Why no cyclopentyne

The reason for this is that the molecule cannot freely rotate about each bond. This is referred to as ring strain.

The smallest carbon membered ring is cyclopropane which only has three carbons. This molecule has the highest ring strain of all the carbon rings. A five membered ring such as cyclopentyne is not too far from that. You may recall that this geometry assumes a bond angle of degrees. Join live cram sessions. Live student success coach. Numerade Educator. Julie G. Millikin University.

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We report the strategic use of cyclohexyne and the more elusive intermediate, cyclopentyne, as a tool for the synthesis of new heterocyclic compounds. Experimental and computational studies of a 3-substituted cyclohexyne are also described. The study of small rings containing triple bonds has been a topic of vast interest for over years.

Roberts, in , validated the existence of benzyne 1 , 3 which can be used today in a host of synthetic applications.

Despite the relatively limited use of 3 and 4 in synthetic applications for the construction of C—C bonds, we envisioned harnessing these strained intermediates to construct new bicyclic heterocyclic scaffolds. Heterocycles are prevalent in drugs, natural products, and other compounds of tremendous importance.

As suggested in Figure 1 , cycloadditions involving 3 or 4 would provide heterocycles 5 or 6 , respectively. In addition, we sought to prepare a substituted cyclohexyne 7 and probe regioselectivities in both nucleophilic trapping and cycloaddition reactions.

Figure 1. Well-studied cyclic alkynes 1 and 2 , cyclohexyne 3 , and cyclopentyne 4 , and objectives of the present study. To initiate our study, we opted to generate cyclohexyne in situ from the corresponding silyl triflate, 9 Table 1. Silyl triflate 9 was first synthesized in , 9a but has seen limited use, for example, in Diels—Alder reactions and formal C—C bond insertion reactions. Specifically, triazoles and pyrazoles were obtained by the trapping of azide and diazo coupling partners, respectively entries 1—3.

We also explored nitrone and nitrile oxide cycloadditions, which provided isoxazoline- and isoxazole-containing products, respectively entries 5 and 6. Moreover, additional new trapping experiments to forge 6-membered heterocycles from cyclohexyne are provided in the Supporting Information SI. It should be emphasized that in contrast to many common methods for heterocycle synthesis, particularly benzyne trapping, the products obtained from cyclohexyne trapping possess more aliphatic character.

Being able to access compounds possessing significant sp 3 character is an important direction in contemporary drug discovery. Reported yields are the average of two experiments and are based on the amounts of isolated products.

Encouraged by our success in building heterocycles from cyclohexyne, we performed trapping experiments of the less well-studied intermediate, cyclopentyne 4 , using silyl triflate 10 Table 2. Thus, 10 was treated with CsF in acetonitrile in the presence of various trapping agents. Most trapping agents gave only low yields or none of the desired products; however, benzyl azide and sydnone partners could be employed to deliver triazole and pyrazole products, respectively entries 1 and 2.

Additionally, we found that trapping of 4 with a cyclic dimethylurea 19 generated a unique product possessing a [5,7]-fused ring system entry 3. Figure 2 shows the optimized structures of cyclohexyne 3 and cyclopentyne 4 see the SI for computational details. The strain has been calculated to be ca. Figure 2. We also compared 3-methoxybenzyne 11 to its non-aromatic counterpart, 3-methoxycyclohexyne 12 Figure 2. In the case of 11 , as we have previously described, 12a, 12b the inductively withdrawing methoxy group at C3 distorts the aryne significantly.

Nucleophilic trapping occurs at C1, the more linear aryne terminus whose reactive orbital possesses more p character, uniformly with high degrees of regioselectivity. To test our prediction, we prepared benzyloxysilyl triflate 13 , the first C3-substituted cyclohexyne precursor, and performed trapping experiments Figure 3.

Similarly, trapping with benzyl azide gave a 5. Figure 3. Experimental results validate regioselectivity predictions in reactions of 3-substituted cyclohexyne Figure 4 shows the calculated competing transition states, TS1 — TS4 , for the reactions shown in Figure 3. Similarly, in the azide cycloaddition, TS3 is favored over TS4 , although the calculated regioselectivity is overestimated.

