Synthesis of hexaphenolbenzene from the multi-step preparation of 1,2 diphenylacetylene and tetraphenyl cyclopentadeinenone combined in a fi-nal Diels-Alder reaction.AUTHOR ADDRESS: Daniel GonzalezUniversity of Texas At Dallas 800 West Campbell Road Richardson 75080-3021

Under guidance of Dr. Ronald Smaldone ,Department of Chemistry, The University of Texas at Dallas

ABSTRACT: Hexaphenylbenzene was pre-pared through a multi-step synthesis utilizing the Diels-Alder addition of tetraphenylcy-clopentadeinenon with 1,2 diphenylacety-lene resulting in a %9.43 yield. Aldol conden-sation under basic conditions was used to synthesize the reagent tetraphenylcyclopen-tadeinenone from benzyl and diphenylketone with a %52 yield. 1,2 Diphenylbenzene was synthesized using a copper free Sonagashira coupling reaction of iodobenzene and benzy-lacetylene producing a yield of %25. All prod-ucts were analyzed using spectroscopic methods such as FTIR, single pulse HNMR and CNMR experiments, and intermediate products were purified via silica gel column chromatography or recrystallization meth-ods.

INTRODUCTION:Hexaphenolbenzene despite it’s relatively simple structure and symmetry has proved quite difficult for researchers to synthesize by electrophilic aromatic substitution and was rather first achieved by a Diels-Alder Re-action. Hexaphenolbenzene’s large conju-gated symmetry makes this molecule ideal as a building block to synthesizing even larger more complex structures specifically of interest in biological interactions. One ex-ample of such structures are glycoden-drimers[1] which are essentially star shaped chains of polysaccharides connected in the center by a hexaphenylbenzene molecule. Glycodendrimers then become valuable, as

they mimic the composition of biofilms se-creted by bacteria. Studying these artificial biofilms further may lead to promising dis-coveries in tissue matrices that can be modi-fied to have antibacterial properties.With such implications in mind, a three step synthesis of hexaphenolbenzene was con-ducted by first synthesizing tetraphenylcyl-copentadeinenone through a double aldol condensation, and 1,2-diphenolacetylene through a copper free palladium catalyzed Sonagashira coupled reaction. The two prod-ucts were then combined in a Deils-Alder re-action to yield hexaphenolbenzene.

Scheme 1.

Scheme 1 depicts the synthesis of tetraphenylcyclopentadienone. This is an ex-ample of an aldol condensation which is de-pendent on the hydroxide from KOH ab-stracting a proton from the vicinal carbon to the carbonyl on diphenylketone, to produce a resonance structure capable of nucleophilic back side attack of the carbonyl of benzyl. This attack happens twice resulting in the five membered cyclic ring of thetraphylcy-clopentadeinone[6].

Scheme 2.

Scheme 2 depicts the Sonagashira coupled reaction of Ethynylbenzene with iodoben-zene in the presence of a strong base and catalyzed by PdCl2.[5]

Figure 1. Sonagashira Coupling[2]

Figure 1 depicts the mechanism for Son-agashira Coupling. First the iodobenzene forms an activated complex with the Palla-dium catalyst allowing it to perform a trans-metalation reaction with ethynyl benzene. This complex then undergoes reductive elim-ination to form the product 1,2 dipheno-lacetylene. The presence of a strong base such as pyrrolidine in this case is to abstract the proton from benzylacetylene. A copper free reaction scheme was performed.

Scheme 3.

Scheme 3 depicts the Deils-Alder reaction between tetraphenolcyclopentadeinenone and 1,2-diphenolacetylene to produce hexaphenylbenzene[7]. CO is also released as a byproduct of the reaction from the bridge formed by the ketone of tetraphenolcy-clopentadeinenone essentially making this reaction irreversible.

