flexibility 23 and self-healing behaviour 28 . However, this hierarchical structuring approach does not appear to have been extended to the preparation of porous organic cage molecules 18 , 29 : that is, to synthesize larger porous cages from smaller organic cage precursors.

The use of organic cages as precursors to synthesize higher-order porous structures is attractive because it embeds cage molecules, with their own chemical complexity, into larger, hierarchical cages with the potential to create new functions while retaining useful properties such as solution processability 19 , 27 , 30 . For example, this strategy might produce porous materials with more sophisticated hierarchical porosities. To tackle this goal, we considered three criteria: (1) geometry—the cage precursors need geometries that can be arranged into a higher-order structure in a useful yield; (2) chemical stability—the chemical bonding in the cages must not be too labile, both to impart stability for applications and also to avoid the dynamic scrambling that might occur, for example, in trying to construct an imine cage from another imine cage 31 ; (3) rigidity—the precursors need sufficient rigidity to direct chemical reactivity to the desired product and to ensure that the resultant hierarchical cage is shape persistent and retains its porous structure after removal of solvent from the voids.

To meet these three criteria, we chose a trigonal prismatic [2+3] ether-bridged cage molecule, Cage-3-Cl , as the polyhedral building block to construct a hierarchical ‘cage of cages’ (Fig. 1 ). The preconfigured rigid geometry and excellent chemical stability of Cage-3-Cl allowed this [2+3] cage to assemble with tetrafluorohydroquinone ( TFHQ ) into the hierarchically structured organic ‘cage of cages’ compound, [4[2 + 3] + 6]cage .

The [ 4[2 + 3] + 6]cage molecule was synthesized via the S N Ar reaction between Cage-3-Cl and TFHQ in the presence of DIPEA. The triangular prism and the yellow sticks in the lower figure scheme represent Cage-3-Cl and TFHQ , respectively.

Results and discussion

Nucleophilic aromatic substitution (S N Ar) reactions have been reported to undergo reversible covalent bond formation when using electron-poor aromatic compounds 32 , 33 , 34 , while still leading to stable molecular products. Reversible error-correction is important for the formation of complex molecules that must self-sort during the reaction from a variety of possible products. Although the S N Ar reaction has been used in the synthesis of ether-bridged cages, most tend to be [2+3] or [2+4] cage products with small intrinsic cavities 35 , 36 , 37 , with the exception of a larger [4+6] ether-linked cage reported by Santos and co-workers 32 . One possible reason for the lack of larger cages synthesized via S N Ar chemistry is the less predictable orientation of the ether bridges compared to the imines and boronate esters for which larger cages are more commonplace 10 , 38 , 39 , 40 , 41 , 42 .

Previous investigations by our group and others have demonstrated that Cage-3-Cl has a highly symmetric and rigid triangular prism geometry both in solution and in the solid state 21 , 36 . This geometry makes Cage-3-Cl an ideal building block for forming higher-order cage molecules, such as molecular barrels 20 . The three residual chlorine atoms exhibit high reactivity 43 , 44 , which is essential for forming ether bridges. We selected TFHQ as the linear bridge between Cage-3-Cl molecules because the fluorine atoms might afford extra barriers to restrict the rotation of the ether bridges, and might improve the solubility of the resulting cage–cage molecules 36 , 45 .

To explore the available bond angles and the relative flexibility of the ether bridges in possible hierarchical cage products, we performed molecular dynamics (MD) and density functional theory (DFT) calculations. Models were constructed with the supramolecular toolkit (stk) software 46 to predict the most likely reaction products. As shown in Fig. 2 , the [4[2+3]+6] stoichiometry is predicted to form a stable, shape-persistent cage structure that exhibits a much lower energy than alternative [2[2+3]+3] and [8[2+3]+12] topologies. The [2[2+3]+3] topology has by far the highest relative energy (660.8 kJ mol −1 ) due to its highly strained geometry. The [8[2+3]+12] topology has higher relative energy (24.04 kJ mol −1 ) than the [4[2+3]+6] cage, which suggests that the [4[2+3]+6] topology is the thermodynamically favoured product, although we stress that these calculations do not include any solvent effects. As such, the [8[2+3]+12] topology might also be accessible under other synthesis conditions, whereas we predict that the [2[2+3]+3] topology is not. The cis – trans configurations of the ether bridges in the hypothetical [8[2+3]+12]cage can result in various positional configurations; all of these structural conformers were predicted to have relative energies that were between 24.0 and 229.1 kJ mol −1 higher than the [4[2+3]+6]cage, indicating a strong preference for the [4[2+3]+6] product (Supplementary Information Section 1 and Supplementary Figs. 1 – 4 ).

x  = number of Cage-3-Cl cages, y  = number of TFHQ linkers. Atom colours: carbon, grey; nitrogen, blue; oxygen, red; fluorine, green. Hydrogen atoms are omitted for clarity. Note the break in the energy scale for the highly strained [2[2+3]+3]cage, which has by far the highest relative energy (660.8 kJ mol −1 ). The DFT energies indicate that the [4[2+3]+6] stoichiometry is predicted to form a stable, shape-persistent cage structure that has a lower relative energy (24.04 kJ mol −1 ) than the alternative [8[2+3]+12] topology.

