BORATE ESTERS: IDENTIFICATION, STRUCTURE, STABILITY, AND CATION COORDINATING ABILITY.
£>-
Martin van Duin
TR diss 1514 On the cover: magic lantern picture from the archives of J. Böeseken, professor of organic chemistry at Delft, 1907-1938: suggested structure of the potassium(l) borate diester of salicylic acid. ïi} /1 s y
BORATE ESTERS: IDENTIFICATION, STRUCTURE, STABILITY, AND CATION COORDINATING ABILITY. BORATE ESTERS: IDENTIFICATION, STRUCTURE, STABILITY, AND CATION COORDINATING ABILITY.
Proefschrift ter verkrijging van de graad van doctor aan de Technische Universiteit Delft, op gezag van de rector magnificus, prof.dr. J.M. Dirken, in het openbaar te verdedigen ten overstaan van het College van Dekanen op dinsdag 2 december 1986 te 16.00 uur
door
2 Promc- !-.-=:.ir-i'3in 1 ™
Martin van Duin, geboren te 's-Gravenhage, scheikundig ingenieur.
Delft University Press, 1986.
TR diss 1514 Dit proefschrift kwam tot stand onder leiding van: prof.dr.ir. H. van Bekkum, eerste promotor, prof.dr.ir. A.P.G. Kieboom, tweede promotor, dr.ir. J.A. Peters. Aan mijn ouders The investigations described in this thesis have been supported by the Netherlands Foundation for Chemical Research (SON) with financial aid from the Netherlands Organization for the Advancement of Pure Research (ZWO).
Typing: Mrs. M.A.A. van der Kooij-van Leeuwen Drawings: Mr. W.J. Jongeleen CONTENTS
1. INTRODUCTION 1 Esters of boric acid and borate: a general introduction 1 Applications of esters of boric acid and borate 3 Analytical chemistry 3 Organic synthesis 7 Chemical technology 10 Cheanical products 11 Biological occurrence and applications 14 Scope of the thesis 15 References and notes 17
2. THE pH DEPENDENCE OF THE STABILITY OF ESTERS OF BORIC ACID AND BORATE IN AQUEOUS ALKALINE MEDIUM AS STUDIED WITH UB NMR 25 Introduction 25 Results and discussion 30 General 30 Glycol 30 Glycolic acid 31 Oxalic acid 33 Glyceric acid 34 Chemical shifts 35 Association constants 36 "Charge rule" for predicting the optimum pH stability 37 Experimental 38 References and notes 39 3. STRUCTURE AND STABILITY OF BORATE ESTERS OF POLYHYDROXYCARBOXY LATES AND RELATED POLYOLS IN AQUEOUS ALKALINE MEDIUM AS STUDIED WITH UB NMR 43 Introduction 43 Results and discussion 44 General 44 Chemical shifts 49 Line widths 52 Association constants 53 Conclusions 58 Experimental 59 References and notes 59
4. STRUCTURAL ANALYSIS OF BORATE ESTERS OF POLYHYDROXYCARBOXYLATES IN WATER USING 13C AND*H NMR 63 Introduction 63 Results and discussion 67 Spectral assignment 67 13 Structure determination of borate esters using C NMR 72 Conformational changes upon borate ester formation as studied with lK NMR 75 Conclusions 76 Experimental 77 References and notes 77
5. THE AQUEOUS D-GLUCARATE-BORATE-CALCIUM(II) SYSTEM AS STUDIED WITH 1H, 11B, AND 13C NMR 81 Introduction 81 Results and discussion 82 The system D-glucarate-borate 82 The system D-glucarate-borate-calcium(II) 86 Effect of concentration, pH, and temperature on the D-glucarate-borate-calcium(II) system 91 Experimental 94 References and notes 94 4. In tegenstelling tot wat Grenier-Loustalot et al. beweren, zijn de niet-gebonden interact ies in de twee gauche vormen van meso-2,3-butaan- diol gelijk.
M.F. Grenier-Loustalot, J. Bonastre en P. Grenier, J. Molec. Struct. 65 (1980) 249.
5. De redenering van Mbabazi met betrekking tot de structuurafhankelijkheid van de stabiliteit van oxyzuuranionesters van polyolen bevat elementaire fouten.
J. Mbabazi, Polyhedron 4 (1985) 75.
6. Het is bepaald onverwacht dat de associatieconstanten van de telluraat- esters van D- en I.-arabinose verschillen; Antikainen en Huttunen beste den hier ten onrechte geen aandacht aan.
P.J. Antikainen en E. Huttunen, Suom. Kemi B46 (1973) 184.
7. Door de parameters van de Haasnoot-De Leeuw-Altona vergelijking te optimaliseren, begeven Masamune et al. zich in een cirkelredenering.
S. Masamune, P. Ma, R.E. Moore, T. Fujiyoshi, C. Jaime en E. Osawa, J. Chem. Soc, Chen. Commun. (1986) 261.
8. Een denticiteit voor tartraat in kation-tartraat complexen van drie is realistischer dan één van vier, zoals door Brittain en Ransom voorgesteld, en verklaart tevens het verschil in stabiliteit van mescr en rac.-tartraat complexen.
H.G. Brittain en M. Ransom, Inorg. Chim. Acta 95 (1984) 113. STELLINGEN
1. In tegenstelling tot wat diverse auteurs beweren, zal D-glucaraat een kation niet gelijktijdig met beide carboxylaatgroepen coördineren.
CL. Mehltretter, B.H. Alexander en CE. Rist, Ind. Eng. Chem. 45 (1953) 2782. CG. Macarovici en L. Czegledi, Rev. Roum. Chim. 9 (1964) 411. P. Spacu, E. Antonescu en S. Plostinaru, Rev. Roum. Chim. 11 (1966) 327. J.G. Velasco, J. Ortega en J. Sancho, J. Inorg. Nuel. Chem. 36 (1976) 889. R.J. Motekaitis en A.K. Mortell, Inorg. Chem. 23 (1984) 18.
2. Diverse auteurs realiseren zich onvoldoende dat met behulp van potentio- metrie in principe alleen het aantal ionisatiestappen en de bijbehorende pK 's bepaald kunnen worden, maar niet de structuren van de aanwezige species.
R.L. Pecsok en R.S. Juvet, J. Chem. Soc. (1955) 202. R.L. Pecsok en J. Sandera, J. Chem. Soc. (1955) 1489. A. Sonesson, Acta Chem. Scand. 13 (1959) 998. CG. Macarovici en M. Volusniuc-Birou, Rev. Roum. Chim. 16 (1971) 823. R.J. Motekaitis en A.E. Martell, Inorg. Chem. 23 (1984) 18. P.B. Abdullah en C.B. Monk, J. Chem. Soc, Faraday Trans. I 81 (1985) 983.
3. Aruga neemt ten onrechte aan dat de verandering van de optische rotatie- eigenschappen van alditolen onder invloed van boraat zeer langzaam is, ten opzichte van de tijd welke nodig is voor de calorimetrische metin gen.
R. Aruga, Talenta 32 (1985) 517. 9. In de literatuur worden evenwichtsconstantes veelal onvoldoende gedefi nieerd. Verder verdient het aanbeveling om meer specifieke termen als associatie-, dissociatie- en ionisatieconstante te gebruiken.
10. Anders dan Akitt en McDonald stellen, zijn de criteria die het elek trisch veldgradiëntnulpunt in een tetraëder vastleggen OP = /Va r en d =
J.W. Akitt en W.S. McDonald, J. Magn. Res. 58 (1984) 401.
11. Behalve van homo sapiens of homo ludens kan men ook van homo structurens spreken.
12. Wetenschapsgeschiedenis en -filosofie zouden niet mogen ontbreken bij wetenschappelijke opleidingen.
13. Het verdient aanbeveling sollicitatieformulieren samen te stellen uit een gestandaardiseerd en een specifiek gedeelte.
