View metadata, citation and similar papers at core.ac.uk brought to you by CORE This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Article Cite This: ACS Omega 2019, 4, 15197−15207 http://pubs.acs.org/journal/acsodf Utilizing the Azaazulene Scaffolds in the Design of New Organic Superbases Danijela Baric*́ Department of Physical Chemistry, Rud̵er Boskovič ́Institute, Bijenickǎ 54, 10000 Zagreb, Croatia *S Supporting Information ABSTRACT: New neutral organic superbases with 1-azaazulene(s) as a molecular backbone are computationally designed, employing two basic substituents: dimethylaminocyclopropen-imines (CPI) and dimethylami- nocyclopropeniminophosphazenes (CPI-P). Their proton affinities, gas basicities, and pKa values in acetonitrile are obtained using density functional theory. Azaazulenes substituted with CPI have a computed PA in −1 the gas phase ranging between 272.9 and 306.8 kcal mol , with pKa values in acetonitrile between 28.8 and 36 units. The substitution with the CPI-P group resulted in even stronger superbases, with a PA from 296.5 to 335.2 −1 kcal mol and corresponding pKa values from 33.9 to 50 units. This exceptionally strong thermodynamic basicity is accompanied by very high kinetic basicity as well; contrary to typical proton sponges, the release of a proton from the conjugate superbase does not demand high activation energy. Because synthetic routes for both substituents and azaazulenes are already known, newly designed superbases represent suitable targets for synthesis and application. 1. INTRODUCTION the strongest commercially available superbase, phosphazene 7b Neutral organic bases are compounds extensively used as tBu-P4, in tetrahydrofuran is 33.9. Moreover, theoretical investigation of fundamental thermochemistry of neutral catalysts in synthetic organic chemistry, due to their ability to ff initiate a reaction by spontaneous deprotonation of reagents.1 organic superbases and exploration of basicity limits can o er The important advantages of neutral organic bases over their insights needed for the design of new reagents and new ionic inorganic counterparts are much better solubility in chemical reactions in synthetic organic chemistry. organic solvents and milder reaction conditions. Organic Depending on basic functional groups present in a molecule, compounds that are more basic than the proton sponge 1,8- neutral organic (super)bases may be grouped into several classes: amines,1,4 amidines,11 guanidines,12 phosphazenes,13 bis(dimethylamino)naphthalene (DMAN), with a proton 14 7b,15 16 affinity (PA) of 245.3 kcal mol−1 and a gas basicity (GB) of pyridines, phosphines, and cyclopropenimines 239 kcal mol−1, are called superbases.2 From the structural (Scheme 1). A combination of these functionalities enables Downloaded via RUDJER BOSKOVIC INST on October 3, 2019 at 14:03:40 (UTC). fi obtaining even more basic compounds, such as cyclo- point of view, the general de nition of superbases characterizes 17 18 3 propeniminoguanidines, guanidinophosphazenes, and cy- them as bases composed of multiple basic units. A great 17b,19 See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. majority of neutral organic superbases known so far are clopropeniminophosphazenes, also shown in Scheme 1. fi 20 nitrogen bases, as pointed out in a recent comprehensive Superbase DMAN, synthesized by Alder fty years ago, review article by Raczynská et al.4 where the gas phase basicity represents a special example of an amine with two of various nitrogen bases including organic compounds, but dimethylamino substituents at positions 1 and 8 of also some biomolecules, is analyzed, based mostly on the naphthalene. Because of the repulsion of electron pairs on experimental data. However, there are some examples of nitrogen atoms, the neutral form of the molecule is prepared superbases where carbon or phosphorus acts as a destabilized; however, in a protonated form this repulsive − ff basicity center5 7 and recently very strong silylene superbases interaction diminishes, which has a positive e ect on basicity. have been designed computationally.8 A theoretical design of Protonation also induces the formation of an intramolecular H- organic superbases along with computational elucidation of bond which additionally stabilizes the protonated form, thus ff leading to further increase of basicity. On the other side, the e ects responsible for their superbasic properties represent a 21,22 vital stage for synthesis and a range of application of these proximity of amino groups induces a proton shielding, compounds, as emphasized in an earlier review article by which means that once the proton is captivated into the Maksićet al.9 Although