These simulation results suggested that it might be possible to synthesize [4[2 + 3] + 6]cage via the S N Ar reaction between Cage-3-Cl and TFHQ (Fig. 1 ). We therefore attempted the reaction experimentally, and screened a range of conditions in which we varied the reagent concentration, solvent and base (Supplementary Table 1 ). From these experiments, we found that the reaction in acetone in the presence of the acid scavenger N , N -diisopropylethylamine (DIPEA) afforded a new product with the highest yield of 53% after purification. The 1 H NMR spectrum for the purified reaction product from the acetone reaction with DIPEA showed two singlets at 7.09 and 6.85 ppm, which we assigned to the two aromatic protons in the [2+3] cage (H a and H b ; Fig. 3a and Supplementary Fig. 5 ). The presence of two singlets indicates different environments, which we attribute to one of the protons being more shielded. However, apart from this splitting of the aromatic proton singlet in Cage-3-Cl , the NMR spectroscopy data indicated that the resulting product had high symmetry in solution. In the 13 C NMR spectrum, we observed three signals in the 174.5–173.1 ppm range (Fig. 3b and Supplementary Fig. 6 ), which we assigned to the triazine ring carbon atoms. We attribute the characteristic splitting, observed at 142.5 and 140.0 ppm with a coupling constant of 250 MHz, to the coupling between the carbon and fluorine atoms in the TFHQ linker (Fig. 3b and Supplementary Fig. 6 ). We also confirmed the presence of these fluorinated aromatic rings by 19 F NMR spectroscopy, observing a singlet at −155.62 ppm (Supplementary Fig. 7 ), indicating that the fluorine atoms were symmetrically equivalent in solution. We also used high-resolution matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry to analyse the reaction product. We found an ion with a mass-to-charge ( m / z ) ratio of 3,002.0756 (Fig. 3c and Supplementary Figs. 8 and 9 ), which matched well with the theoretical value of [ [4[2 + 3] + 6]cage  + H] + (3002.0871), indicating the formation of [4[2 + 3] + 6]cage .

a , 1 H NMR (400 MHz, acetone- d 6 ) spectra of Cage-3-Cl (green, bottom) and [4[2 + 3] + 6]cage (blue, top). b , 13 C NMR (100 MHz, dioxane- d 8 ) spectra: TFHQ (yellow, bottom), Cage-3-Cl (green, middle) and [4[2 + 3] + 6]cage (blue, top). Insets: zoom-ins of the boxed regions. The NMR spectra highlight the splitting of peaks due to the formation of a hierarchical ‘cage of cages’ structure. c , High-resolution MALDI-TOF spectrum of [4[2 + 3] + 6]cage , showing an ion with an m / z ratio of 3,002.0756 assigned to [ [4[2 + 3] + 6]cage  + H] + . Two internal calibrants (Spherical) with m / z ratios of 2,979 and 3,423 that bracketed the ion of interest were used to limit the m / z error to ±5 ppm.

Source data

We next grew crystals for single-crystal X-ray diffraction analysis to confirm the structure of the [4[2 + 3] + 6]cage molecule. Slow evaporation of a mixture of acetone/ethanol afforded single crystals suitable for X-ray analysis using synchrotron radiation (Supplementary Fig. 10 and Supplementary Table 2 ). The synchrotron single-crystal structure, which we refined in the monoclinic P 2 1 space group, revealed that the [4[2 + 3] + 6]cage molecule adopts a tetrahedral topology, where four Cage-3-Cl cage molecules serve as the vertices and six TFHQ molecules are located as the edges (Fig. 4a ). The interior and the exterior aryl caps of the Cage-3-Cl cage molecules form a core–shell structure, defining an inner and outer truncated tetrahedron with edge lengths of 6.4 and 13.7 Å, respectively (Fig. 4b ). We also calculated the electrostatic potentials for the [4[2 + 3] + 6]cage molecule, which showed that the centre of the [4[2 + 3] + 6]cage molecule is surrounded by aromatic rings, affording π–π interactions for any guest molecules within the cage (Fig. 4c and Supplementary Information Section 1 ).