METHODS:All methods were carried out under the guid-ance of Dr. Robert Smaldone in Berkner Hall’s teaching laboratory at The University of Texas at Dallas. All mass measurements were taken using analytical balance 4 and all NMR spectra were collected from a JEOL unit using a single pulse experiment with deuter-ated chloroform as the solvent. IR spectra were obtained using KBr pelleting methods with an FTIR device calibrated to correct for water and CO2.

Figure 2. Reagents List

Synthesis of tetraphenylcyclopentadeinone:

Figure 3. Synthesis Apparatus for Scheme 1

In scheme 1 the apparatus as shown in fig-ure 2 was assembled with one molar equiva-lents of benzyl and diphenylketone added to the round bottom flask. Slowly a solution of .071g KOH in .357ml ethanol was added to the flask and brought to reflux for 15 min-utes. The flask was then removed from heat, allowed to cool to room temperature and subsequently placed in an ice bath for 20 minutes to allow formation of crystals. The product was then isolated with a Hirsch fun-nel system and washed with 95% ethanol. The melting point was then taken by the cap-illary tube method and determined to be 218.6˚C which was within the literature range of 218-220˚C for tetraphenylcyclopen-tadeinone . It was observed that at the beginning of the experiment the reagents benzyl and diphenylketone were yellow and white pow-ders respectively. During the course of the reaction there was a noticeable color shift from yellow, to orange, to brown, and then dark black/ deep purple. When dry the prod-uct resembled a carbon/ soot like texture and appeared jet black in nature. When dissolved in chloroform the sample appeared as a pur-ple red, nearly the color of dilute grape juice.

Figure 4. Beginning color of tetraphenylcy-clopentadeinone

Figure 5. Color Change of tetraphenylcy-clopentadeinone synthesis

Figure 6. Final color of tetraphenylcyclopen-tadeinone

Figure 7. Dry appearance of tetraphenylcy-clopentadeinone

Figure 7 depicts the product tetraphenylcy-clopentadeinone on the left and the wash of ethanol on the right after vacuum filtration using a Hirsch funnel.

Synthesis of 1,2-diphenylacetylene:

Figure 8. Synthesis Apparatus of 1,2-dipeny-lacetylene

In Scheme 2 the apparatus as shown in fig-ure 8 was assembled and molar equivalents (.0024mol) of iodobenzene and ethynylben-zene were added into a clean round bottom flask, along with 18.4mg of PdCl2 catalyst. 12.5ml H2O was used as the solvent system and 4.2 ml of pyrrolidine was placed in the flask. The flask was heated for 2 hours and monitored with a thermometer to be main-tained at 50˚ C. The flask was then left in the bath to cool and a yellow whitish precipitate was observed. The flask was then stored to be separated later. Upon reentry of the lab, the flask was taken and 10ml of ethylacetate was added causing the solution to separate into two distinct layers, a dark brown organic layer and a colorless aqueous layer. The product was extracted from the aqueous layer using a separatory funnel 3 times and added to the organic layer.

Figure 9. use of Separatory funnel to Extract 1,2 diphenylacetylene for the aqueous layer.

The dark organic layer was taken and using a rotovapor, evaporated down to a more con-centrated solution. This solution was then tested using TLC on silica gel plates to deter-mine what resolving solvent system would be ideal before the product was placed in a column.

Figure 10. TLC Reaction Chambers

Figure 10 depicts the set up of 3 TLC reaction chambers using solvent systems of 50, 75,and 100% portion of ethylacetate to hex-ane as a resolving mobile phase. A paper towel was soaked in the solvent to keep the chamber’s atmosphere ideal for a TLC exper-iment and prevent evaporation of the mobile phase off the plate.

Figure 11. TLC Plates

Figure 11. is a diagram of the TLC plates that were spotted with the crude product of the synthesis of 1,2-diphenylacetylene. It was determined that a 75% ethylacetate to hex-ane mobile phase would be ideal to separate 1,2-diphenylacetylene from impurities result-ing from unreacted iodobenzene and ethynyl benzene which will travel slower on a TLC plate and slower on a Silica gel column.