14. Met behulp van de verhoudingsfactoren 1.10 voor vrouwen/mannen en 5.00 en 0.53 voor zwemmen/hardlopen en schaatsen/hardlopen kan men met hoge correlatie uit de wereldrecords bij mannen voor hardlopen de overeenkom stige records bij vrouwen en voor zwemmen en schaatsen voorspellen.
M. van Duin 2 december 1986 6. SYNERGIC CALCIUM(II) COORDINATION IN AQUEOUS BORATE-POLYHYDROXY- CARBOXYLATE SYSTEMS 97 Introduction 97 Results and discussion 99 Calcium(II) sequestering capacities 99 Origin of the synergic calcium(II) coordination in the borate-polyhydroxycarboxylate system 100 Quantitative analysis of the calcium(II)-borate-poly- hydroxycarboxylate MIS 106 Synergic calcium(II) coordination as a function of the polyhydroxycarboxylate 110 Experimental 112 References and notes 113
7. INTERACTIONS OF CATIONS WITH OXYACID ANION BRIDGED ESTERS OF D-GLUCARATE IN AQUEOUS ALKALINE MEDIUM 117 Introduction 117 Results and discussion 119 Cation addition to the boric acid- D-glucaric acid system at pH = 10.5 119 Calcium(II) coordination in oxyacid anion- D-glucarate systems 125 Experimental 129 References and notes 129
8. A GENERAL COORDINATION-IONIZATION SCHEME FOR POLYHYDROXYCAR- BOXYLIC ACIDS IN WATER 133 Introduction 133 Data and discussion 134 References and notes 142
9. A 1H, 11B, AND 13C NMR STUDY OF BORATE ESTERS OF 1,3-DIONES, INCLUDING CURCUMIN 147 Introduction 147 Results and discussion 150 Experimental 152 References and notes 155 10. 1H NMR SPECTRA OF CARBOHYDRATE-DERIVED POLYHYDROXYCARBOXYLATES 157 Introduction 157 Results and discussion 158 Experimental 160 References 160
11. THE CONFORMATIONS OF THE SIMPLE VICINAL DIOLS AS STUDIED WITH MOLECULAR MECHANICS CALCULATIONS 161 Introduction 161 Calculations 162 Discussion 164 General 164 1,2-Ethanediol 165 (S)-l,2-Propanediol 167 1,3-Propanediol 168 (.ff,S)-2,3-Butanediol 168 (,S,S)-2,3-butanediol 169 Steric interactions in the series of vicinal diols 170 Conclusions 171 References and notes 172
12. CONFORMATIONS AND PSEUDOROTATION OF 1,3-DIOXOLANE AND SOME METHYL SUBSTITUTED DERIVATIVES AS STUDIED WITH MOLECULAR MECHANICS CALCULATIONS 175 Introduction 175 Experimental 177 Calculations 177 *H NMR 180 Discussion 181 General 181 1,3-Dioxolane 181 4,5-Dimethyl substituted 1,3-dioxolanes 182 2,2-Dimethyl substituted 1,3-dioxolanes 182 H NMR experiments 183 References and notes 184 13. CONFORMATIONS AND PSEUDOROTATION OF BORATE MONOESTERS OF THE SIMPLE VICINAL DIOLS AS STUDIED WITH MOLECULAR MECHANICS . CALCULATIONS 189 Introduction 189 Calculations 190 Discussion 191 Configuration of the B(OH)„ moiety 191 Pseudorotation of the borate monoester ring 193 Stability of borate monoesters 194 References and notes 195
SUMMARY 197
SAMENVATTING 201
DANKWOORD 205
CURRICULUM VITAE 207 -1-
CHAPTER 1
INTRODUCTION
Esters of boric acid and borate: a general introduction.
The distinction between organic and inorganic chemistry is a historical one and is at least partly artificial. For instance, compounds characterized by an X-O-C moiety range from "pure" organic compounds, such as ethers, esters, and anhydrides (X = C) to coordination compounds like carboxylates and alcoholates (X = metal ion). Esters of bor(on)ic acid and bor(on)ate (Figure 1), often denoted as complexes, are in an intermediate position (X = B).
R—B
R = R' = OH boric acid ester borate monoester borate diester R = alkyl/aryl: R' = OH boronlc acid ester boronate ester R = R'= alkyl/aryl - borinate ester
Figure 1. Cyclic esters of bor(on)ic acid and bor(on)ate.
In analogy with the organic esters, esters of boric acid and borate are obtained by condensation of a hydroxyl donating species (boric acid or börate) and a hydroxy compound with loss of water. Here, cleavage and 1 2 formation of B-0 bonds occur. ' Formally the central boron is a trivalent 3 cation. But its ionic radius is so small and its charge/radius density is so large, that boron penetrates the electron cloud of oxygen upon bond 4 formation, resulting in orbital overlap and in a B-0 bond having a predominantly covalent character. However, the bondmoment is 0,8 D (C-O: 7 0.44 D ), which indicates polarity. -2-
ooc -O coo B- v / coo ooc
OH
Figure 2. Variation of the denticity (number of coordinating donor atoms) of the organic hydroxy compound in the solid state structures of the 10 borate tetraester of methanol (a), the borate diester of (5,5)- 11 12 -tartrate (b), the diborate ester of scyiVo-inositol (c), and 13 boromycine (d), respectively
Just as coordination compounds, the esters of boric acid and borate are 2 in fast equilibrium with the parent compounds in aqueous solution (k = 10 - -10 Ms at 25 °C). The stability of these esters in water is low except when chelation occurs, resulting in one or more rings. Borate esters of mono-, bi-, tri-, and tetradentate alcohols have been shown to exist (Figure 2). From 1920 to 1940, Böeseken and coworkers in this laboratory have been the first to study the chemistry of esters of boric acid and borate ("Böeseken complexes") systematically, using conductometry and -3- polarimetry. In the following decades refractometry, solubility and cryoscopic measurements, calorimetry, chromatography (GC and LC), electro- phoresis, spectroscopie techniques (IR, Raman, UV/Visible, fluorescence, luminescence, phosphorescence, and NMR), X-ray diffraction, polarography, 15-24 and thermal analysis have been applied as analytical tools. Recently, the development of new techniques, such as high field multinuclear NMR, have provided new stimuli to study these esters. This thesis should be regarded in this perspective.
Applications of esters of boric acid and borate.
The countries with the largest production of boron containing mineral are the United States (1972: 1.1 million ton with a value of 96 million US $), Turkey, and Argentina. Boric acid and simple inorganic salts comprise over 24 99% of the boron containing products. The number of applications of esters of boric acid and borate is overwhelming. It is well known that product properties and process characteristics, involving hydroxyl containing compounds, can be affected by addition of boric acid or borate. The effects have usually been studied in a rather empirical way. In this paragraph a concise review is presented of the applications of esters of bor(on)ic acid and bor(on)ate in analytical chemistry and chemical synthesis. A survey of technical applications in chemical processes and 24 products is restricted to general topics and literature from the last decade. A brief summary of biological aspects is given, as these have been 25 reviewed by Kliegel.
Analytical chemistry
Applications of esters of bor(on)ic acid and bor(on)ate in analytical chemistry are found in quantitative determination, structure elucidation, and separation techniques. The formation of esters of boric acid and borate enables the quantitative determination of boric acid/borate as well as of chelating dihydroxy compounds. The acidity of boric acid can be enhanced by addition of -4- alditols, such as D-glucitol and D-mannitol, * or even better by op OQ calcium(II) D-gluconate. ' In this way direct titrimetric determination of boric acid with a strong base is possible. Boronic acid and borinic acid 24 are determined in a similar way. The decrease of pH upon iron(III) complexation by borogluconate (a reaction mixture of boric acid and D-gluconate at adjusted pH) is a quantitative measure for the amount of 30 iron(III) present. Precipitation of barium(II) borotartrate has been 24 exploited in the gravimetric determination of boron. Precipitation of boric acid as a borotartrate, followed by filtration and oxidation with 31 cerium(IV) is a rather cumbersome procedure for boric acid determination. More straightforward methods are the spectroscopie boric acid determinations 32 24 33 or in chloranilic- D-glucaric acid, anthraquinone, azomethin-H (with or ,34 without extraction with 2-ethyl-l,3-hexanediol), and curcumin-acid (mineral or oxalic acid) systems (Figure 3). The latter systems are also 24 used in the determination of boronic and borinic acid.
