Nucleophilic Base Research Articles

Exploring the role of halogen bonding in iodonium ylides: insights into unexpected reactivity and reaction control.

Halogen bonding is commonly found with iodine-containing molecules, and it arises when Lewis bases interact with iodine's σ-holes. Halogen bonding and σ-holes have been encountered in numerous monovalent and hypervalent iodine-containing compounds, and in 2022 σ-holes were computationally confirmed and quantified in the iodonium ylide subset of hypervalent iodine compounds. In light of this new discovery, this article provides an overview of the reactions of iodonium ylides in which halogen bonding has been invoked. Herein, we summarize key discoveries and mechanistic proposals from the early iodonium ylide literature that invoked halogen bonding-type mechanisms, as well as recent reports of reactions between iodonium ylides and Lewis basic nucleophiles in which halogen bonding has been specifically invoked. The reactions discussed herein are organized to enable the reader to build an understanding of how halogen bonding might impact yield and chemoselectivity outcomes in reactions of iodonium ylides. Areas of focus include nucleophile σ-hole selectivity, and how ylide structural modifications and intramolecular halogen bonding (e.g., the ortho-effect) can improve ylide stability or solubility, and alter reaction outcomes.

Electrochemical Aziridination of Tetrasubstituted Alkenes with Ammonia

Ammonia (NH3) is an ideal nitrogen source in terms of availability, reactivity, safety, atom economy, environmental compatibility, and ease of isolation. However, its utility for amine synthesis is...

CO2 (De)Activation in Carboxylation Reactions: A Case Study Using Grignard Reagents and Nucleophilic Bases

Carbon dioxide (CO2) is an intrinsically stable molecule. However, its reactivity toward nucleophilic bases has constituted an appealing characteristic for applications such as CO2 capture and func...

Basicity‐Engineered Graphite Fluoride Functionalization and Beyond: An Unusual Reaction between Ultraweak Nucleophile and Ultrastrong CF Bonds

AbstractGraphite fluoride‐launched graphene functionalization has attracted increasing interest in recent years. Highly basic nucleophiles are normally employed for ultrastrong CF bonding. However, frequently, an appreciable majority of C–F units of graphite fluoride are reductively eliminated, leading to low functionalization degrees. It is hypothesized that graphite fluoride could likely be functionalized to a larger degree by lowering the basicity of the nucleophiles. Herein, ultraweakly basic NH3·H2O is adopted as a nucleophile to react with extremely inert graphite fluoride, and the resulting reaction affords amino/hydroxyl cofunctionalized graphene (NH2–G–OH). As expected, the NH2/OH functionalization degree and the ratio of substituted C–F units to reduced ones reach high values of 0.34 and 1.62, respectively. Due to the dual energy‐storage mechanisms of the electrochemical double‐layer capacitance coupled with Faradaic pseudocapacitance, the NH2–G8–OH‐based all‐solid‐state supercapacitors are flexible and robust and deliver state‐of‐the‐art capacitive characteristics, while exhibiting high rate capability and electrochemical cycling stability. In addition, NH2/OH moieties remain highly reactive to be post‐functionalized by versatile electrophiles, not only achieving an umpolung of graphite fluoride, but also enabling NH2–G8–OH a competitive alternative to monopolistic GO, and opening up an innovative pathway for development of high‐performance graphene derivatives amenable to multifarious applications.

Ring-opening polymerization of \u03b2-butyrolactone in the presence of alkali metal salts: investigation of initiation course and determination of polymers structure by MALDI-TOF mass spectrometry

Several alkali metal salts that activated 18-crown-6 were applied as initiators of β-butyrolactone anionic ring-opening polymerization in tetrahydrofuran at room temperature. Some of them, i.e., Ph2PK, Ph3HBK, (Me3Si)2NK, and t-BuOK, deprotonate the monomer which results in macromolecules with trans-crotonate starting group. Other salts, for example, MeOK, i-PrOK, PhCH2OK, and CbK (Cb denotes carbazolyl group), deprotonate monomer or open its ring in the acyl-oxygen position. After ring-opening KOH forms as intermediate and initiates further polymerization. Ph3CK and monopotassium salt of ethylenediaminetetraacetic acid also deprotonate monomer and open its ring, however, in the alkyl-oxygen position. Monopotassium salts of glycolic acid, diglycolic acid, or malonic acid initiate polymerization mainly by ring opening in the alkyl-oxygen position. It results in the formation of polymers with two reactive terminal groups. The salts used react with the monomer as strong bases, nucleophilic bases, or nucleophiles. It determines unsaturation of the polymers obtained in the wide range of 2–100 mol%.