the great number of neutral organic superbases is already available, most of them are still not as Received: July 7, 2019 basic as inorganic bases such as lithium diisopropylamide Accepted: August 20, 2019 10 whose pKa in tetrahydrofuran is 35.7. For comparison, pKa of Published: September 4, 2019 © 2019 American Chemical Society 15197 DOI: 10.1021/acsomega.9b02087 ACS Omega 2019, 4, 15197−15207 ACS Omega Article Scheme 1. Main Classes of Neutral Organic (Super)bases molecule, it cannot be easily released. This behavior, which is Scheme 2. Formation of a Cyclopropenium Cation typical of bases similar to DMAN where the aromatic backbone enables proximity of basic substituents, is the reason whythistypeofsuperbasesiscalledprotonsponges. Pozharskii et al. extensively investigated different naphtha- lene-based proton sponges and its analogs, including those with expanded N-alkyl groups and N-substituents other than alkyl groups,23a chiral proton sponges,23b proton sponges with different ortho-substituents (e.g., based on tertiary alcohols)23c The combination of CPI and phosphazene moieties results in “higher-order cyclopropenimino superbases”,17b cyclo- that interact with dimethylamino groups. It is interesting that propeniminophosphazenes (CPI-P), compounds that are some naturally occurring compounds, like mycosporine-like more basic than each of its components taken separately. amino acid named porphyra-33424a and aplicyanines,24b also One such superbase, consisting of phosphazene as a core and act as proton sponges. The kinetic inertness of typical proton three diisopropylaminocyclopropenimino substituents, was sponges in some cases limits their use as basic catalysts in 17b 22c synthesized, and its pKa in acetonitrile was found to be organic synthesis. 42.1. The CPI-P functionality was also utilized in the The computational investigation of the basicity of super- computational design of very strong proton sponges, with a bases that contain substituents based on 1,2-(N,N-dimethyla- −1 calculated gas phase PA above 323 kcal mol and a pKa in mino)-cyclopropenimine (in further text CPI) predicted that acetonitrile of 48 units,19 which represents the most basic they should be more basic than guanidines1,2,9 and possibly 13 proton sponge designed so far. However, similar to other even phosphazenes. In 2010 a convenient two-step synthesis proton sponges, this superbase is kinetically inert; the of cyclopropenimines was reported by Alcarazo and co- 25 calculated activation energy needed for the release of a proton workers, which encouraged further research and develop- from the conjugate acid is very high.19 ment of superbasic compounds with a cyclopropenimine motif. We wondered what alternative aromatic scaffold could be The synthesis of the enantioselective Brønsted base organo- used in combination with a CPI and CPI-P motif that would 16c catalyst 2,3-bis(di-isopropylamino)cyclopropenimine con- result in a strong superbasicity and, at the same time, would firmed the theoretical predictions of its solution basicity with not suffer from kinetic inertness that occurs in proton sponges. apKa measured in acetonitrile of 26.90, which is indeed more Azaazulenes are nitrogen-containing analogs of azulene, an basic than guanidines (pKa of analogous guanidine 23.56). aromatic molecule which is an isomer of naphthalene. Among Subsequently, proton sponges with CPI as pincer ligands were azaazulenes, 1-azaazulene is known as a very stable and easily prepared too.26 Superbases containing cyclopropenimino synthesized compound, with several well-established synthetic − functionality owe their high basicity to the aromatic paths for its preparation and preparation of its derivatives.28 31 stabilization of the cyclopropenium cation that is formed The experimental data on the basicity of 1-azaazulene are not upon protonation of the system, as shown in Scheme 2.27 available, but the calculated GB of this compound is 231.9 kcal 15198 DOI: 10.1021/acsomega.9b02087 ACS Omega 2019, 4, 15197−15207 ACS Omega Article −1 −1 36 mol (PA = 239.5 kcal mol ). So far, azaazulenes have never experimental value of pKa of 12.53 served as a reference been used in the design and preparation of organic superbases. base Bref. In this work, we present a novel, computationally designed neutral organic superbases, obtained by utilizing two types of Scheme 3. Thermodynamic Cycle Utilized for the substituents dimethylaminocyclopropenimines, CPI, and di- K Calculation of p a with the CPCM Approach methylaminocyclopropeniminophosphazenes, CPI-P which are combined with 1-azaazulene as a core unit(s). Further, we have investigated their kinetic basicity by calculation of free energy barriers