It is notable that this trend is observed for both the imidazole and azide trapping agents, despite their different electronic properties. As shown in Scheme 1 , triazole 16 , prepared from the benzylazide cycloaddition of 14 Figure 3 , was converted to azide 18 through an uncommon functionalization of a pseudobenzylic benzyloxy group. Figure 4. Energies are provided in kcal mol —1.

In summary, we have demonstrated that cyclohexyne and the more elusive intermediate, cyclopentyne, serve as effective tools for the synthesis of new heterocyclic compounds.

Detailed experimental and computational procedures, compound characterization, Cartesian coordinates, electronic energies, entropies, enthalpies, Gibbs free energies, and lowest frequencies of the calculated structures. Such files may be downloaded by article for research use if there is a public use license linked to the relevant article, that license may permit other uses.

H , Bristol—Myers Squibb, the S. Li Foundation, the A. Silyl triflate 9 has also been employed in a Pd-catalyzed cyclotrimerization reaction; see ref In the absence of CsF, no reaction occurs, which suggests that a mechanism involving cycloaddition followed by elimination of the silyl triflate is not operative.

No identifiable byproducts were obtained from these reactions; thus, we attribute the loss of mass to substantial nonspecific decomposition. Interestingly, the corresponding trapping experiment involving cyclohexyne precursor 9 in place of 10 failed.

Other stationary points on the potential energy surface of the well-known cyclopentyne to cyclobutylidenecarbene rearrangement were also located. These structures are not relevant for this study, although the moderate yields obtained experimentally suggest competitive processes in which these carbene-like species could be involved. In addition to the minimum energy conformer shown in Figure 2 , we located another half-chair conformer of 12 , which is 0.

See the Supporting Information for details. Methyl azide is used as a model for benzyl azide; 12 is used as a model for View Author Information. Cite this: J.

ACS AuthorChoice. Article Views Altmetric -. Citations Abstract High Resolution Image. Figure 1 Figure 1. High Resolution Image. Table 1. Cycloaddition Reactions of 3 to Construct 5-Membered Heterocycles. Table a Reported yields are the average of two experiments and are based on the amounts of isolated products. Table b Benzene was used as a cosolvent. Table c Et 2 O was used as a cosolvent. Table 2. Trapping Experiments of Cyclopentyne 4. Scheme 1. Elaboration of Benzyloxycyclohexyne 16 to Triazolopyrrole Supporting Information.

Author Information. Neil K. Jose M. Travis C. The authors declare no competing financial interest. Elsevier Science Ltd. A review including structure and reactivity, the generation of arynes, pericyclic reactions of arynes, nucleophilic addns. A review.

Organic Preparations and Procedures, Inc. The review is intended to be update of ortho-benzyne chem. The focus of this review is on the application of arynes in org. American Chemical Society. Since the first aryne-based total synthesis in , there has been a progression from early strategies that monofunctionalize aryne intermediates to approaches that utilize the full potential of the uniquely reactive triple bond to generate 1,2-disubstituted arenes.

The authors summarize recent uses of arynes in various org. This minireview highlights recent advances in the field of aryne and cyclohexyne chem. The syntheses presented rely on the use of these reactive species in chemoselective transformations and follow unprecedented synthetic strategies that are inspiring for the practitioners of synthetic org.

Roberts, John D. No satisfactory explanation has been published for the rearrangements which occur in the amination of nonactivated aryl halides with alkali-metal halides cf. Bunnett and Zahler, C. A crit. If a sym. The study of biomols. Technologies developed in the last few years for the selective modification of biol. Key to these new techniques are bioorthogonal chem.

Herein the authors describe the bioorthogonal chem. Tetrahedron , 1 , — Google Scholar There is no corresponding record for this reference. Tetrahedron , 32 , — Google Scholar There is no corresponding record for this reference.