Recent advances in site-selective functionalization of carbohydrates mediated by organocatalysts

As one of the four fundamental building blocks of life, carbohydrates assume varied and expansive roles in biological contexts. More in-depth understanding of carbohydrates and their interactions, however, is often restricted by our inability to synthesize and subsequently functionalize them in a site-selective manner. This review will summarize recent advances in the site-selective functionalization of carbohydrates using organocatalysts, including achiral catalysts, chiral nucleophilic bases, chiral N-heterocyclic carbenes, and chiral phosphoric acids, with an emphasis on the catalytic nature in each case. As in many endeavors, taking an alternative approach can often lead to success, and selected examples of these achievements will be highlighted as well.

Direct Catalytic Enantioselective Benzylation from Aryl Acetic Acids.

We demonstrate that metal-catalyzed enantioselective benzylation reactions of allylic electrophiles can occur directly from aryl acetic acids. The reaction proceeds via a pathway in which decarboxylation is the terminal event, occurring after stereoselective carbon-carbon bond formation. This mechanistic feature enables enantioselective benzylation without the generation of a highly basic nucleophile. Thus, the process has broad functional group compatibility that would not be possible employing established protocols.

Deprotonation of a Hydridoborate Anion.

The first deprotonation of a borohydride anion was achieved by treatment of [BH(CN)3 ]- with strong non-nucleophilic bases, which resulted in the formation of alkali-metal salts of the tricyanoborate dianion B(CN)32- in up to 97 % yield and 99.5 % purity. [BH(CN)3 ]- is less acidic than (Me3 Si)2 NH but a stronger acid than iPr2 NH. Less sterically hindered, more nucleophilic bases such as PhLi and MeLi mostly attack a CN group under formation of imine dianions [RC(N)B(CN)3 ]2- , which can be hydrolyzed to ketones of the [RC(O)B(CN)3 ]- type. The boron-centered nucleophile B(CN)32- reacts with CO2 and CN+ reagents to give salts of the [B(CN)3 CO2 ]2- dianion and the tetracyanoborate anion [B(CN)4 ]- , respectively, in excellent yields.

Ring-opening of hindered cyclic epoxides with potassium carboxylates in the presence of conjugate acids

During attempts to ring-open a highly hindered epoxide, traditional methods were found to be ineffective. An alternative strategy for opening epoxides was implemented that employed a potassium carboxylate in the presence of its conjugate acid in a solvent mixture containing polar and potassium-sequestering components. A systematic analysis of the components of the reaction mixture indicated that the addition of the conjugate acid was the most important feature for providing good conversion. This reaction appears to be general for most classes of carboxylic acids including cinnamic, aromatic, and highly hindered carboxylic acids (30%–79% yield) and only fails with weak carboxylate nucleophiles. Three highly substituted and hindered cyclohexene oxide derivatives were examined for reactivity and the reaction conditions appear to tolerate a variety of functional groups to provide the ring-opened species. This pH-moderate system proved useful for hindered cyclic epoxides when all other techniques failed and should prove general to a wide spectrum of epoxide and carboxylic acid partners in those cases where the use of a strong Lewis or protic acid catalyst, or a strong basic nucleophile, is inappropriate.

Generation and Conjugate Additions of o‐Quinone Methides Under Mild Base Conditions: Rapid Synthesis of N‐Substituted Aryl Glycine Derivatives

AbstractA one‐step approach was observed to give N‐substituted aryl glycine derivatives in good to excellent yields (up to 93 %) from (ortho‐hydroxymethyl)aryl benzoates. A cascade mechanism was proposed for the generation and in situ conjugate addition of the ortho‐quinone methides. This mechanism is strongly supported by our subsequent findings that tertiary amines could promote the process. Different functional groups on the (ortho‐hydroxymethyl)aryl benzoates and various amines were investigated to explore the scope of this cascade process. The substituents on the substrates strongly affected the reaction time and yield, and various primary and secondary amines were used as nucleophiles. The addition of tertiary amines enhanced the addition process for less basic nucleophiles.

Electronic and solvent effects on kinetics of SNAr substitution reactions of substituted anilines with 2,6-bis(trifluoromethanesulfonyl)-4-nitroanisole in MeOH-Me2SO mixtures of varying composition: one reaction with two mechanistic pathways.

