(Hetero)Adamantane Synthesis: A Triple Alkylation Reaction

Abstract

(Hetero)­adamantanes containing tetrel bridgeheads (C, Si, and Ge) are useful structures in select areas of surface and materials science. The synthesis of diverse (hetero)­adamantane-based molecules with interchangeable functional groups for broad applications is an area ripe for innovation. The discovery of an expedient and convergent method for the synthesis of (heteroadamantane) scaffolds is described. The convenient synthetic route proceeding via a triple alkylation reaction represents a breakthrough in accessing the adamantane molecular class. Application of this transformation to the synthesis of (hetero)­adamantane-based tripods containing tetrel bridgeheads (C- and Ge-) was explored.

Adamantane and the related diamondoids have inspired the synthetic endeavors of chemists owing to their high stability and material properties. Improved synthetic methods (Figure A) allowed for the synthesis and isolation of adamantane over its extraction from crude oil with less than 0.0004% efficiency. , The synthesis of useful adamantane-based drugs, ligands, and optical materials was enabled by either tetrasubstitution (1,3,5,7-functionalized) or monosubstitution of the adamantane core, followed by linear synthetic routes that often include harsh conditions. ,, Adamantanes with two substituted bridgeheads have also been widely explored. Asymmetric adamantanes with one bridgehead moiety differing from the other three bridgehead positions, known as (3 + 1)-scaffolds, have been crucial in molecular recognition studies and chemisorption to surfaces and interfaces. Thiol-footed diamondoid tripods have been used for ordered hexagonal self-assembled monolayers (SAMs) on Au(111) surfaces (Figure B). In materials science, the nonlinear optical properties imbued by heteroadamantanes have been utilized for the development of cluster-glass. Advances in the synthesis of Si–Ge heteroadamantanes , led to their use in scanning tunneling microscopy break-junction (STM-BJ) experiments, where Si₈Ge₂ adamantane wires increased single-molecule conductance by 60% as compared to Si₁₀ adamantane wires; representing groundbreaking applications of Ge-doped silaadamantanes in quantum transport measurements. ,

1.

Synthetic routes to (hetero)­adamantanes. Schleyer’s adamantane synthesis (A). Selected (hetero)­diamondoid scaffolds pertinent to surface and materials science (B). Synthetic route to heteroadamantanes containing bridgehead tetrels (M = Si, Ge) (C). Retrosynthetic analysis of the direct, yet unconventional, disconnection strategy enabling the triple alkylation reaction (D). Optimization (E); yield (NMR: mesitylene internal standard), yield of isolated product in brackets (0.5–1.0 mmol scale of 1a). ^a–78 °C−Δ, TBAI (1 equiv). ^bΔ, o/n. ^c 3aa′-I (22% yield, 10% yield w/tBuLi; See Supporting Information). EWG, electron-withdrawing group; LiTMP, lithium 2,2,6,6-tetramethylpiperidide; BuLi, butyllithium; DIPA, N,N-diisopropylamine; HMDS, hexamethyldisilazane; TMEDA, N,N,N′,N′-tetramethylethylenediamine; THF, tetrahydrofuran; TBAI, n-tetrabutylammonium iodide.

The synthesis of heteroadamantanes was expanded to include Si- and Ge-bridgeheads by Boudjouk and colleagues with their description of the synthesis of 1-methyl-1-silaadamantane and 1-methyl-1-germaadamantane (Figure C). , The rare heterodiamondoids require multistep syntheses containing some harsh and low yielding steps, laborious purification, and low atom efficiency with respect to Si and Ge for the AlCl₃-mediated rearrangement reaction. In our hands, using traditional methods for bridgehead substitution of adamantane (3 + 1)-scaffolds was not amenable to 1-methyl-1-germaadamantane bridgehead functionalization. ,, In the context of synthesis, methods that enable access to asymmetric (hetero)­adamantanes containing C-, Si-, and Ge-bridgeheads represent a breakthrough in the synthesis of this key molecular class (Figure D). Herein, the discovery of a triple alkylation reaction that enables the expedient synthesis of asymmetric (hetero)­adamantanes is reported. Utilizing the rich chemistry of adamantane functional group modification, applications of selected (hetero)­diamondoids to the synthesis of tripod motifs are described (Figure D).