a , Structure of an individual [4[2 + 3] + 6]cage molecule. Atom colours: carbon, grey; hydrogen, white; nitrogen, blue; oxygen, red; fluorine, green. b , Representation of the [4[2 + 3] + 6]cage molecule using two truncated tetrahedra on the inner and outer aryl caps of the [2+3] Cage-3-Cl cage molecules. For clarity, all atoms here are coloured grey. c , Electrostatic potential maps of the [4[2 + 3] + 6]cage molecule. The red and blue surfaces represent negative and positive regions of potential, respectively. Colour bar, −31.4 to 94.1 kcal mol −1 . d , e , Pore channels in the extended [4[2 + 3] + 6]cage crystal structure as viewed along the a axis ( d ) and the b axis ( e ). For clarity, hydrogen atoms are omitted in b , e and f . The yellow surfaces in d and e represent the contact surface as measured using a 1.2 Å diameter probe. f , Scheme explaining the window splitting in the [4[2 + 3] + 6]cage crystal structure along the a axis; the window of the lower blue cage is partially occluded by the aryl face of the upper yellow cage.

The interior of the cage core exhibits an electron-poor character because of the V-shaped electron-deficient clefts formed by the triazine rings of Cage-3-Cl and the fluorine-decorated aromatic rings. This environment might be useful for selective guest molecule separation 47 , 48 , 49 . In the extended crystal structure of this cage of cages, the asymmetric cell contains one [4[2 + 3] + 6]cage molecule, which assembles into a porous supramolecular structure by interacting with 12 neighbouring [4[2 + 3] + 6]cage molecules through van der Waals forces (Supplementary Fig. 11 ). Two of the windows in the [4[2 + 3] + 6]cage molecule are narrowed into smaller channels by the Cage-3-Cl vertices from neighbouring cage molecules (Fig. 4d,f and Supplementary Fig. 12 ), yielding three-dimensional interconnected pore channels (Fig. 4d,e ). Using Zeo++ 50 , we calculated that the pore-limiting diameter of the [4[2 + 3] + 6]cage crystal structure was 6.4 Å and the largest cavity diameter was 8.9 Å (Supplementary Table 3 and Supplementary Figs. 13 – 15 ), suggesting that the structure is microporous. From these calculations, we also determined that voids in the [4[2 + 3] + 6]cage crystal structure that are accessible to a 1.65 Å CO 2 probe occupy 32.0% of the unit cell volume (Supplementary Table 3 ).

There was strong agreement between the predicted structure for the [4[2 + 3] + 6]cage molecule and the molecule observed in the crystal structure (Fig. 5 ). This validates the theoretical predictions, and the close match between the crystal structure prediction (CSP)-predicted structure and experimental crystal structure adds confidence in the crystal structure refinement (Supplementary Fig. 17 ). The root mean squared displacement (r.m.s.d.) was calculated as 0.5 Å with a maximum distance between atoms of 1.4 Å. However, the experimental displacement parameters are large due to disorder in the crystal structure (Supplementary Fig. 11a ). Further attempts to synthesize the larger [8[2+3]+12] product by varying the reaction conditions were unsuccessful, based on MALDI-TOF analysis of the resulting products (Supplementary Table 1 and Supplementary Fig. 8 ), in line with the molecular stability predictions (Fig. 2 ).

a – c , The predicted structure (red) overlaid with the single-crystal X-ray diffraction structure (blue) is shown as viewed along the a ( a ), b ( b ) and c ( c ) crystallographic axes. The r.m.s.d. was calculated as 0.5 Å with a maximum distance between atoms of 1.4 Å, highlighting the close structural similarity between the predicted and experimental structures.

In principle, catenation of this cage is possible, given its large intrinsic voids (>10 Å diameter), as observed for considerably smaller imine cages 11 . However, we saw no evidence for catenated cage side-products, either by NMR or by MALDI-TOF characterization.

We next used CSP to explore the solid-state packing of these hierarchical cages. The lattice energy landscape was explored using quasi-random sampling of the crystal packing space with the Global Lattice Energy Explorer (GLEE) 51 . Initial trial structures were generated from rigid molecules and subjected to lattice energy minimization using an empirically parameterized potential with atomic multipole electrostatics 52 (see Supplementary Information Section 4 , Supplementary Tables 4 and 5 , and Supplementary Figs. 16 – 25 for full details).