OH
OCH,
O O
Figure 3. Mixed borate diester of curcumin and oxalic acid.
The curcumin-boric acid system is used in dicarboxylic and a-hydroxycar- 35 boxylic acid determinations. In liquid chromatography carbohydrates can be determined fluorometrically with borate-taurine and borate- 2-aminopropio- OC 0*7 nitril fumarate reagents. ' Invert sugar determination is possible with 38 potentiometry after addition of borax. A non-destructive catechol assay in 39 polymers is based on borate ester formation. Fluorescence in systems of borate and (hydr)oxy derivatives of anthraquinone, tetracycline, and 25 flavonoids is used in quantitative analysis. Reaction of polyols with BEt„ results in diethylborinic and ethylboronic acid esters with evolution of ethane. The amount of released ethane is a 40 41 measure for the number of hydroxyls present in the polyol. ' -5-
OH 3,I HO HO- HO y^\ o ö • B(OH)3 . H20 - V J • H A . 149
BtOH), -K- HO
Figure 4. Enhancement of the conductivity of a boric acid solution (expres- 14 sed as A) upon addition of cis- and tra«.s-l,2-cyclopentanediol.
The strict spatial requirements for multidentate ligands upon ester formation with bor(on)ic acid and bor(on)ate, i.e. the proximity of two or more hydroxyl functions, have made these boron containing compounds useful in studying structural, configuratlonal, and conformational problems. BUeseken and coworkers have applied this principle in the carbohydrate field 14 using conductometry and polarimetry. Cis- and tra/7s-l,2-cyclopentanediol have been used as model compounds for the furanose sugars (Figure 4). These studies might be considered as the origin of conformational analysis, although later chemists have for the most part been unaware and not appreciative of this research. 23 43 Mass spectra of boronic acid esters, ' chromatographic and 17 44 45 electrophoretic data for borate containing mobile phases, ' ' and changes in selectivity of reactions, such as periodate oxidation in the OO AC presence of borate ' also provide direct answers to structural questions. 13 Boric acid and borate are used as NMR shift reagents (mainly C NMR) for 47 48 the assignment of the signals of both diols ' and carbohydrates (and 49 50 derivatives) ' and for the elucidation of the configuration of ,. 51-53 diols n . Esters of bor(on)ic acid and bor(on)ate are of importance in the removal of boric acid/borate and in the isolation of hydroxy compounds. A classical method for the removal of bor(on)ic acid is the formation of B(0Me)„ and boronic acid esters of glycol or 1,3-propanediol, repectively, followed by 14 54 evaporation. ' A more sophisticated way is extraction with 2-ethyl-l,3- -6-
55 56 24 55 -hexanediol, ' 2,2,4-trimethyl-l,3-pentanediol, ' or diol functiona- 54 lized resins (cf. technical processes). Preeoncentration before boron 33 determination is achieved in this way. Boronic acids can. be purified and 23 54 characterized as the catechol esters. ' The separation and purification of carbohydrates via distillation or fractional crystallization of esters of boronic acid is also known for a 23 long time. With respect to modern analytical separation techniques of hydroxy compounds, bor(on)ic acid and bor(on)ate have found widespread use 22 23 25 57 in gas and liquid chromatography and in electrophoresis. ' ' ' GC of polar compounds, such as carbohydrates (and derivatives) is difficult, unless they are derivatized, for instance by methylation, acetylation, or trimethylsilylation. These derivatizations result in different anomeric forms with overlapping peaks and thus long retention times. A good alternative is the formation of volatile butyl- and phenylboronic acid esters. Standard procedures have been developed for both GC and GC-MS of carbohydrates. Analytical enantiomeric separation of aliphatic diols is possible through their boronic acid esters, using complexation GC with 59 chiral nickel(II) complexes as stationary phase. These derivatizations are rather time consuming and separation techniques for the liquid phase, despite the lower separation capacities, have superseded GC in a number of cases. In this respect, applications of 1R bor(on)ate are found in zone electrophoresis and in thin layer, paper, and oo no cfj anion exchange chromatography. ' ' After the initial use of simple 1 rj MC crj cf\ fjl borate buffers, > > > > refinement of these applications has resulted in subtle pH gradients in polyol-borate buffers for zone electrophoresis and 62—64 anion exchange chromatography. In LC immobilization of boronate by coupling to an insoluble polymer has been introduced to separate mixtures of more complex molecules, such as 22 25 57 nucleosides, nucleotides, glycoproteins and -lipids, and enzymes ' ' and 65 in the analysis of the effluent of paper factories. The properties of phenylboronate columns are affected by the nature of the support matrix (cellulose, dextran, acrylamide, and polystyrene) ' and by substitution of the benzene ring. One of the most recent developments is the ligand 57 mediated chromatography (Figure 5). The affinity ligand, that offers possible binding sites for the retardation of macromolecules (shaded form), is bound via its diol function to the boronate resin. Finally, uphill -7-
HO-
HO-
O o-i J& B(OH), HO O HO^O_|| ^
Figure 5. Schematic diagram of ligand-mediated chromatography (cf. text). 57 transport of monosaccharides between two liquid phases of different pH 67 across an organic, liquid membrane is mediated by phenylboronate.
Organic synthesis
Apart from a role as intermediates in the preparation of boron containing 24 compounds, esters of bor(on)ic acid and bor(on)ate are applied to affect the reactivity and selectivity of reactions involving hydroxy compounds, especially in the carbohydrate field. It has been reported that the presence of bor(on)ic acid and bor(on)ate in solutions of reducing sugars can shift the isomerization equilibria (increased ketose/aldose ratio: D-fructose/ R8—74 /D-glucose, D-maltulose/D-maltose, and D-lactulose/D-lactose ) and may 75 increase the amount of acyclic forms. Furthermore, diol functions can be protected selectively, with the advantage of easy deprotection. ' Thus upon addition of bor(on)ic acid or borate an enhancement of selectivity has been observed in a variety of reactions with carbohydrates (and derivatives), such as esterification [(chloro)acetylation, benzoyla- 23 77 tion, /7-tosylation, and phosphorylation], ' etherification (methyla- 2*3 78—80 81 82 tion), isopropylidation, bromine oxidation, ' hydrogenation 83 84 (Figure 6), and dehydration. Polystyrene boronic acid resins are also applied for this purpose, ' with the advantage of simple purification. Noteworthy is the application of these resins in the preparation of 7G 87 otherwise difficult accessible carbohydrates. ' Similarly, the reactivity of carbohydrates can be decreased in the presence of borate, for instance 25 copper(II), iron(III), and iodine oxidation and the alkaline degradation 88 of carbohydrates can be inhibited by borate addition. The diethylborinic and ethylboronic acid esters of polyols, obtained upon -8-
Cu Cu
Figure 6. Enhanced selectivity of the D-glucose hydrogenation to D-mannitol: chemisorption of the borate diester of p-D-fructofuranose and QO anti-ring-0 side H-attack.