Results and Discussion

Reaction Design

The crucial nucleophiles and electrophiles required for the transformation proposed in Figure D are readily accessible from commercially available starting materials (See Supporting Information for details) and enable the synthesis of (hetero)­adamantane (3 + 1)-scaffolds. Convincing synthetic precedence of the viability of a triple enolate intermediate generated from trimethyl cis,cis-cyclohexane-1,3,5-tricarboxylate (1a; EWG = CO₂Me, Figure E) hinted at the possibility of a path to adamantane cores with appropriate reagent selection. ,

We anticipated potential complications when designing the synthetic pathway highlighted in Figure D. First, the desired electrophiles are sterically encumbered and will be subject to the neopentyl effect, making them resistant to nucleophilic substitution. , Second, the alkylation step could pose similar concerns with steric parameters toward generating quaternary carbon-centers. Third, the nucleophilic component, upon deprotonation to the proposed triple enolate, could suffer from solubility issues. Fourth, these intermediates could be subject to degradation through intermolecular self-reaction. Finally, we suspected that the proposed reaction may require forcing conditions (elevated temperature) to favor the formation of the adamantane cage starting from relatively unreactive starting materials.

To our delight, the trialkylation approach to adamantane cage formation proved to be fruitful under relatively mild conditions, where the desired product 3aa was formed even at room temperature (Figure E). The optimized conditions for the triple alkylation reaction were established by varying the base (entries 1–5; DIPA, TMP, HMDS), BuLi and additive (entries 6–8; nBuLi, tBuLi, and TMEDA), and nature of the electrophilic leaving group (entries 9–11; 2a-X; X = Cl, Br, I, OTs). Thus, the optimal conditions for the transformation were treatment of nucleophile 1a (1.0 equiv) in THF with LiTMP (3.3 equiv) in the presence of TMEDA (15 equiv) from −78 °C-to-room temperature, followed by addition of electrophile 2a (pentaerythrityl tetrabromide; 1.1 equiv) and subsequent stirring (room temperature or at reflux), providing 3aa in up to 45% yield (Figure E; See Supporting Information: Tables S1–S3 and S8). Upon triple deprotonation with LiTMP and formation of the proposed triple enolate intermediate (supported by a D₂O quenching experiment, vide infra), the reaction formed a thick slurry/gel consistency. The addition of TMEDA broke the gel up into a stirrable precipitation. Although the ratio of Li-aggregation in solution with respect to the triple enolate was not determined, the addition of TMEDA appears to break up higher-order oligomers (tetramers, octamers, etc.) to lower-order aggregates (for example, consisting of monomers and dimers). −