Surprisingly, the CSP landscape for [4[2 + 3] + 6]cage (Fig. 6 ) showed catenated structures, along with the non-catenated cage that was observed experimentally, even though the discrete [4[2 + 3] + 6]cage molecule was used for the CSP calculations. Three distinct catenations were identified in the predicted crystal structures: triply interlocked cage dimers (Fig. 6c ), singly interlocked cage dimers (Fig. 6d ) and singly interlocked one-dimensional (1D) cage chains 12 , 53 (Fig. 6e ). The details of the methods used for catenation detection are provided in Supplementary Information Section 4 and Supplementary Figs. 18 ‒ 20 . All sampled structures within a 197 kJ mol −1 energy window from the global energy minimum were found to be catenanes (Supplementary Figs. 21 and 22 ), indicating a strong thermodynamic preference over the non-catenated cages observed by experiment. To verify the relative energies calculated using the rigid-molecule, force-field approach, a selection of catenated and non-catenated predicted structures were re-evaluated using periodic DFT, which confirmed this greater thermodynamic stability (see Supplementary Information Section 4 for full details).

a , Computational crystal energy landscape of [4[2 + 3] + 6]cage with colour-coded categorization based on catenation type: discrete, non-catenated cages (uncoloured circles), triply interlocked cage dimers (green circles), singly interlocked cage dimers (blue) and singly interlocked 1D cage chains (orange). The yellow star and blue cross represent the predicted structures matching the experimentally observed [4[2 + 3] + 6]cage crystal structure and [4[2 + 3] + 6]cage·acetone solvated structure, respectively. b , Energy landscape after removal of the catenated structures, with colour coding based on the diameter of the largest sphere ( D f ) capable of freely moving within the crystal structure’s channel(s). Channels are found based on their ability to accommodate a CO 2 molecule. D f  = 0 corresponds to no channel being found. c – e , Atomic structures depicted for examples of a triply interlocked cage dimer ( c ), a singly interlocked cage dimer ( d ) and a singly interlocked 1D cage chain ( e ).

While the CSP study did not explicitly target catenated structures, the sampled catenated configurations suggest that triply interlocked catenanes (green points, Fig. 6a ), in particular, might be much more thermodynamically stable in the solid state. This echoes previous findings for [4+6] imine cages, in which discrete cages were found to transform into triply interlocked catenanes upon exposure to acid, suggesting that the individual cages were the kinetic rather than the thermodynamic product 11 . The absence of catenanes in our experiments might be explained by the much lower reversibility of the ether bonding in the [4[2 + 3] + 6]cage molecule, which is not accounted for in the CSP calculations. Prompted by these solid-state CSP results, we also explored the relative thermodynamic stability of catenanes at the molecular level. DFT calculations of catenane dimers showed that the energy difference between the molecular equivalent non-catenated [4[2 + 3] + 6]cage dimer and trimer fragments retrieved from the global lowest-energy CSP, and the corresponding triply interlocked catenane molecular fragment was 373.7 kJ mol −1 and 324.7 kJ mol −1 , respectively, reaffirming strong thermodynamic favour towards the catenane structures.

When we remove the catenated structures from the CSP plot (Fig. 6b and Supplementary Fig. 23 ), this reveals the observed experimental structure positioned at the bottom of a low-density ‘spike’ in the energy landscape, approximately 13.6 kJ mol −1 higher than the global energy minimum for non-catenated cages. The predicted crystal structure reproduces the geometry of the experimentally determined [4[2 + 3] + 6]cage crystal structure accurately (Supplementary Fig. 17 ), confirming that the crystal structure determined by X-ray diffraction corresponds to a low-energy local minimum in lattice energy. The colour coding in this ‘non-catenated’ crystal structure landscape represents the diameter of the largest sphere capable of unrestricted movement within the crystal structure channels. Channel dimensions are determined based on their capacity to accommodate a CO 2 molecule with a kinetic radius of 1.65 Å (Supplementary Figs. 24 and 25 ). In the landscape depicted in Fig. 6b , void analysis has been restricted to structures within 20 kJ mol −1 of the low-energy edge of the energy-density distribution of structures. Except for a very small number of predicted structures (purple points, Fig. 6b ), all investigated structures, including the synthesized structure, show potential for CO 2 uptake. That is, CSP suggests that [4[2 + 3] + 6]cage has an intrinsic propensity to be porous in the majority of its potential crystalline packing modes.