reaction with BEt„ (cf. analytical chemistry), have been applied in the 89—92 selective synthesis and in the purification of polyols by 41 41 distillation. BEt„ can be applied in the dehydration of carbohydrates. Bor(on)ic acid and bor(on)ate have been shown to catalyze condensations, additions, and hydrolyses by formation of a bor(on)ate ester in the vicinity 25 93 of the reactive site (Figure 7). ' Such a scheme is also suggested for the NaBH. reduction of (hydr)oxy esters. It may be noted that these types of 25 93 reactions are studied as model systems for enzyme catalysis. ' The (stereo)selectivity of aldol condenstations is increased when the ketone is converted into the borinyl acid ester of its enol form, prior to addition of the aldehyde. The transition state is supposed to resemble the 94 dialkylborinate e3ter of the p-hydroxyketone product (Figure 7a). More recently, mixed boric acid esters of the enol form of the ketone and glycol
L L L 0..L SBH, >B7 >B' / O (O O xO O O ^PVCHR. /i\^\ xv^^„ ^Y~> 2 Rf®^f ^R, ' ^~^ O' Me Me
Figure 7. Suggested role of boron in the stereoselective aldol condensation (a), the o-hydroxymethylation of phenol with formaldehyde (b), and the NaBH. reduction of (hydr)oxy esters (c). -9-
95-97 have been applied. The product composition of the formose reaction, i.e. the oligomerization of formaldehyde in aqueous alkaline solutions to the so-called formose sugars, is also affected by borate. Substituted 102 103 1,7-dipheny1-5-hydroxyhepta-l,4,6-triene-3 -ones, such as curcumin (cf. Figure 3), are obtained by condensation of acetylacetone with two equiva lents of an aldehyde in the presence of boric acid. An example of a boric acid catalyzed addition is the o-hydroxymethylation of phenol with formaldehyde. The transition state once again is 25 characterized by a cyclic borate ester structure (Figure 7b). The (intramolecular) borate catalyzed hydrolysis of hydroxyesters is assumed to follow a similar pathway. ' Usually, carboxylic acid esters and lactones are essentially inert towards KBH. and NaBH- reduction. However, several exceptions are known. Esters with complexing, neighbouring functions, such as (hydr)oxyesters, can be reduced with these borohydrides. A probable explanation is the formation of -C-0-BH„ structures (Figure 7c), followed by 93 intramolecular reduction. The NaBH. reduction of carbohydrates and the 112 trialkylborane reduction of 0-hydroxyketones are stereoselective for the same reason. An alternative is the addition of reagents, for instance primary alcohols, that increase the reductive power of NaBH., due to NaBH. (OR) formation. ' ' The use of special solvents, such as lflfi polyethylene glycol 400, is also effective, probably for the same reason. Thermal decomposition of boric acid esters of tertiary alcohols gives the corresponding alkenes. This principle is used to separate mixtures of secondary and tertiary alcohols, via conversion of the alcohols into the boric acid esters, followed by pyrolysis of the tertiary alkyl boric acid 24 esters. Some miscellaneous reactions involving bor(on)ic acid or bor(on)ate esters have been reported recently. Chain extension of boronic acid esters 115 is effected with LiCHCl„. In the presence of boronic acid esters of pinanediol, enantioselective synthesis of insect feromones and aminoalcohols 11 fi is achieved. Borate has also been used as a template in the synthesis of 117 macrocyclic compounds (Figure 8). Boric acid esters are used as 24 alkylating agents in Friedel-Crafts reactions. Boric acid is a catalyst 118 for the Friedel-Crafts acylation of catechol. Benzyl bromide is carboxy- 119 lated in the presence of B(Oalkyl)_. Upon oxidation of chiral boronic -10-
CHO CHO
Dl-O H HO- -IQ h-O H HO- U =N-wvN = CHO 117 Figure 8. Synthesis of macrocyclic compounds with borate as template acid esters with the flavoenzyme cyclohexanone oxygenase, boric acid esters 120 are obtained with conservation of chirality.
Role in technical processes
In the last decade the main technical applications of esters of bor(on)ic acid and bor(on)ate have been in the large scale oxidation of paraffins and in extraction processes.
paraHin 4 alkine wash NaOH + H20 pa ratlin ," cycle
Figure 9. Flow sheet for the Bahkirov oxidation process of paraffins (reproduced with permission from reference 121). -11-
Boric acid esters of secondary fatty alcohols are obtained in the liquid phase oxidation of paraffins with air at 150-170 °C in the presence of stoichiometric amounts of boric acid or boron oxides (Figure 9), thus 121 122 preventing through oxidation. ' The alcohols, obtained by hydrolysis, 121-123 are precursors for non-ionic surfactants. The esters B(OR)„ with R = Pr, Bu, Ph, and cyclohexyl are applied for the same selectivity purpose. The oxidation of 1,3-butadiene to butanediols and of cycloalkanes to cycloalcohols ' ' are also carried out in the presence . of these boron compounds. Olefins are oxidized to epoxides in the presence 128 129 of boric acid or with Hiutyl hydroperoxide-borate. ' Extraction of boric acid or borate is achieved by solvent extraction or with functionalized resins and is of importance in the boron production and recovery, in purification of MgCl„ brines, and in waste water 24 130-132 plants. ' The solvent extraction processes are characterized by boric acid/borate transport from an aqueous solution to an organic solvent via ester formation. In the case of boric acid in (acidic) leaching 55 133 solutions, 1,3-diols such as trimethyl-l,3-butanediol, 2-ethyl-l,3- 130 134 -hexanediol, or alkoxy-l,3-butanediols are dissolved in the organic phase. In the case of borate, aromatic diols like alkylcatechols, alkylsalicylic acids, and 2-chloro-4-(l,l,3,3-tetramethylbutyl)-6-hydroxy 24 133 methylphenol are used. ' Polymers of phenol, aldehyde, aminopolyols, and aliphatic polyamines, poly(vinyl alcohol) resins, and resins 137 functionalized with hexose moieties are applied as boric acid exchange material. Aqueous borax solutions, on the other hand, are used to extract 24 polyhydroxycarboxylates from petroleum oxidation products. Finally, esters of boric acid and borate have potentials as a catalyst for the polymerization of alkenes, dienes, and isocyanates and for 24 124 crosslinking epoxy resins. ' Boric acid (esters) are used in the 138 dehydration of 1,3-diols to conjugated dienes.
Chemical products
Esters of boric acid and borate as such are available as commercial products, but are also used as additive to improve product properties. The cation sequestering capacity of the biodegradable and non-toxic polyhydroxycarboxylates for calcium(II), iron(III), and aluminium(III) in -12- aqueous alkaline solutions is increased upon addition of boric acid/borate. Borogluconate (Glucona BV., Ter Apelkanaal, The Netherlands) and boroglucoheptonate (Croda Chemicals Ltd., Cowick Hall, United Kingdom) are available as commercial sequestering agents and have a wide range of 139 applications (Table 1).
Table 1. Function and field of application of borogluco(hepto)nate 139 sequestering agents
function field of application
degreasing, desoxidation, paintstrip- galvanic industry ping, alkaline etching, electropla te ., 140 , ...... ting, and corrosion inhibition alkaline cleaning and descaling glass industry, breweries, and dairy industry set retardation and plasticization cement and concrete industry additive in bleaching and dyeing process textile industry 141 142 triphosphate substitute ' detergent industry increasing the solubility of calcium(II) treatment of hypocalcaemic condi tions (milkfever and parturient and delivery paresis)
Increase of the viscosity or gelation of aqueous solutions of polyols, such as polyvinyl alcohol, dextran, glycan, starch, and gelatin upon addition of boric acid or borate - resulting from crosslinking due to borate ester formation and hydrogen bonding - is applied in thickening and gelation 24 143-146 agents. ' These gels are used as drill fluids in oil winning processes, to encapsulate pesticides and other agrochemicals for slow 146 147 release purposes, ' and as adhesives, amongst others 124 143 148 149 for linerboards. ' ' ' Paper envelopes, containing detergent additives, can be impregnated with polyols. The presence of borate in the washing water results in dissolution of the polyols, followed by release of 150 the additives Furthermore, these high viscosity liquids are sold as childrens plaything ("Slime"). -13-
24 Borate esters of tanning agents are used in the leather treatment. Borate esters of polyols are used as resist or discharge agents in the 152 printing process of synthetic fabrics. In some fabric softeners, negatively charged borate diesters act as counterion for benzylammonium 153 compounds to increase the solubility in water. Borate esters of a variety of hydroxy compounds are used as surface active agents, amongst others in 24 detergents. The properties of lubricating oils, greases, and hydraulic fluids, for instance as found in brake systems, can be improved upon addition of 24 124 154-156 bor(on)ic acid esters of (polyethylene) glycol or B(Oalkyl)„ ' ' 24 and are claimed to be relatively water insensitive. The presence of esters of boric acid and borate in (propylene)glycol brake and antifreeze liquids 157 counteracts the influence of water and the borate diesters of glycerol 124 and D-glucitol are applied as anticorrosion additives. Solutions containing triborate polyol esters (for instance pentaerythritol monooleate) 158 159 or borax-disaccharides mixtures are applied as lubricating oil. ' Borate diesters of 3-mercapto-l,2-propanediol are antiwear additives for 124 lubricating oils. Boric acid esters of glycol are appliedi inn automobile 24 fuels to increase the octane number and as antiicing additive.' The applications in polymers are also numerous5 (Tabl(T8 e 2). Liquid crystals 1 3R3T based upon phenylboronic acid esters are known. BBorat e esters of glycol 24 and catechol can be used as capacitor electrolytes.