Pentaerythrityl tetrabromide 2a-Br was found to be the only compatible pentaerythrityl-based electrophile derivative during optimization (Figure E; Table S4). 2a-I (pentaerythrityl tetraiodide) underwent complex degradation, whereas 2a-Cl (pentaerythrityl tetrachloride) was unreactive and 2a-OTS (pentaerythrityl tetratosylate) was insoluble. The observed reactivity trends are supported by rate studies of neopentyl tri­(pseudo)­halides in prior art. , This transformation was also successful using LDA in place of LiTMP, however, we favored LiTMP to minimize any possibility for side-product formation through substitution reactions. The addition of n-tetrabutylammonium iodide (TBAI) was found to provide modest increases in yield by decreasing residual cis,trans-cyclohexane-1,3,5-tricarboxylate 1a′ and simplifying the isolation of desired product (Figure E, entry 8; Table S8). In such cases, the iodine congener of 3aa was not observed, indicating that no substitution of the bromine functional group of 3aa (45% yield; entry 8) by iodide occurred under these conditions. It is proposed that TBAI may act as a phase-transfer reagent (solid-to-liquid) with respect to further breaking up/solubilizing the precipitous Li-aggregates/enolates. Quenching of the proposed triple enolate intermediate with D₂O provided d ₃ -1a′ in 74% yield (d ₃ -1a’:d ₃ -1a 75:25; 92% D-incorporation for d ₃ -1a′ and 95% D-incorporation for d ₃ -1a). The deuterium isotope labeling experiment (Figure S1), taken in conjunction with other triple enolate quenching studies (Tables S5–S7), confirmed two aspects of this transformation: 1) formation of the triple enolate intermediate results in full deprotonation (giving 1a’:1a 75:25 upon reprotonation), and 2) 74% yield reflects the upper bounds of conversion to desired product in the described method. A sample of 1a′ was subjected to the optimized reaction conditions and provided 3aa in 20% yield, Figure S2.

Substrate Scope

With establishment of the optimized conditions through the synthesis of 3aa, a variety of electrophiles were investigated to evaluate the scope of the transformation, Figure A,B. Applying tribromo-based electrophiles (2b–g) to this reaction provided information regarding the tolerance toward steric and electronic parameters with respect to the functional group remaining on the asymmetric bridgehead of the desired products (Figure A; 3ab–3ag). Methyl substitution (2b), sterically the smallest group studied, resulted in low yields (12% yield for 3ab). A comprehensive approach to evaluating alkyl steric profiles was attempted with the synthesis of ethyl, isopropyl, and tert-butyl congeners of 2b, however, the final step of their syntheses resulted in significant degradation to intractable mixtures due to possible skeletal rearrangements (Figure S4). , CH₂OTBS-containing 2c yielded 3ac in 9% yield, whereas larger phenyl-substituted 2d gave 3ad in 17% yield while giving 52% of 2d that had not undergone subsequent iodide substitution in the presence of TBAI. Electrophiles 2e–g provided an opportunity to assess long-range electronic effects while imposing larger steric properties. With modification of the 4-position, electron-withdrawing (4-CF₃, 4-Cl, and 4-Br; 2e–g), gave the desired products 3ae, 3af, and 3ag in 18% (23% conversion), 23%, and 30% yields, respectively. Unfortunately, relatively electron-donating S9 (4-OMe) gave the desired product in low yield <10%, among other side-products (See Figure S5 for unsuccessful substrates). Carbon-centered electrophiles with larger aryl substituted R-groups, had a small beneficial effect on the transformation yields. These results suggest that the low conversion to desired product was due to triple enolate decomposition occurring more readily than addition to the carbon-centered electrophile (X = Br), as the electrophiles could be largely recovered without degradation. The orientation of the alkylation process (stepwise or concerted, Figure D, A vs B) may be crucial to obtaining the desired product with respect to the tribromo-based electrophiles.

2.

Scope investigation. Yield; See Supporting Information for details. (Hetero)­diamondoid substrate scope related to carbon-centered electrophiles (A), Ge- and Si-based electrophiles (B), and various nucleophiles (C). ^aTBAI (1.0 equiv); bracketed = conversion to desired product. ^b0.9 g (3.5 mmol) scale of 1a. ^c1.0 g (4.0 mmol) scale of 1a. ^d3.7 g (14.3 mmol) scale of 1a. ^e5.6 g (18.5 mmol) scale of 1b.

Notably, if the R-group of the electrophile is small, we posit that the barrier for the transformation to proceed through a deleterious double alkylation pathway (Figure D; R-group over the ring: 3′) is lower, leading to lower yields of the desired product. The proposed side-product 3′ (as shown in Figure ) was not observed under optimized conditions and may be subject to oligomerization pathways, where the desired product may be inert to this type of decomposition due to proximity to the adamantane core. Aryl R-groups that were significantly larger than CH₂Br that may also have benefited from stabilizing interactions with ester/enolate groups performed slightly better than when R = Me (alkyl) in this study.