Molecular crystals exhibiting permanent porosity in the solid state are attractive for applications such as gas capture, separation and catalysis 18 , 54 . One successful approach that we and others have developed is to form porous organic crystals by synthesizing cages with prefabricated shape-persistent cavities that are retained after solvents are removed during activation 18 , 50 , 54 . Our calculations revealed that the ether bridges in the [4[2 + 3] + 6]cage skeleton appeared to be relatively rigid, suggesting shape persistence. We therefore investigated the porosity in the [4[2 + 3] + 6]cage crystals using gas sorption analysis. We activated the [4[2 + 3] + 6]cage crystals by first exchanging the ethanol and acetone crystallization solvents with diethyl ether or n -pentane, which we chose because of their low surface tensions. Then, we removed any residual solvent from the crystals under a dynamic vacuum at room temperature. Subsequent powder X-ray diffraction (PXRD) analysis revealed that the [4[2 + 3] + 6]cage crystals retained some crystallinity after being activated using these conditions (Supplementary Fig. 26 ). The [4[2 + 3] + 6]cage crystals activated via the diethyl ether solvent exchange route appeared more crystalline, and this sample was used for the subsequent gas sorption experiments described here.

Nitrogen sorption isotherms recorded at 77 K revealed that the crystalline [4[2 + 3] + 6]cage exhibits a type I N 2 sorption isotherm with a relatively high Brunauer–Emmett–Teller surface of 1,056 m 2  g −1 (Fig. 6a and Supplementary Figs. 27 ‒ 29 ), consistent with a microporous solid and the pore size distribution plot calculated using Zeo++ 51 (Supplementary Table 3 and Supplementary Fig. 13 ). We found that crystalline [4[2 + 3] + 6]cage has a CO 2 uptake capacity of 3.98 mmol g −1 at 1 bar and 273 K (Fig. 7b and Supplementary Fig. 30 ). This CO 2 uptake is high compared with other porous organic crystalline materials, such as covalent organic frameworks 55 , at comparable temperatures and pressures, and is one of the highest CO 2 uptakes reported to date for a porous organic cage (Supplementary Table 6 ) 56 , 57 . The calculated isosteric heat of adsorption of CO 2 on crystalline [4[2 + 3] + 6]cage ranges between 21.1 and 23.2 kJ mol −1 (Supplementary Fig. 31 ), which indicates a strong affinity between the adsorbed CO 2 gas and polar [4[2 + 3] + 6]cage crystal pores, rationalizing this high uptake capacity. In addition, we found that crystalline [4[2 + 3] + 6]cage has a high SF 6 uptake capacity of 3.21 mmol g −1 at 1 bar and 273 K (Supplementary Fig. 32 ). The calculated isosteric heat of adsorption of SF 6 on crystalline [4[2 + 3] + 6]cage ranges between 29.2 and 29.5 kJ mol −1 , which again indicates a strong affinity between adsorbed SF 6 gas molecules and the [4[2 + 3] + 6]cage crystal pores (Supplementary Fig. 33 ). Analysis of the [4[2 + 3] + 6]cage powder after the gas sorption isotherms by PXRD analysis indicated that the material remained crystalline during these measurements (Supplementary Fig. 34 ).

a , N 2 sorption isotherms recorded at 77 K showing hysteresis in the desorption isotherm. b , CO 2 gas sorption isotherms recorded at 273 K (cyan) and 298 K (orange) showing an uptake capacity of 3.98 mmol g −1 at 1 bar and 273 K. Closed and open symbols represent the adsorption and desorption isotherms, respectively.

We also uncovered a second crystal structure of the [4[2 + 3] + 6]cage molecule during this study, referred to as [4[2 + 3] + 6]cage·acetone , which crystallized from slow evaporation of an acetone- d 6 solution (Supplementary Fig. 35 ). [4[2 + 3] + 6]cage·acetone crystallized in the cubic space group \(I\bar{4}3m\) ( a  = 23.2901(15) Å, V  = 12633(2) Å 3 , Supplementary Table 7 ) with the ether-bridged cage adopting a perfect tetrahedral geometry in the structure (Supplementary Fig. 36 ). The [4[2 + 3] + 6]cage·acetone lost crystallinity rapidly after being removed from the acetone- d 6 solvent and cracked (Supplementary Fig. 35 ). We therefore performed single-crystal analysis by sealing a solvated crystal in a borosilicate capillary containing residual acetone- d 6 solvent. However, due to the poorer crystal stability of 4[2 + 3] + 6]cage·acetone , we did not investigate its solid-state properties further. The instability of this form was further investigated through computational geometry optimization of the crystal structure. Employing the same energy model as used in the CSP study, rigid-molecule geometry optimization of the structure after solvent removal resulted in considerable structural distortion from the original cubic lattice, adopting a monoclinic form, in keeping with the observed experimental instability. Details can be found in Supplementary Information Section 8 . The relaxed structure, denoted by a blue cross in the landscape of Fig. 6a , is situated 103 kJ mol −1 above the global energy minimum on the landscape of non-catenated structures. This energy difference underscores the crucial role of solvent stabilization in the synthesis of this solvated structure, and can also help to rationalize why this tetrahedral molecular structure was not predicted using gas-phase (that is, solvent-free) DFT calculations (Fig. 5 ).