Figure 12. Apparatus of Silica column for pu-rification of 1,2 diphenylacetylene

A silica gel column was prepared with a 75% solution of ethylacetate in hexane as the re-solving solvent. A 100ml burette was packed with glass wool and filled with a slurry of sil-ica gel in solvent. The column was tapped and air was forced through to keep the col-umn tightly packed with no cracking. The

product was loaded in using a glass Pasture pipette and the column was kept running until the first fraction with a red brown ap-pearance was completely collected. The product collected from the column was a dark brown in appearance and was rotova-pored until all that remained was a tar-like brown residue. It was found that evaporating the solvent was exceedingly difficult. In the rotovapor ample ice was required and the device was left running for nearly an hour before all the solvent was evaporated. The solvent was then scraped from the sides of the rotovapor flask and left in a reaction vial to be characterized with IR and NMR.

Figure 13. Isolation of 1,2-Diphenylacetylene after column chromatography

IR and NMR spectra were obtained using the KBr pellet method, and dissolving a very small portion of product in d-chloroform re-spectively.

Synthesis of hexaphenylbenzene:

Figure 14. Apparatus of hexaphenylbenzene Synthesis

In scheme 3, the apparatus in figure 14 was used to synthesize hexaphenylbenzene from 1,2-diphenylacetylene and tetraphenylcy-clopentadeinone in a Deils-Alder reaction. All of both products were added to the flask along with a stir rod and 7ml of diphenylether. The reaction was allowed to progress under 320˚C heat while being stirred for an hour until nearly all of the sol-vent was evaporated. At this point, the flask was removed from heat and allowed to cool at room temperature to form crystals of product. After the flask had cooled to room temperature the flask was placed in a cool water bath to aid in the formation of any ex-tra crystals. The crystals were scraped from the round bottom flask and placed on a Hirsch funnel and washed with hexanes. The product appeared as a maroon solid with vis-ible crystals resembling the color and ap-pearance of a cherry popsicle. After washing with hexanes the crystals were flushed of color and remained as a sparkling pinkish compound. This compound was allowed to dry, massed and was isolated as the final product hexapehnylbenzene.

Figure 15. Final product, Hexaphenylbenzene

The final product appeared as a pinkish sparkling compound

Figure 16. Wash of final Product

The dark maroon color of the hexaphenly-benzene crystals was washed out after the application of hexanes under vacuum suction of a Hirsch funnel.

RESULTS: Table 1. Yields of Synthesis Reactions

Figure 17. IR of Tetraphenylcyclopenta-dienone

Figure 18. HNMR of Tetraphenylcyclopenta-dienone

Hydrogen PeakA 7.3ppmB 7.15ppmC 6.9ppm

Figure 19. IR of 1,2-diphenylacetylene

Figure 20. CNMR of 1,2-diphenylacetylene

Figure 21. HNMR of 1,2-diphenylacetylene

A

B C

Figure 22. IR of Hexaphenolbenzene

Figure 23. HNMR of Hexaphenylbenzene

Figure 24 CNMR of Hexaphenylbenzene

DISCUSSION:Overall the expieriemnt was indeed success-ful with the synthesis of tetraphenylcyl-copentadienone, 1,2 diphenylacetylene, and the combination of the former two in order to synthesize hexaphenylbenzene. The IR spec-tra and NMR spectra of diphenylacetylene and tetraphenylcylcopentadienone matched up nicely for the most part with literature values from online databases[3,4] with the IR spectra visually being inspected and used to reconcile significant structural features or lack thereof. Poor resolution was obtained from the carbon 13 NMR spectrum of diphenylacetylene ,provided courtesy of Vic-toria, most likely due to not remaking the sample at a higher concentration. Although this claim can not be confirmed, it would pro-vide a possible explanation as to why such low intensity peaks were observed at rela-tively well placed values. The HNMR taken of diphenylacetylene does compare nicely to lit-erature values though, with two peaks corre-sponding to two distinct aromatic hydrogens. The final synthesis of hexaphenylbenzene was slightly problematic, as getting the prod-uct to crystalize proved challenging due to the addition of far too much diphenylether (7ml) as opposed to 1ml. Diphenylether hav-ing a relitively high boiling point for organic solvents at 121˚C, proved very difficult to boil off to allow for the tetraphenylcyclopen-tadienone and dipehnylacetylene to react