The method was further extended to Ge- and Si-containing electrophiles (Figure B). Tris­(iodomethyl)-electrophiles containing (phenyl)­germane (2h) and (phenyl)­silane (2k) groups led to the desired phenylgerma- and phenylsilaadamantane products 3ah and 3ak in 70% yield (89% per alkylation) and 33% yield, respectively. While the upper bounds of the conversion of this transformation remain the same, the use of more reactive triiodo-based electrophiles that are less sterically encumbered at the MCH₂–X bond (longer Ge–CH₂ and Si–CH₂ bond lengths vs C–CH₂ bond lengths in tribromo electrophiles) increased the efficiency of this transformation. We also postulate that the increased electronegativity of the carbon-centered electrophiles in comparison to the Ge- and Si-centered electrophiles result in facile electron transfer processes with the triple enolate intermediate when using pentaerythrityl tetraiodide (2a–I; See Supporting Information). , Tetrakis­(iodomethyl)­germane (2j) gave 3aj in 19% yield with little recovery of the electrophile, indicating that iodine containing products may be susceptible to further degradation pathways under the reaction conditions.

Lastly, the scope of the nucleophile for this transformation was evaluated, Figure C. The ethyl ester containing 1b provided 3bh in 52% yield when reacted with 2h, and 3bi in 31% yield when reacted with tetrakis­(chloromethyl)­germane (2i). This was notable since carbon-centered 2a-Cl was inert to reaction with 1a. The nitrile containing 1c furnished 3ca in 16% yield upon treatment with 2a and 3ch in 39% yield upon reaction with 2h; a useful alternative to known preparations of nitrile-functionalized adamantanes. Unfortunately, initial attempts using dimethyl piperidine-3,5-dicarboxylate (1d) when treated with 2h and tris­(chloromethyl)­phosphine oxide (2l) when treated with 1a did not furnish the desired products, which would have provided expedient routes to aza- and phosphaadamantane cores (Figure S5). Products 3ag, 3ah, and 3bi were amenable to reaction on larger scales (3.5–18.5 mmol).

Application to the Synthesis of Tripods

For decades, interests in studying surface-bound (chemisorbed) molecules with increased levels of saturation (> sp ³ , < sp ²) have grown. As the parameters to the surface reaction and characterization of chemisorbed molecules are fundamentally different to those used in routine synthetic organic chemistry, the following selection criteria simplify the development of 3D (saturated) structures for molecule–surface combinations: 1) high molecular symmetry; 2) functional groups that undergo covalent attachment to the surface; 3) relatively flexible attachment points (legs) with a rigid core structure; 4) matching the substrate to the lattice to minimize possible surface geometries and binding configurations; 5) the ability to characterize possible surface-bound structures; and 6) the ability to further derivatize surface-bound molecules in situ (light, heat, field, etc.). In pursuit of this mission, tripod-based molecules bearing alcohol legs and an adamantane core satisfy criteria 1–4, and the inclusion of iodine-based functional groups satisfy criteria 5 and 6, when applied to silicon-based surfaces (for example, Si(100)-2 × 1), presenting chemically reactive feedstocks normal to the surface. The design of a general adamantane synthesis blueprint via the triple alkylation reaction has revolutionized our ability to synthesize diverse germaadamantane tripod (3 + 1)-scaffolds, Figure .

3.

Synthetic diversification of (germa)­adamantanes for the synthesis of selected tripods (A–E). See Supporting Information for the specific reaction conditions used for each step.