For practical applications, gas sorption capacity is not the only criterion. For example, most CO 2 capture applications involve wet or humid gas streams, and hence water stability is important. Many porous organic cage materials, such as imine cages and (particularly) boronate ester cages, are unstable to water. We therefore explored the hydrolytic stability of the [4[2 + 3] + 6]cage molecule by immersing the synthesized crystals in water for 12 days. Subsequent analysis of the sample by 1 H NMR spectroscopy revealed that [4[2 + 3] + 6]cage remained chemically intact under these conditions (Supplementary Fig. 38 ). PXRD analysis of the same sample also revealed that the [4[2 + 3] + 6]cage crystals retained their crystallinity under these conditions (Supplementary Fig. 39 ). Hence, both the chemical and crystal structure of [4[2 + 3] + 6]cage molecule appear to have good hydrolytic stability.

We report the assembly of a more complex type of porous organic cage—a ‘cage of cages’—that was synthesized using a two-step hierarchical self-assembly strategy. In this study, we demonstrate the strategy by assembling four trigonal cages into a larger tetrahedral cage. The resulting [4[2 + 3] + 6]cage molecule exhibits excellent stability in water, and crystals of the [4[2 + 3] + 6]cage show permanent porosity and a high surface area of 1,056 m 2  g −1 . The abundance of polar atoms in the cage cavity endows it with high CO 2 and SF 6 uptake capacity. The good solubility of [4[2 + 3] + 6]cage in acetone indicates it has the potential to be used as a building block for even more complex structures, such as porous cage co-crystals. More broadly, this illustrates a strategy for hierarchical molecular assembly using computation as a guide to assess the most likely reaction products. For example, it might be possible in the future to design analogous systems where the [2+3] cages contribute discrete, prefabricated porosity into a higher-order, hierarchically porous crystal.

This study also showcases the use of computational design in supramolecular synthesis, both at the molecular level (Fig. 5 ) and in the solid state (Fig. 6 ). It is notable that triply interlocked cage catenane dimers emerged as the most stable predicted crystal packings (Fig. 6a ). Such catenanes were not observed in experiments, most likely because they are kinetically disfavoured, but they are nonetheless synthetically plausible because analogous structures have been formed using more reversible [4+6] imine cage-forming reactions 11 . Less obviously, infinite 1D catenated cage chains are also produced in these simulations (Fig. 6e ), and in some cases these structures are predicted to have similar lattice energies to the experimentally observed non-catenated cage (Fig. 6a ). This highlights how a priori structure predictions have the power to suggest non-intuitive new materials, although it is unclear how one might design a kinetic pathway to these chain structures, even though analogous structures have been observed for less complex macrocycles 53 .

Molecular simulations

Both Cage-3-Cl and cage-of-cages models were constructed in Tri2Di3, Tri4Di6 and Tri8Di12 topologies using the stk software 46 . All cages were annealed with an MD simulation at 700 K for 50 ns with a time step of 0.5 fs after a 100 ps equilibration time with the OPLS4 force field as implemented in the Macromodel Suite 58 . Five hundred random configurations from the total MD duration were sampled and energy minimized, with the lowest energy configuration selected for DFT calculations. DFT calculations were performed with CP2K v.2023.1 (ref. 59 ) software using the generalized gradient approximation theory with the Perdew–Burke–Ernzerhof functional 60 and def2-TZVP basis sets 61 . A planewave cut-off value of 400 Ry and a relative cut-off value of 100 Ry were parameterized to obtain converged energy levels and dispersion interactions were accounted for with Grimme’s DFT-D3 approach 62 .

The geometries of the [4[2 + 3] + 6]cage were then fully optimized by means of the hybrid M06-2X functional in Gaussian16 (ref. 63 ). The def2-SVP basis set 64 , 65 was applied for all atoms. No symmetry or geometry constraint was imposed during optimizations. The optimized geometries were verified as local minima on the potential energy surface by frequency computations at the same theoretical level 63 .