Biological occurrence and applications2 5
Boron is present as boric acid, borate, esters, and salts in biological systems. It is essential for higher plants. In lower plants, boron sometimes is not found at all. Some boron containing antibiotics are known [boromycine (cf. Figure 2) and aplasmomycine], that are used against gram-positive bacteria. Boron is always present in animals, but it is unclear whether it is essential. The lethal dosis of boric acid for higher animals is about 1-2 g/kg. The larger part of the biological boric acid and borate is present as esters of polyols, polyhydroxycarboxylates, carbohydrates (and derivatives), and aromatic alcohols. It may be noted that the use of boric acid or borate 164 (for instance borax buffers ) in biological samples can have large -14-
Table 2. Applications of esters of boric acid and borate in polymers. function additive applied in
124 vulcanizing agent B(Oalkyl)„ and borate neoprene, chloroprene, 24 diesters of pyrocatechol and butadiene-styrene rubber curing agent borate esters of methanol, epoxy, pheno1/urea catechol, cresol, and formaldehyde resins i • i ^ 24 salicylate antioxidant borate diester of pyroca (brominated) butyl techol,124 B(Oalkyl) 24 and rubber and polyvinyl 24 arylboronic acid esters chloride 24 plasticizer B(Oalkyl) natural and synthetic resins antistatic surface borate esters of glycolstea- polyethene . . .. . 160-162 active compound rate and -paImitate heat stabilizer B(Oalkyl)„, borate diester of polyvinyl chloride and glycerol, and borate esters polystyrene 124 of polyol-fatty acid esters flame retardant borate diester of brominated ,. , 124 diols effects. 133 Boric acid is toxic for vegetation when it exceeds the 5 ppm level. Thus, the boric acid ester of 1,2-propanediol is applied in wood conservation and the borate esters of polyols in the conservation of samples of biological origin, such as urine during transport or storage and also 167 124 as fungicide. B(0alkyl)_ is applied as insect sterilant. Alditols, on the other hand, are used as antidote for boric acid poisoning. In solutions of boric acid/borate and a dihydroxy compound, the 165 solubility of both species is enhanced by borate ester formation. 1 RR Applications of borotartrate in liquid fertilizers and of borate esters 169 of carbohydrates as grain seed developer are based on this principle. The solubility of alkaloids and antibiotics (caffeine, procaine, epinephrine, and Amphotericine B) is increased when borogluconate is the -15-
170 171 counterion. ' The application of calcium(II) borogluconate in the treatment of low calcium(II) plasm levels in cattle has already been mentioned. B labelling of dopamine is used in the cancer research to mark 172 melanomes and in the neutron capture therapy of tumors (Figure 10).
Figure 10. Structure of borate monoester of L-dopa.
Scope of the thesis
The first part of this thesis (chapters 2-9) deals with the identifi cation, structure, and stability of borate esters in aqueous medium. It provides a chemical basis for understanding the effects of boric acid/borate upon product properties or process characteristics, as summarized in the previous paragraph. The central theme is the (synergic) cation coordinating ability of borate esters of polyhydroxycarboxylates in aqueous solution (cf. Table 1), as studied by multinuclear NMR and calcium(II) ion selective electrode measurements. Borate esters of 1,3-diones are also studied because 103 of their importance in the synthesis of curcumin and in the spectroscopie 24 33-35 determination in boric acid-curcumin systems. ' In the second part of this thesis (chapter 10-13) a more detailed study on the structure and conformation of both borate esters and the parent compounds is presented. The effect of pH on the stability of esters of boric acid and borate with dihydroxy compounds in water is studied with B NMR (chapter 2). The results are explained with a "charge rule" that allows prediction of the pH region of optimum stability for a particular ester. The various borate esters that exist for a compound containing several diol functions are identified with B NMR (chapter 3). The factors that determine the B chemical shift and line width and the stability of the borate esters are -16- discussed. The borate binding sites in polyhydroxycarboxylates and the 13 occurrence of diastereomerism in the borate diesters are determined with C NMR (chapter 4). The confonnational changes of the polyhydroxycarboxylates upon borate ester formation are determined with H NMR. 11 13 The D-glucarate-borate-calcium(II) system is studied using B, C, and H NMR, including the effects of pH, concentration, and temperature (chapter 5). The species responsible for the synergic calcium(II) coordination are determined and the composition of the calcium(II) coordinating sites is discussed. The conclusions for this system are generalized for calcium(II)- -borate-polyhydroxycarboxylate systems (chapter 6). Fitting the data on the (synergic) calcium(II) coordination, obtained with calcium(II) ion selective electrode measurements, with a model, containing all important species of these systems, allows quantification of the phenomena. The scope of the synergic cation coordination is studied for various oxyacid anion- D-glucarate systems (chapter 7). The effects of the cations on the relative borate diester stability are correlated with their charge/radius densities and polarizing abilities, whereas the effects of the oxyacid anions are explained with the pH rule of thumb derived for borate in chapter 2. Finally, a general coordination-ionization scheme for polyhy- droxycarboxylate complexes, based on literature data for 40 metal ions and oxyacid anions, is given (chapter 8). A fundamental explanation for the phenomena is provided. Borate esters of 1,3-diones are studied with B, C, and H NMR (chapter 9). They are expected to have different stability effects in comparison with those of diols, because of the opposite charges of the respective esters. A H NMR study of free polyhydroxycarboxylates is presented (chapter 10). The chemical shifts and vicinal coupling constants are explained in terms of substitution and preferred conformations. Molecular mechanics calculations using the MM2 force field give detailed insight in the conformations and confonnational energies of some simple diols (chapter 11). Steric hindrance, the gauche effect, and hydrogen bonding are included in the discussion. An empirical force field study is performed on the pseudorotation and conformations of substituted 1,3-dioxo- lanes, which are used as model compounds of borate monoesters (chapter 12). Vicinal H coupling constants are calculated from the molecular mechanics -17-
results and compared with experimental data. Finally, some calculations on borate monoester geometries are described and compared with X-ray structures (chapter 13). Calculated stabilities of borate monoesters are compared with experimental data.
References and notes
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CHAPTER 2
THE pH DEPENDENCE OF THE STABILITY OF ESTERS OF BORIC ACID AND BORATE IN AQUEOUS MEDIUM AS STUDIED WITH UB NMR*
Introduction
Esters of boric acid and borate have found.widespread use as a tool in configurational analysis, for instance of carbohydrates, and in a variety 2 of separation and chromatography techniques. This class of compounds has 3 4 been studied for more than a century, using several analytical techniques. The possible equilibria between boric acid, borate, and the corresponding esters are summarized in Figure 1. Boric acid (B ) is a Lewis acid and can bind a hydroxyl ion, forming the borate anion (B ). Both boric acid and borate can react with a suitable dihydroxy compound (L), resulting in the boric acid ester (B L) and the borate monoester (B L), respectively. Subse-
^OH OHe HO^o^OH B" HO-BC; ■- /B B' ^OH HO OH
•OH OH -OH OH
OH _ r O^e^OH B'L B L o'N)H
r°~ -°1 L-o' B~L2
Figure 1. Equilibria between boric acid, borate, and a dihydroxy compound in aqueous medium.