The kinetics and mechanism of the aromatic nucleophilic substitution reactions of 2,6-bis(trifluoromethanesulfonyl)-4-nitroanisole with para-X-substituted anilines (X = OH, OMe, Me, H, F, I, Cl) were studied in MeOH–Me2SO mixtures and pure Me2SO at 25.0 °C. The second-order rate coefficients depend on the substitutent in aniline and give good Hammett and Brønsted correlations; a polar SNAr reaction is proposed for the reaction in different MeOH–Me2SO mixtures. The measured rate coefficients of the reaction demonstrated dramatic variations for aniline donor with the increasing dimethyl sulfoxide composition in MeOH–Me2SO mixtures. In this case, the Hammett and Brønsted plots are biphasic and concave upwards with a break point at 4-methylaniline. These results indicate a change in mechanism from the polar (SNAr) for less basic nucleophiles (X = 4-Cl, 4-I, 4-F, and H) to the single electron transfer (SET) for more basic nucleophiles (X = 4-OH, 4-OMe and 4-Me). The changes of the structure of the transitions states with substituents and solvent are in accordance with the results of kinetics studies. The solvation model described is well supported by the solvatochromism exhibited by aniline in the solvent mixture under investigation. These results provide an ideal framework for understanding the paramount importance of the specific molecular structure of solvent molecules in determining chemical reactivity versus solvent effects.Graphical abstract Electronic supplementary materialThe online version of this article (doi:10.1007/s00706-013-1030-7) contains supplementary material, which is available to authorized users.

Nonlinear Brønsted and Hammett Correlations Associated with Reactions of 4‐Chloro‐7‐nitrobenzofurazan with Anilines in Dimethyl Sulfoxide Solution

AbstractThe kinetics and mechanism of nucleophilic aromatic substitution reactions of 4‐chloro‐7‐nitrobenzofurazan 1 with 4‐X‐substituted anilines 2a–g (X = OH, OCH3, CH3, H, I, Cl, and CN) are investigated in a dimethyl sulfoxide (Me2SO) solution at 25°C. The Hammett plot of log k1 versus σ is nonlinear for all the anilines studied due to positive deviations of the electron‐donating substituents. However, the corresponding Yukawa–Tsuno plot resulted in a good linear correlation with σ+r (σ+−σ). The corresponding Brønsted‐type plot is also nonlinear, i.e., the slope (βnuc) changes from 1.60 to 0.56 as the basicity of anilines decreases. These results indicate a change in a mechanism from a polar SNAr process for less basic nucleophiles (X = I, Cl, and CN) to a single electron transfer for more basic nucleophiles (X = OH, OCH3, and CH3). The satisfactory log k1 versus Eo correlation obtained for the reactions of 1 with anilines 2a–d in the present system is consistent with the proposed mechanism. Interestingly, the βnuc = 1.60 value measured for 1 in Me2SO reflects one of the highest coefficients Brønsted ever observed for SNAr reactions. © 2013 Wiley Periodicals, Inc. Int J Chem Kinet 45: 152–160, 2013

Simultaneous Determination of Interfacial Molarities of Amide Bonds, Carboxylate Groups, and Water by Chemical Trapping in Micelles of Amphiphiles Containing Peptide Bond Models

Chemical trapping is a powerful approach for obtaining experimental estimates of interfacial molarities of weakly basic nucleophiles in the interfacial regions of amphiphile aggregates. Here, we demonstrate that the chemical probe 4-hexadecyl-2,6-dimethylbenzenediazonium ion (16-ArN(2)(+)) reacts competitively with interfacial water, with the amide carbonyl followed by cleavage of the headgroups from the tail at the amide oxygen, and with the terminal carboxylate groups in micelles of two N-acyl amino-acid amphiphiles, sodium N-lauroylsarcosinate (SLS) and sodium N-lauroylglycinate (SLG), simple peptide bond model amphiphiles. Interfacial molarities (in moles per liter of interfacial volume) of these three groups were obtained from product yields, assuming that selectivity toward a particular nucleophile compared to water is the same in an aqueous reference solution and in the interfacial region. Interfacial carboxylate group molarities are ~1.5 M in both SLS and SLG micelles, but the concentration of the amide carbonyl for SLS micelles is ~4.6-5 times less (ca. 0.7 M) than that of SLG micelles (~3 M). The proton on the secondary N of SLG helps solubilize the amide bond in the aqueous region, but the methyl on the tertiary N of SLS helps solubilize the amide bond in the micellar core, reducing its reaction with 16-ArN(2)(+). Application of chemical trapping to proteins in membrane mimetic interfaces should provide insight into the topology of the protein within the interface because trapping of the amide carbonyl and cleavage at the C-N bond occurs only within the interface, and fragment characterization marks those peptide bonds located within the interface.