Examples of molecular targets containing the desired alcohol-based legs, (germa)­adamantane cores, and various functional groups (including carbon–iodine functionality) are illustrated vide infra, however, one can imagine the boundless opportunities for molecular design using this architecture. Figure A shows the transformation of compound 3ag to compound 8 in high yields using synthetic methods standard to synthetic organic chemistry (See Supporting Information). Specifically, triester 3ag was converted to triol 4 (DIBAL reduction), triol protection to 5 (TBS–Cl), alkynylation to 6 using Sonogashira coupling conditions, followed by hypervalent iodine mediated alkyne dehydroiodination (7), and subsequent deprotection of the OTBS groups using pyridinium p-toluenesulfonate (PPTS), furnishing iodophenethynyl-functionalized triol 8. Notably, all steps were high yielding in this route.

The utility of the heteroadamantane synthesis strategy was demonstrated with the rapid construction of phenyl-germaadamantane triester 3ah (Figure B–D); asymmetric germaadamantane cores that are difficult to access through simplified synthetic routes. 3ah was converted to the desired 13 (germa-substituted iodoethynyl congener of 8) through a high yielding route including reduction (DIBAL) of the triester to triol 9, protection (TBS–Cl) of the triol to 10, followed by an in situ 3-step sequence (chlorodearylation (I–Cl), alkynylation of the intermediate Ge–Cl (Li–C≡C–TMS), and removal of the TMS-group (K₂CO₃/MeOH)) providing alkyne-functionalized 11 (for OTBS deprotection conditions to 11’; See Supporting Information), Figure B. Iodoethynyl-functionalized germaadamantane 13 was obtained using a similar iodination-deprotection strategy. A route to the triethanol functionalized congener 19 of 13 (trimethanol) was made possible through employment of triol 9 in a strategy including oxidation to the trialdehyde (DMP) and subsequent Wittig-olefination to trivinyl 14, where hydroboration-oxidation (9-BBN/NaBO₃) provided triethanol-substituted phenyl-functionalized germaadamantane 15, Figure C. The triethanol containing iodoethynyl-functionalized germaadamantane 19 was obtained in high yield through similar transformations described for the conversion of 9 to 13. Interestingly, a 2-step-1-pot sequence provided germaadamantane 20 from 3ah (I–Cl chlorodearylation/DIBAL reduction; a 7-fold reduction), Figure D. Finally, 22 was obtained in good yield through triester reduction of 3bi (DIBAL) and subsequent Finkelstein substitution (NaI), Figure E. The synonymous nucleophilic exchange of 4aa (bromomethyl adamantane; See Figure S3 for synthetic details) was unsuccessful due to the steric environment in close proximity to the adamantane core, highlighting the synthetic utility of the chloromethyl-substituted germaadamantane core that is less sterically encumbered due to the longer C–Ge bonds in comparison to C–C bonds.

Heteroadamantane Tripods in Mechanosynthesis

Beyond the broader applicability of the reported synthetic improvements to such areas as surface science, biology, and new materials development, the design and synthesis of tripodal molecules has been performed here to study functional structures, or molecular tools, in tandem with inverted-mode scanning tunneling microscopy (IM-STM), a recent development in SPM where molecular tools can act dually as probe apex imagers and for performing chemical reactions (Figure ). , The described synthetic developments have facilitated the exploration of SPM-mediated mechanosynthesis on silicon surfaces based on IM-STM, a potential first step in realizing one of the foundational pursuits in the field that became nanotechnology. , Herein, we define SPM-mediated mechanosynthesis as chemical synthesis using mechanically constrained movements and positioning of reactants with subangstrom precision to control reaction outcomes using SPM techniques; we view SPM-mediated mechanosynthesis as a branch of mechanochemistry, a term that describes the use of force to drive chemical reactions (ball-milling, mechanophores, etc.). Mechanoselectivity, by extension, represents the chemo, regio, or stereoselectivity imparted by mechanically controlled trajectories that direct reactive molecules to specific bonding outcomes using mechanosynthetic techniques such as SPM. To provide additional background context, an initial assessment of molecular tool design led to a set of criteria, vide supra, that yielded molecules capable of binding to silicon surfaces in an orientation that place an additional functional group normal to that surface. The alcohol legged heteroadamantane-based tripods were ideal for this purpose given their rigid 3D framework, small size, established silicon surface functionalization chemistry, and the favorable deposition characteristics of proposed targets for ultrahigh vacuum (UHV) applications. Figure A depicts a hydrogen-atom transfer (HAT) reaction, a subtractive mechanosynthetic event, between 19 (chemisorbed on a Si(100)-2 × 1 surface) and an H-passivated surface (H:Si(100)-2 × 1) that was recently reported from our group. Central to this reactivity was the ability to activate the embedded C–I bond with either light or bias (applied potential) to produce the highly reactive alkynyl radical under IM-STM/UHV conditions (for experimental details). , Upon approach of the reactive intermediate by the H-passivated silicon probe chip (SPC) apex, the HAT reaction proceeded as expected based on the relative bond dissociation enthalpies (BDEs) of the H-functionalized products: Si–H_surf = 77 kcal/mol³³ vs C ≡ C–H = 130 kcal/mol.