Synthesis of [4[2+3]+6]cage

To synthesize [4[2 + 3] + 6]cage , DIPEA (61 µl, 0.35 mmol) was dissolved in acetone (25 ml) and purged with N 2 for 10 min. To the acetone solution, a mixture of Cage-3-Cl (58.7 mg, 0.1 mmol) and TFHQ (27.3 mg, 0.15 mmol) in acetone (6 ml) was added dropwise over 3 h under a N 2 atmosphere. After the addition was complete, the reaction was stirred at room temperature for 36 h. The solvent was then removed by rotary evaporation, and the crude product was purified by column chromatography using acetone/CH 2 Cl 2 (10% vol/vol acetone) as eluent to afford [4[2 + 3] + 6]cage as a white solid in 53% isolated yield: 40 mg (0.013 mmol). 1 H NMR (400 MHz, acetone- d 6 ): δ (ppm) 7.09 (s, 12H, H b ), 6.85 (s, 12H, H a ); 19 F NMR (376 MHz, acetone- d 6 ): δ (ppm) −155.62; 13 C NMR (100 MHz, dioxane- d 8 ): δ (ppm) 174.5, 173.5, 173.1, 153.2, 152.8, 142.5, 140.1, 140.0, 128.3, 115.2, 114.8. MALDI-TOF [M + H] + , [C 120 H 24 F 24 N 36 O 36  + H] + : calculated, 3002.0871; found, 3002.0756.

CSP involves the following general steps: (1) molecular geometry optimization; (2) trial crystal structure generation; (3) local lattice energy minimization of trial structures; and (4) duplicate removal.

The geometry of the molecular cage was optimized at the B3LYP/6-311 G(d,p) level using Gaussian09 software 66 , and the resulting geometry was kept fixed throughout the subsequent steps. Trial crystal structures are generated using the Global Lattice Energy Explorer (GLEE) code 51 . Subsequently, these trial structures undergo lattice optimization while preserving the rigidity of the molecular cage. For this task, we employ an empirically parameterized intermolecular atom–atom exp-6 potential coupled with atomic multipole electrostatics. The force-field parameters are acquired from the FIT force field 67 , 68 . Atom-centred multipoles up to hexadecapole on each atom were derived from the electron density through DMA, and partial charges (used in early stages of optimization) were fitted to the molecular electrostatic potential generated by these multipoles 69 , 70 . The overall model is denoted as FIT + DMA.

The search for space groups involves sampling the ten most common space groups for organic crystals along with four trigonal space groups (143, 144, 145 and 146), each with one molecule in the asymmetric unit. A quasi-random method is used to search these selected space groups separately, and valid structures are lattice energy minimized using DMACRYS software 52 in a two-stage protocol. The first stage involves FIT + DMA with partial charges, followed by the second stage with multipole electrostatics. More details can be found in Supplementary Information .

Data availability

The authors declare that the data supporting the findings of this study are available within the paper, its Supplementary Information files, and the Cambridge Crystallographic Data Centre (deposition numbers 2303319 for [4[2 + 3] + 6]cage and 2326368 for [4[2 + 3] + 6]cage·acetone ). The crystal structures and structure factor data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif . The CSP data are available at the University of Southampton Institutional Research Repository at https://doi.org/10.5258/SOTON/D2929 (ref. 71 ).

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Acknowledgements

A.I.C. thanks the Royal Society for a Research Professorship (RSRP\S2\232003). C.Z. acknowledges the China Scholarship Council for financial support (202106745008). R.H. acknowledges the Iridis 5 High Performance Computing facility, and associated support services at the University of Southampton. Via our membership of the UK’s HEC Materials Chemistry Consortium, which is funded by the Engineering and Physical Sciences Research Council (EPSRC) (EP/R029431 and EP/X035859), this work used the Archer2 HPC facility. We acknowledge A. Hunter for performing the MALDI-TOF analysis at the National Mass Spectrometry Facility (NMSF) at Swansea University, and Diamond Light Source for access to beamlines I19 (CY30461). We received funding from the EPSRC (EP/V026887/1) and the Leverhulme Trust via the Leverhulme Research Centre for Functional Materials Design. This project has received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation programme (grant CoMMaD number 758370).

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Materials Innovation Factory and Department of Chemistry, University of Liverpool, Liverpool, UK

Qiang Zhu, Hang Qu, Chengxi Zhao & Andrew I. Cooper

Leverhulme Research Centre for Functional Materials Design, University of Liverpool, Liverpool, UK

Qiang Zhu & Andrew I. Cooper

Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London, UK

Gokay Avci & Kim E. Jelfs

Computational Systems Chemistry, School of Chemistry, University of Southampton, Southampton, UK

Roohollah Hafizi & Graeme M. Day

Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering East China University of Science and Technology, Shanghai, China

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Q.Z. led the experimental work and the synthesis and characterization of the materials. A.I.C., K.E.J. and M.A.L. conceived the idea and modelling strategy with Q.Z. and supervised the project. H.Q. and M.A.L. conducted the single-crystal X-ray diffraction analysis and solved the structure. G.A., K.E.J. and C.Z. performed the molecular simulations. R.H. and G.M.D. performed the CSP, and G.M.D. supervised this part of the project. Q.Z., G.A., R.H., G.M.D., K.E.J., M.A.L. and A.I.C. analysed the data and prepared the paper. All authors discussed the results and contributed to the paper.