Tandem application of C-C bond-forming reactions with reductive ozonolysis.

Several variants of reductive ozonolysis, defined here as the in situ generation of aldehydes or ketones during ozonolytic cleavage of alkenes, are demonstrated to work effectively in tandem with a number of C-C bond-forming reactions. For reactions involving basic nucleophiles (1,2-addition of Grignard reagents, Wittig or Horner-Emmons olefinations, and directed aldol reactions of lithium enolates), the one-pot process offers a rapid and high-yielding alternative to traditional two-step protocols.

Efficient and regioselective ring-opening of arylaziridines with alcohols, thiols, amines and N-heteroaromatic compounds using sulphated zirconia

Sulphated zirconia is an efficient catalyst for the regioselective ring-opening of aryl-substituted aziridines. This heterogeneous catalyst can be used several times without loss of activity and is compatible with a variety of acid sensitive and slightly basic nucleophiles.

Oligoethylene Glycols as Highly Efficient Mutifunctional Promoters for Nucleophilic‐Substitution Reactions

Herein, we report the promising use of n-oligoethylene glycols (oligoEGs) as mutifunctional promoters for nucleophilic-substitution reactions employing alkali metal salts. Among the various oligoEGs tested, pentaethylene glycol (pentaEG) had the most efficient catalytic activity. In particular, when compared with other nucleophiles examined, a fluorine nucleophile generated from CsF was significantly activated by the pentaEG promoter. We also performed various facile nucleophilic-displacement reactions, such as the halogenation, acetoxylation, thioacetoxylation, nitrilation, and azidation of various substrates with potassium halides, acetate, thioacetate, cyanide, and sodium azide, respectively, in the presence of the pentaEG promoter. All of these reactions provided their desired products in excellent yields. Furthermore, the combination of pentaEG and a tert-alcohol medium showed tremendous efficiency in the nucleophilic-displacement reactions (fluorination and methoxylation) of base-sensitive substrates with basic nucleophiles (cesium fluoride and potassium methoxide, respectively). The catalytic role of oligoEGs was examined by quantum-chemical methods. The oxygen atoms in oligoEGs were found to act as Lewis bases on the metal cations to produce the "flexible" nucleophile, whereas the two terminal hydroxy (OH) groups acted as "anchors" to orientate the nucleophile and the substrate into an ideal configuration for the reaction.

Kinetics and Mechanism of the Benzylaminolysis of O,O-Dimethyl S-Aryl Phosphorothioates in Dimethyl Sulfoxide

= 0.91 with the strongly basic nucleophiles. Proposed reaction mechanism is a stepwise process with a rate-limiting leaving group expulsion from the intermediate involving a backside nucleophilic attack with thestrongly basic nucleophiles and a frontside attack with the weakly basic nucleophiles. The kinetic results arecompared with those of the benzylaminolysis of O,O-diphenyl Z-S-aryl phosphorothioates.Key Words : Phosphoryl transfer reaction, Benzylaminolysis, O,O-Diethyl Z- S-aryl phosphorothioate, Cross-interaction constant, Concave downward free energy correlationIntroductionThe various phosphoryl and thiophosphoryl transfer reac-tions have been studied kinetically by this lab: anilinolysis,

Kinetics and Mechanism of the Benzylaminolysis of O,O-Diethyl S-Aryl Phosphorothioates in Dimethyl Sulfoxide

The reactions of O,O-diethyl Z-S-aryl phosphorothioates with X-benzylamines are kinetically investigated in dimethyl sulfoxide at <TEX>$85.0^{\circ}C$</TEX>. The Hammett (log <TEX>$k_2$</TEX> vs <TEX>${\sigma}x$</TEX>) and Br<TEX>$\ddot{o}$</TEX>nsted [log <TEX>$k_2$</TEX> vs <TEX>$pK_a$</TEX>(X)] plots are biphasic concave downwards for substituent X variations in the nucleophiles with a break point at X = H. The signs of the cross-interaction constants (<TEX>${\rho}xz$</TEX>) are positive for both the strongly and weakly basic nucleophiles. Considerably great magnitude of <TEX>${\rho}xz$</TEX> (= 6.56) value is observed with the weakly basic nucleophiles, while <TEX>${\rho}xz$</TEX> = 0.91 with the strongly basic nucleophiles. Proposed reaction mechanism is a stepwise process with a rate-limiting leaving group expulsion from the intermediate involving a backside nucleophilic attack with the strongly basic nucleophiles and a frontside attack with the weakly basic nucleophiles. The kinetic results are compared with those of the benzylaminolysis of O,O-diphenyl Z-S-aryl phosphorothioates.