Cf. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 40 (1984) 2901. -26-
L glycol glycolic acid oxalic acid
B°L I JÏB-OH ^B-OH ^B-OH Co>-° T°>-° oX^-O '
B~L L-o^ ""-OH L0/ \OH nJ-o' OH O'
B-L, I _;B; I I >- I T°^° /^Nr
Figure 2. Esters of boric acid and borate for glycol, glycolic acid, and oxalic acid. quently, these two esters can react with another dihydroxy compound to give the borate diester (B L„). Throughout this thesis a distinction between esters of boric acid and of borate is made by the use of B L and B L (n = 1,2), respectively. The indices "o" and "-" do not always stand for the actual charges of the esters, but denote the charges of the B0„ or BO. moieties. As dihydroxy compounds diols, hydroxycarboxylic acids, and dicarboxylic acids are possible. The corresponding esters possess structures as shown in Figure 2. 5 Carbonyl functions can be estérified after hydration or enolization. The association constants for the various equilibria involved are defined as follows:
B° + OH" Ï=Z B" K|- = [B"]/([B°][OH_]) = 8.5*104 M_1 (l)6
O
B° + L ^ B°L + 2 H20 KgOL = [B°L]/( [B°] [L]) (2)
B~ + L ^ B~L + 2 H20 KJj-L = [B~L]/( [B~] [L]) (3)
B~L + L ^ B~L2 + 2 H20 KJ-J = [B"L2]/([B"I] [L]) (4) line phase the central boron atom is surrounded by three oxygen atoms in an Boric acid and boric acid esters are neutral compounds. In the crystal almost planar fashion with O-B-0 valency angles of about 118°. Although three-coordinated boron compounds form adducts with suitable nucleophiles, -27-
o boric acid does not form B(OH)„(OH„) adducts in aqueous solution. The central boron atom in borate and borate esters is coordinated by four oxygen atoms. The geometry is tetrahedral, because the O-B-0 valency angles are 7 circa 109°. Borate and borate esters are negatively charged. A mechanism for the formation of borate esters from boric acid has been 9 proposed by Pizer and Selzer. A more extended mechanism is shown in Figure 3. Boric acid and boric acid-like structures are considered to be the reactive species in the esterification, due to the ease of the attack by a dihydroxy compound in comparison with the substitution of a hydroxyl ion in borate or borate-like structures. The rate of exchange between boric acid and borate is very fast and diffusion controlled. ' All the other steps involving proton or hydroxyl transfer are assumed to be fast too. As a result of the chelate effect the ring closure is relatively fast, in comparison with the attack of a free dihydroxy compound at a reactive boric acid-like species. Thus the latter steps are considered to be the rate determining steps in the formation of esters of boric acid and borate. The equilibria between B and B L and between B L and B L, as given in Figure 1, are therefore not realistic from a kinetical point of view, but can be defined thermodynamically. Some 50 papers have dealt with the stability of esters of boric acid and borate. The influence of the pH on the stability, however, has not been studied systematically. In addition, most of the techniques used (such as potentiometry and polarimetry) give no direct information concerning the identity of the esters involved. In our laboratory several multinuclear NMR techniques are applied to 12 study cation complexation phenomena of poly(hydr)oxycarboxylic acids and of combinations of these acids with borate. B NMR is an obvious choice in the study of esters of boric acid and borate, especially because this technique provides direct information concerning ester formation. Table 1 gives some important physical data of the two boron isotopes, B and B, which are both NMR sensitive. B NMR is more suitable than B NMR for two reasons. Firstly, the NMR sensitivity in a 1.0 M solution for B is approximately 30 times larger than that for B. This is due to the differences in natural abundance and in the NMR sensitivity for an equal number of nuclei. Secondly, the resolution in B NMR spectra is better. This is a result of the higher resonance frequency of B NMR and of the smaller electric quadrupole moment 11 14 of B, which rules the line width. -28-
OH" © B(OH)3 B(OH)<
® 6 -0-B(OH)2 ÏE= 0-B(OH)j HO-Si1 H HO-J H
O—B(OH)3
B(OH),
OH' Q0>B(OH) ^= L0>B(OH)2
OH © ©.O-, O-B^ | O-BC <©H) 1 ^O —I HO -I H HO - H
OH" ©^O- O-B' ~| (OH) >-<: = ^O—' HO J' HO J
pO^f/O-, L®0/B^0J I H
r-O^g/O-, B L0/ ^oJ
Figure 3. Mechanism for the formation of esters of boric acid and borate. -29-
Table 1. Physical data for B and B nuclei.
10 U nucleus B B spin 3 3/2 resonance frequency at 4.70 T (MHz) 21.49 64.19 natural abundance (.%) 18.83 81.17 relative sensitivity at constant field for an equal number of nuclei (XH = 1.00) 0.0188 0.165 relative sensitivity in 1.0 M. aqueous solution ( H = 1.00) 0.0036 0.12 —28 2 electric quadrupole moment (10 m ) 0.111 0.0355
Until now B NMR has mostly been used in the studies on boranes, carboranes, heterocyclic (N, 0, and P) boron compounds, and metallo derivatives in organic solvents. ' B NMR studies on compounds with boron coordinated only by oxygen atoms are more scarce and usually have been performed in organic solvents. B NMR has been used to study the equilibria between boric acid, borate, and several polyborate species in water, especially with respect to the dependence of the total boron concentration, the pH, and the presence of metal ions. ' In dilute solutions only one average signal is observed and, therefore, the exchange between boric acid (8 = 0.0 ppm) and borate (8 = -17.6 ppm) is fast on the B NMR time scale. Furthermore, it has been demonstrated that polyborate formation 21 occurs only at total boron concentrations above 0.2 M. Henderson et al. have been the first to use B NMR for identifying borate esters of diols in 22 water. The results have been applied in the carbohydrate field. Borate ester formation and hydrolysis is slow on the B NMR time scale and thus chemical shifts for borate mono- and diesters of 1,2- and 1,3-diols can easily be determined. The calculated association constants show good 21 correspondence with values obtained by other techniques. In this chapter a B NMR study is presented dealing with the influence of the pH on the stability of esters of boric acid and borate in aqueous solution. As dihydroxy compounds a 1,2-diol (glycol), an a-hydroxycarboxylic acid (glycolic acid), a dicarboxylic acid (oxalic acid), and a compound combining a 1,2-diol and an a-hydroxycarboxylic acid function (glyceric acid = 2,3-dihydroxypropanoic acid) are used. A general rule for determining pH dependent concentration optima for esters of boric acid and borate is put forward. -30-
Results and discussion
General
In Figures 4-7 the influence of the pH on the concentration of the 23 different boron compounds is given for L = glycol, glycolic acid, oxalic acid, and glyceric acid, respectively. The points were determined experi mentally with B NMR, while the curves were calculated from the association constants obtained (except for L = glyceric acid). Chemical shifts [6(B°) = 0.0 ppm] are given in Table 2. The association constants (Table 3) were calculated using Equations (l)-(4), together with the pK's of the dihydroxy compounds and the following material balance equations:
CB = [B°] + [B~] + [B°L] + [B~L] + [B"L2] (5)
_ CL = [L] + [B°L] + [B~L] + 2[B L2] (6)
Glycol
For L = glycol (Figure 4) only one signal was observed at pH < 8. This signal showed an upfield shift upon an increase of the pH and is assigned to the equilibrium between B and B , which is fast on the B NMR time scale. At pH > 8 two new signals were observed, which are assigned to B L and B L„-
Thus the exchange between B and B L and between B L and B L9 is slow on the
0-10
c[M]
005
O 0 4 8 12 ►pH
Figure 4. Glycol (L: 1.0 M) and boric acid/borate (B°/B~: 0.1 M): distribu- 23 tion of boron containing species as a function of the pH. -31-
B NMR time scale. A further increase of the pH above 11 had no effect on the concentrations of B L and B L„. These phenomena can be explained by rewriting the equilibria from Figure 1 as:
B° + L ?=£ B~L + H+ + H„0
_ + B° + 2 L ^ B L2 + H + 3 H20
B L and B L„ are formed at high pH, which means in practice that B is present in solution. Consequently, borate esters of glycol can only be expected in the region where pH > pK(boric acid) = 9.1; experimentally pH > 8 is found. At pH = 11, [B ] a 0 and a further increase of the pH has o - - 24 no effect on [B ]. Therefore, [B L] and [B L„] reach maxima. The presence of B L could not be demonstrated. When this ester does exist B° o
KDoT should be small or S(B L) a 0 ppm. In the latter case the experimental signal at 6 = 0.0 ppm has to be assigned to the equilibrium between B and B L (fast exchange on the B NMR time scale). Paal, however, has shown B° that the former explanation is correct: K_oT » 0. D L Glycolic acid
When L = glycolic acid the pH dependence was quite different (Figure 5). At low pH a single signal was observed with a chemical shift between +0.4 and 0.0 ppm. It is assigned to the equilibrium between B and B L, which is fast on the B NMR time scale. Rise of the pH resulted in a second signal, attributed to B L„ with a maximum intensity at pH - 3. A third signal appeared for B L with a maximum intensity at pH = 7. A further increase of the pH resulted in the disappearance of the B L and B L„ signals and only the signal of B remained. The difference in the pH dependence for L = gly colic acid in comparison with L = glycol is due to the easy deprotonation of the former compound:
L ü: L~ + H+ pK(glycolic acid) =3.8 26 -32-
0- 1 01-.