with each other in solution. Due to this mis-take the reaction time took significantly longer than expected and poor yield was ob-tained with only %9.43 of the theoretical mass able to be recovered. Despite this, re-crystallizing the product, which initially fell through the Hirsch funnel the first time (con-tributing to lost yield), allowed for a rela-tively pure sample as can be seen in the IR and HNMR spectras obtained for hexaphenyl-benzene. The carbon 13 NMR of hexaphenyl-benzene is unusual though as only 3 peaks were observed rather than 5 for each unique carbon environment. Despite this, the C13 spectra most likely had issues due to the fact that the hexapehnylbenzene was not able to properly dissolve in solution resulting in a slightly colloidal appearing NMR tube sam-ple, rather than a translucent pink. Despite best efforts including heating in deuterated chloroform, the C NMR sample was not able to be dissolved sufficiently and resulted in problems when trying to shim the sample in the NMR magnet. Interestingly enough this issue was not encountered when trying to prepare the HNM sample of hexphenylben-zene, most likely due to a smaller concentra-tion of product attempted to be (and suc-cessfully) dissolved in deuterated chloro-form. The C13 NMR of hexaphenylbenzene would have been re-attempted, however due to very low yields of product initially, there was not sufficient product to prepare a sec-ond sample. In order to improve the overall yield of hexaphenyl benzene form this experiment I would recommend several modifications, such as using a higher quality column sys-tem such as an HPLC to reduce lost yield of diphenylacetylene in the purification process. In addition to this, I would recom-mend using newer Hirsch funnel gaskets that will form a better vacuum seals with the wet filter paper to avoid losing yield through the filtration system. Upon performing this ex-periment again given the same materials and equipment, I would be far more diligent with the amount of diphenylehter added in the final synthesis step of hexaphenylben-zene. It can be determined with a fair degree on confidence that by placing too much sol-vent in the system, yield was dramatically decreased as the molecules would have trou-ble finding each other in solution to react and in essence would simply not form prod-uct. Aside from these notes and considera-

tions though, the experiment overall was still successful and the multistep synthesis of hexapehnylbenzene was accomplished and spectroscopically confirmed through HNMR and verified by FTIR.

REFFERENCES:

(1) Chabre, M Yoann, Hexaphenylbenzene as a Rigid Template for the Straightforward Syn-theses of “Star-Shaped” Glycodendrimers, J. Org. Chem.[online] 2011, 76, 724–727 http://pubs.acs.org/doi/pdf/10.1021/jo102215y

(2) Goryochemical: Sonagashira coupling http://goryochemical.com/english/wp-con-tent/uploads/2012/11/sonogashira_cou-pling02.gif (accessed 4/3/16)

(3) Chemicalbook.com: diphenylacetylene/chemical properties. http://www.chemical-book.com/SpectrumEN_501-65-5_1HNM-R.htm (accessed 4/4/16)

4)Molbase.com:en/nmr/hexapehnylbenzene http://www.molbase.com/en/search.html?search_type=text&search_keyword=hexaphenylbenzene (accessed 4/4/16)

(5) Liang, Bo Copper-Free Sonogashira Cou-pling Reaction with PdCl2 in Water under Aerobic Conditions J. Org. Chem. 2005, 70, 391-393

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7) Fieser, Mechanism of Hexaphenylbenzene Synthesis from Diels-Alder Reaction; L.F. In Org Synth, Coll. Vol. 5; Baumgarten, H.E., Ed.; Wiley: New York, 1973; p. 604.