4.

Examples of subtractive and additive mechanosynthesis under IM-STM/UHV conditions. HAT between activated 19 (chemisorbed on a Si(100)-2 × 1 surface) and H:Si(100)-2 × 1 SPC apex (A) and possible reaction outcomes between activated 19 (chemisorbed on a Si(100)-2 × 1 surface) and Si(100)-2 × 1 SPC apex including additive (C₂-transfer) and subtractive (Si-atom abstraction) mechanosynthesis (B). ^aBDEs calculated using ωB97X-D/Def2-TZVPP of model compounds 1-ethynyl-1-germaadamantane (model of molecular tool) and 1-ethynyl-1,1,1-trisilylsilane (model of surface-bound acetylene).

While subtractive mechanosynthesis has been demonstrated with hydrogen on silicon (Figure A) and explored with gold computationally, the capability to modify an SPM probe by additive mechanosynthesis in a positionally controlled, atomically precise manner was also reported recently by our group (Figure B; shown on H:Si(100)-2 × 1 for simplicity, vide infra for discussion on Si(100)-2 × 1 surfaces). , Key to any additive mechanosynthetic operation is the transferability of a reactive species, such as an alkynyl radical (C₂-unit), from a delivery platform such as a molecular tool, to a transfer surface. The significance of the functionalized germanium bridgehead as a first synthetic target for exploring additive mechanosynthesis was justified as bridgehead germaadamantanes provide a position for covalent bonding of species that can be employed in chemical transformations with far greater chemical tractability and stability than a comparable tin or lead analogue. While the germanium bridgehead is predicted to be well-suited for carbon transfers onto carbon surfaces because of the large difference in BDEs between C–Ge and C–C bonds, the recent advances in additive mechanosynthesis on silicon surfaces under IM-STM conditions warranted a closer inspection of relative bond strengths. ,