Kinetics and Mechanism of the Pyridinolysis of Methyl Phenyl Phosphinic Chloride in Acetonitrile

The pyridinolysis of methyl phenyl phosphinic chloride is investigated kinetically in acetonitrile at -20.0 <TEX>$^{\circ}C$</TEX>. The Hammett and Br<TEX>${\o}$</TEX>nsted plots for substituent X variations in the nucleophiles are biphasic concave downwards with a break point at X = H, and unusual positive <TEX>${\rho}_X$</TEX> (= 2.94) and negative <TEX>${\beta}_X$</TEX> (= -0.48) values are obtained for the strongly basic nucleophiles. A stepwise mechanism with a rate-limiting step change from bond breaking for the weakly basic pyridines to bond formation for the strongly basic pyridines is proposed on the basis of biphasic concave downward Hammett and Br<TEX>${\o}$</TEX>nsted plots. Unusual positive <TEX>${\rho}_X$</TEX> and negative <TEX>${\beta}_X$</TEX> values are rationalized by the isokinetic relationship. The pyridinolyses and anilinolyses of four <TEX>$R_1R_2$</TEX>P(=O)Cl-type substrates, dimethyl, diethyl, methyl phenyl, and diphenyl phosphinic chlorides in acetonitrile are compared to obtain systematic information on phosphoryl transfer reaction mechanism. The combination of the two ligands, Me and Ph, shows unexpected kinetic results for both the anilinolysis and pyridinolysis: greatest magnitude of <TEX>$k_H/k_D$</TEX> (= 2.10) involving deuterated anilines <TEX>$[XC_6H_4NH_2(D_2)]$</TEX> for the anilinolysis, and exceptionally fast rate and biphasic concave downward free energy correlation for the pyridinolysis.

Kinetics and Mechanism of the Benzylaminolysis of O,O-Diphenyl S-Aryl Phosphorothioates in Dimethyl Sulfoxide

Kinetic studies of the reactions of O,O-diphenyl Z-S-aryl phosphorothioates with X-benzylamines have been carried out in dimethyl sulfoxide at 55.0 <TEX>$^{\circ}C$</TEX>. The Hammett (log <TEX>$k_2$</TEX> vs <TEX>${\sigma}_X$</TEX>) and Bronsted [log <TEX>$k_2$</TEX> vs <TEX>$pK_a(X)$</TEX>] plots for substituent X variations in the nucleophiles are biphasic concave downwards with a maximum point at X = H, and the unusual positive <TEX>${\rho}_X$</TEX> and negative <TEX>${\beta}_X$</TEX> values are obtained for the strongly basic benzylamines. The sign of the cross-interaction constant (<TEX>${\rho}_{XZ}$</TEX>) is negative for both the strongly and weakly basic nucleophiles. Greater magnitude of <TEX>${\rho}_{XZ}$</TEX> value is observed with the weakly basic nucleophiles (<TEX>${\rho}_{XZ}$</TEX> = -2.35) compared to with the strongly basic nucleophiles (<TEX>${\rho}_{XZ}$</TEX> = -0.03). The deuterium kinetic isotope effects (<TEX>$k_H/k_D$</TEX>) involving deuterated benzylamines [<TEX>$XC_6H_4CH_2ND_2$</TEX>] are primary normal (<TEX>$k_H/k_D$</TEX> > 1). The proposed mechanism is a concerted <TEX>$S_N2$</TEX> involving a frontside nucleophilic attack with a hydrogen bonded, four-center-type transition state for both the strongly and weakly basic nucleophiles. The unusual positive <TEX>${\rho}_X$</TEX> and negative <TEX>${\beta}_X$</TEX> values with the strongly basic benzylamines are rationalized by through-space interaction between the <TEX>${\pi}$</TEX>-clouds of the electron-rich phenyl ring of benzylamine and the phenyl ring of the leaving group thiophenoxide.