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Nature Synthesis thanks Chenfeng Ke, Bernhard Schmidt and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alison Stoddart, in collaboration with the Nature Synthesis team.

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Supplementary information.

Supplementary Figs. 1–9, Tables 1–8, Scheme 1, synthetic procedures and methods, molecular simulation, NMR, MALDI-TOF, powder X-ray diffraction, single-crystal X-ray diffraction, crystal structure prediction and gas sorption analysis.

Supplementary Data 1

Simulated structures of [2[2 + 3] + 3]cage.xyz, 4[2 + 3] + 6]cage.xyz, [8[2 + 3] + 12]cage.xyz, [8[2 + 3] + 12]cage_1.xyz, [8[2 + 3] + 12]cage_2.xyz, and [8[2 + 3] + 12]cage_3.xyz.

Supplementary Data 2

X-ray crystallographic data of [4[2 + 3] + 6]cage, CCDC 2303319.

Supplementary Data 3

Crystallographic data of [4[2 + 3] + 6]cage·acetone, CCDC 2326368.

Supplementary Video 1

Video showing the single crystal structure of [4[2 + 3] + 6]cage.

Supplementary Data 4

Tabulated source data used to prepare Supplementary Figs. 1–2, 8, 13, 14, 26–34 and 39.

Supplementary Data 5

Raw NMR spectroscopy data used to prepare Supplementary Figs. 5, 7 and 38.

Source Data Fig. 3

Raw NMR spectroscopy data and MALDI-TOF data.

Source Data Fig. 7

Source data for carbon dioxide gas sorption isotherms recorded at 273 and 298 K in Fig. 7.

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Zhu, Q., Qu, H., Avci, G. et al. Computationally guided synthesis of a hierarchical [4[2+3]+6] porous organic ‘cage of cages’. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00531-7

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Machine learning enhanced high-level synthesis research wins best paper at Quality Electronic Design conference

May 1, 2024 | Boston University , News

“AutoAnnotate: Reinforcement-learning-based code annotation for high-level synthesis,” a paper resulting from a project at the Red Hat Collaboratory at Boston University, was selected as one of four Best Papers at the 25th International Symposium on Quality Electronic Design (ISQED’24). ISQED is a widely recognized and established conference in the field of electronic design, with submissions from prestigious organizations across academia, industry, and government. Receiving a Best Paper award means that “Autoannotate” was ranked in the top 2% of all papers submitted. The authors are Hafsah Shahzad and Martin Herbordt of Boston University and Ulrich Drepper, Sanjay Arora, and Ahmed Sanaullah of Red Hat Research. 

The paper represents an important milestone in the research project “Practical programming of FPGAs with open source tools.” The tooling being researched as part of the project aims to substantially improve developer productivity by leveraging machine learning, which in turn reduces the effort required to generate high-quality software and hardware for our target compute platforms.

Specifically, the goal of the project is to build practical and extensible frameworks that leverage machine learning techniques, such as reinforcement learning and graph neural networks, to automatically improve the quality of binaries generated by FPGA and CPU compilers. This includes, but is not limited to, compiler pass reordering, compiler flag tuning, and code annotation. Through these approaches, the project aims to significantly improve generated binary size, performance and other metrics for output quality, without requiring developers to manually modify the source code and/or compiler.  

About AutoAnnotate and high-level synthesis

High-level synthesis (HLS) is a process through which applications written in software programming languages can be compiled down to functionally equivalent hardware designs. However, the resulting automatic hardware designs may not be of high quality, because the nuances of hardware design are abstracted by the software programming language. 

Code annotations are a simple yet powerful solution to this problem, because they can guide the HLS compiler to more effectively optimize the code. The challenge with code annotations, however, is that the possible design space is huge. Knowing which annotations to apply and where to apply them requires a high level of expertise, and the list of annotations and their effects can change even for different versions of the same compiler. The consequence of improperly applied annotations is a reduction in output quality, incorrect functionality, or even a failure to compile. 

AutoAnnotate presents an extensible framework for automatically applying annotations to HLS codes using reinforcement learning. It supports multiple compilers, each with its own sets of annotations, and automatically validates output hardware to ensure functional correctness. Through the use of machine learning for design space exploration, AutoAnnotate can effectively discover annotations that improve user-defined metrics of hardware quality. And if something changes, we can easily retrain the model. Results across a number of benchmarks, detailed in the paper, demonstrated orders of magnitude improvements in performance over unannotated code. The paper also demonstrated the value of combining code annotations with effectively structured input code. 

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