c[M]
0 05 -
Figure 5. Glycolie aci d (L: 1.0 M) and boric acid/borate (B /B : 0.1 M): distribution of boron containing species as a function of the pH.
The amount of B L will be large when [B ] and [L] are large, therefore, at pH < pK(glycolic acid). When both [L] and [L ] are large, formation of B L„ will be optimum according to:
B + L + L ï; B 12 + 3 HjO
At pH = pK(glycolic acid), where [L] = [L ], a maximum in [B L„] is reached. In principle, B L can be formed either from B and L or from B and L. The latter possibility, however, can be excluded because pK(glycolic acid) < < pK(boric acid). This means that B L exists when L is present, i.e. upon dissociation of glycolic acid:
B°+ L~ B L + H20
When the pH reaches pK(boric acid), [B ] increases. The equilibrium for B L may be rewritten as:
B + L 2^ B L + OH + H„0
It is obvious that an increase of the pH causes dissociation of B L. In other words, the pH optimum for B 1 is attained at pK(glycolic acid) < pH < < pK(boric acid). Our experimental results fully agree with this picture.27,29 As was stated above, the difference in the pH dependence of the stabili- -33- ties of the borate esters of glycol and glycolic acid can be understood by the difference in pK (»14 and 3.8, respectively). This is in agreement with 31 the results of Sienkiewicz and Roberts, who have studied the influence of the pH on the stability of the phenylboronate esters of 4,5-dihydroxynaphta- lene-2,7-disulfonic acid and 2,3-dihydroxynaphtalene-6-sulfonic acid. Boronate monoester formation with these aromatic diols showed also pH optima, viz. at pH = 6-7 and 8-9, which are close to the corresponding pK values (5.5 and 8.1, respectively).
Oxalic acid
When t = oxalic acid (Figure 6) only one signal could be observed, besides the signal for the equilibrium between B and B . This signal is attributed to B L. A maximum for [B L] has to be found at the pH where [L ] and [B ] are maximum:
u B + L ^=a B L + H20
Since oxalic acid is a dicarboxylic acid (pK, = 1.2; pK„ = 4.2 ), the pH optimum for B L has to be pH = (pK. + pK„)/2 = 2.7. This value is close to - 11 the experimental maximum for [B L] at pH = 3. B NMR gave no indication for the occurrence of B L„, which would be expected at pH = pK,. Therefore, only the upper limit for K_- could be calculated (Table 3). Again B°L could not be detected.
0-10 i-
c[M]
005
B~L
12 — pH
Figure 6. Oxalic acid (L: 0.25 M) and boric acid/borate (B°/B : 0.1 M): distribution of boron containing species as a function of the pH. -34-
Glyceric acid
Although glyceric acid is the simplest molecule in which 1,2-diol and oc-hydroxycarboxylic acid functions are combined, its picture for ester formation as a function of the pH is rather complicated as shown in Figure 7. Here two types of esters are possible as depicted in Figure 8, which holds generally for polyhydroxycarboxylic acids. The notations L,. , and L-)H . , indicate the way glyceric acid is esterified, viz. as a 1,2-diol or
0 10 B"L(aOHacid)+ B"+ B" c[M]
0 05
Figure 7. Glyceric acid (L: 1.0 M) and boric acid/borate (Bu/B : 0.1 M): distribution of boron containing species as a function of the pH.
BL(diol)0 ^ BL(oOHzr)0
pH«4 pH«9 L/\ BL(diol) ^ BL(oOHzr)" pH-7
BL(diol)L(aOHzr)"
pH»4 L(oOHzr) •> L(aOHzr)"
Figure 8. Equilibria between boric acid, borate, glyceric acid, and glycerate in aqueous solution. -35- as an oe-hydroxycarboxylic acid. At low pH an average signal for the equilibrium between B and B L was observed. Since K_o. for L = glycol is smaller than that for L = glycolic acid, glyceric acid will be bound as an a-hydroxycarboxylic acid in B°L. Between pH 1 and 8 glyceric acid behaves like glycolic acid and signals for B (.^^^acid^ and B ^LaOHacid^2 were observed. Maximum concentrations of these two species were found at pH = 2 and 6, respectively. A further increase of the pH reduced the stability of these borate esters of the a-hydroxycarboxylic acid type, but enhanced the stability of the borate esters of the diol type. A new signal for B (L,. ,)? appeared, while the chemical shift of B L changed slightly, probably as a result of a shift from B (L .„ . ,) to B (L.. .). As was observed for cxOHacia diol _
L = glycol, an increase of the pH above 11 had no effect on [B (L,. ,)] and
[■^diol^-24 Chemical shifts
With the aid of Table 2 it is obvious that each type of ester of boric acid and borate is characterized by a chemical shift range, viz. S(B L) = +1 to 0 ppm, 6(B~L) = -11.5 to -14.5 ppm, and 6(B""L„) - -8.0 to -10.5 ppm. For - - 21 B L and B L (L = diol) this has already been reported by Henderson et al. The chemical shifts of B L and B L„, reported by these authors for L = glycol (6 = -13.4 and -9.6 ppm, respectively), agree with our values. The variation of chemical shifts within the given ranges can be explained using increments, as will be shown in the next chapter. Other chemical shift data of borate esters reported in the literature belong to acyclic borate
Table 2. B chemical shifts of esters of boric acid and borate. species glycol glycolic aci d oxalic aci d glyceric acid
ocOHacid diol
B°L +0.4C +0.4C B~L -13.9 -11.9 -14.4 -12.8 -13.1 rf B-L2 -10.1 -8.4 -12.0 -9.4 -8.7
In ppm, relative to 0.1 M boric acid in D_0 as external reference. D„0; 25 °C. C Estimated. d Reference 32. -36- esters [B (OR).: R = Me and Ph; S = -15.6 to -16.3 ppm ] and cannot be used for a comparison with our data. Chemical shifts of boric acid esters are only known for acyclic species [B (OR)„: R = alkyl and Ph; 6 = 0.5 to -3.3 ppm] and for boric acid esters with the residual hydroxyl group substituted 33 by an alkoxy group (8 = + 4.3 to -0.8 ppm). Our experimental shifts of +0.4 ppm are in the same range.