The predicted BDEs for acetylene-functionalized germaadamantanes and acetylene-functionalized silicon surfaces were computed using ωB97X-D/Def2-TZVPP , BDE calculations with Gaussian16 for model compounds such as 1-ethynyl-1-germaadamantane (C ≡ C–Ge) and 1-ethynyl-1,1,1-trisilylsilane (C ≡ C–Si_surf), Figure . The calculations place C ≡ C–Ge at 128.1 kcal/mol (300 K; 124.6 kcal/mol at 4 K) and C ≡ C–Si_surf at 127.6 kcal/mol (300 K; 123.9 kcal/mol at 4 K). In the model compound 1-(1-germaadamantyl)-2-(tris­(silyl)­silyl)­acetylene, the influence of the presence of both ethynyl substituents results in smaller predicted differences: C ≡ C–Ge = 120.0 kcal/mol (300 K; 119.9 kcal/mol at 4 K) and C ≡ C–Si_surf = 117.7 kcal/mol (300 K; 118.5 kcal/mol at 4 K). With small predicted relative enthalpy differences, the varied complexities of performing mechanosynthetic operations under SPM conditions (dopant location, contact potential, and local vacancies or other defects on either surface that might impact the local chemistry) may contribute to the uncertainty in mechanoselectivity for reliable additive (transfer of C₂-units from the germanium bridgehead) or subtractive (silicon-atom abstraction from the Si(100)-2 × 1 surface) mechanosynthesis products. , For additive mechanosynthesis on Si(100)-2 × 1, one could envision the surface-bound alkynyl radical relaxing to various surface configurations through the formation of another C–Si bond (inter-row (depicted in Figure B on H:Si(100)-2 × 1), inter-dimer, or on-dimer–to name a few). For subtractive mechanosynthesis on Si(100)-2 × 1, surface Si-atom abstraction (Si–Si_surf = 50–60 kcal/mol) is complicated by the breaking of three Si–Si_surf bonds and the subsequent stabilizing surface rearrangement (monovacancy liberation barrier = 28–30 kcal/mol) , Recent developments have shown that the target location and approach/retraction trajectory of the SPC affects the mechanoselectivity for C₂-transfer products or silicon-atom abstraction when interacting with activated surface-bound 19. A C-bridgehead congener of 13 imparted complete selectivity for subtractive mechanosynthetic products due to the increased C ≡ C–C bond strength eliminating the possibility for additive C₂-transfer products. The extent to which targeting/trajectory parameters and molecular tool structure can be modulated to impart mechanoselectivity in additive and subtractive processes, and within additive processes (surface configuration of products), is currently under investigation. An initial version of this work was deposited in ChemRxiv.

Conclusions

Collectively, the described compounds represent a diverse suite of tripod-based molecules for applications in surface science. The syntheses of the described (hetero)­adamantane-based tripods were made possible by the discovery of the triple alkylation reaction, presenting a useful alternative to traditional adamantane (3 + 1)-scaffold bridgehead substitution methods. We expect three-dimensional molecules such as the tripods described herein to be foundational in atomically precise fabrication processes (for example: the use of SPM-mediated mechanosynthesis to make materials with atomic precision) on Si(100)-2 × 1 surfaces and the synthesis of such tripods to be enabled by the triple alkylation reaction. ,,,,

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.6c01679.

• Experimental details on the materials, methods (optimization, synthesis of products and starting materials, and characterization data), and NMR spectra are available free of charge via the internet at (PDF)

§.

Cambrex, Charles City, IA, 50616, USA

∥.

Children’s Hospital of Eastern Ontario (CHEO), Ottawa, ON, K1H 8L6, Canada.

⊥.

Health Canada, Ottawa, ON, K1A 0K9, Canada.

#.

Machine Phase Systems, San Jose, CA, 95125, USA.

Conceptualization: TM, M. Mamone, AH, MD Methods and investigation: TM (developed methods for triple alkylation and tripod synthesis), SR (developed methods for electrophile synthesis), MM, HYS, SS, KT, AJH, and MD (developed methods for tripod synthesis and purification), M. Mamone, NZ, and GC (developed methods for triple alkylation and scale-up), DGA (BDE calculations). Visualization: TM Project administration: TM Resources: TM, SR, MM, HYS, SS, KT, M. Mamone, NZ, GC, DGA, AH, MD Supervision: TM Validation: TM, SR, MM, HYS, SS, KT, M. Mamone, NZ, GC, DGA, AH, MD Writingoriginal draft: TM Writingreview and editing: TM, SR, MM, HYS, SS, KT, M. Mamone, NZ, GC, DGA, AH, MD.

The authors declare the following competing financial interest(s): The authors declare that a patent (US11708384B2) has been filed that lists some authors (AH, MD, DGA, TM, M. Mamone, NZ, KT) as inventors, in affiliation with CBN Nano Technologies, Inc. (CBNNT), with respect to the utilization of compounds 19 and 22. CBNNT is a company seeking to commercialize atomically precise 3D manufacturing.