Association constants
The association constants as obtained from Figures 4-7 are shown in Table 3. Boric acid esters proved to be more stable for L = cc-hydroxycarboxylic acid than for L = diol and dicarboxylic acid. This is in agreement with 25 34 results found in the literature. ' Perhaps electronic effects and ring B~ B_L strain play a role. The association constants K--. and KJI~T (I1= glycol) 2 11 agree with the values obtained already by other workers, using B NMR or 21 other techniques. The association constants for L = glyceric acid bound as a diol are larger than those for L = glycol, as is to be expected from an extrapolation of published association constants of substituted glycols such as 1,2-propanediol, 3-methoxy-l,2-propanediol, and l-chloro-2,3-propanediol 21 35 36 (Kj-L = 2-20 and KJ-J = 0.5-2.5). ' >
Table 3. Association constants of esters of boric acid and borate.
L glycol glycolie ac id oxalic acid glyceric acid
aOHacid diol
- 1.0 - a 1 - KB°L 4i 1.0 1.4*105 1.7K108 ,105 6.2 „B~L 0.16 20 < 0.5 a 25 0.62
S L 1.2 2.9 * 1
a 1 b In M ;Cfl = 0.1 M; CL = 1.0 M; DO; 25 °C; I = 3.0. C^ = 0.25 M. -37-
The stability of B L for L = carboxylic acid can be redefined more realis tically as:
n° - n - R" IC-T = [B L]/([B ][L ]) = K„-. K(boric acid)/K(carboxylic acid) (7) oh b L according to the actual equilibrium:
B° + L~ iz B~L + H20
B° Values of K -. calculated in this way are also included in Table 3. A D L B° B comparison of KBoT with K„-T (L = oc-hydroxycarboxylic acid) shows that the affinity of boric acid is equal for L and L . A comparison with literature data ' ' indicates that our K--. values are circa 10 times smaller. The literature method used, potentiometry, provides less direct information and thus one cannot be sure that the supposed number and type of compounds in B R~L the system is correct. The fact that KD-T and K_-T for L = diol are smaller 21 37 than for L = a-hydroxycarboxylic acid agrees with literature data ' and is probably based on electronic effects.
"Charge rule" for predicting the optimum pH stability
On the basis of the present results the following general rule of thumb may be formulated:
Esters of boric acid and borat e in aqueous medium show the highest stability at that pH, where the sum of the charges of the free esterifying species is equal to the charge of the ester.
This "charge rule" will be illustrated by some examples. Boric acid esters are most stable at low pH, where dissociation of both B and L hardly
B° + L ^-^ B°L + 2 H„0 -38-
Ionization of boric acid favours the formation of borate esters of diols, i.e. a rather high pH [pH > pK(boric acid)] is required:
B_ + n L ^ B~L + 2n H 0 n Io
With borate ester formation of oe-hydroxycarboxylic acids and dicarboxylic acids, pH dependent optima are involved. The borate diester of an oe-hydroxy carboxylic acid shows maximum stability at pH = pK(L), where the acid and its anion are present in equal amounts and boric acid is in its neutral form:
B° + L + if :T^ B~L2 + 3 H20
The borate monoester, however, occurs preferentially at pK(L) < pH < < pK(boric acid), where the carboxylic acid function is ionized and boric acid is in its neutral form:
B° + L~ -ZZ. B~L + H„0
A similar situation occurs with dicarboxylic acids at pH = (pK. + pK„)/2. Finally, the pH dependent stability of borate esters of polyhydroxy- carboxylic acids can be understood by combining the rules for diols and oe-hydroxycarboxylic acids. Thus when the pH reaches pK(boric acid), borate esters of the oe-hydroxycarboxylic acid type convert into borate esters of the diol type. With the aid of this "charge rule" it is possible to predict the species present in a solution at a certain pH and one can avoid misin terpretations of the experimental results, especially in the case of poly- hydroxycarboxylic acids.
Experimental
All B NMR spectra were recorded at 25 °C on an Nicolet NT-200 WB spectrometer at 64.19 MHz with 0.1 M boric acid in D_0 as external reference. The conditions for the four experiments were equal, viz. the total boron concentration C = 0.1 M, the total concentration of the B dihydroxy compound C, = 1.0 M (except for oxalic acid where C. = 0.25 M), and the ionic strength I = 3.0 (NaCl). The samples were prepared by dissolution of the appropriate amounts of boric acid and organic compound in -39-
D„0. The pH was adjusted with 40X NaOD in D„0 (Merck) and measured with a calibrated MI 412 micro-combination probe from Microelectrodes, Inc. The total volume of each sample was 5 ml. Glyceric acid was obtained by ion exchange of calcium(II) glycerate using Biorad AG 50W-X8 ion exchanger, followed by freeze drying. The amount of crystal and absorbed water was determined by H NMR.
References and notes
1. J. Boeseken, Adv. Carbohydr. Chem. 4 (1949) 189. 2. R.J. Ferrier, Adv. Carbohydr. Chem. 35 (1978) 31. 3. L. Vignon, Compt. Rend. 78 (1874) 148. 4. U. Weser, Struct. Bonding (Berlin) 2 (1967) 160. 5. M. van Duin, J.A. Peters, A. Sinnema, A.P.G. Kieboom, and H. van Bekkum, to be published; this thesis, chapter 9. 6. R. Montgomery, Adv. Chem. Ser. 117 (1973) 197. 7. O-B-0 valency angles are mean values calculated using crystal structures from the Cambridge Data File; O-B-0 valency angles range from 109 to 123 for boric acid esters and from 98 to 119° for borate esters. 8. C.F. Baes and R.E. Mesmer, "The Hydrolysis of Cations", John Wiley Interscience, New York (1976). 9. R. Pizer and R. Selzer, Inorg. Chem. 23 (1984) 3023 and references cited therein. 10. W.R. Gilkerson, J. Chem. Phys. 27 (1957) 914. 11. T. Yasunaga, N. Tatsumoto, and M. Miura, J. Chem. Phys. 43 (1965) 2735. 12. J.A. Peters and A.P.G. Kieboom, Reel. Trav. Chim. Pays-Bas 102 (1983) 381. 13. H. Nöth and B. Wrackmeyer, NMR Basic Princ. Prog. 14 (1978). 14. In solutions of boric acid (90% B enriched; 0.1 M) and D-mannitol or
D-glucaric acid (CT = 0-0.2 M) in D„0 at pH = 11.0 and 25 °C, the ex- - - - - 10 change between B and B L and between B L and B L„ is slow on the B NMR time scale (21.49 MHz), just as in the case of B NMR. The spectral resolution in NMR spectra is determined by the line widths and the difference in chemical shifts (in Hz) of two signals. The ratio of the line widths of the B and B NMR signals was calculated using Equation
(9) from chapter 3: Av-.Q /Av,, = 0.65. Experimental values of 0.7 (B° - B in and B ) and 0.3-0.5 (B L ) were obtained. B chemical shifts of all signals (in ppm, relative to 0.1 M boric acid in D„0 as external -40-
reference) were equal to the corresponding B chemical shifts, which indicates that isotope effects are negligble. However, the separation of the B resonances (in Hz) was about three times smaller than that of the nB resonances, as a result of the difference in resonance frequency between the two boron isotopes (Table 1). 15. A.R. Siedle, Annu. Rep. NMR Spectrosc. 12 (1982) 117. 16. A.K. Covington and K.E. Newman, J. Inorg. Nucl. Chem. 35 (1973) 3257. 17. T.P. Onak, H. Landesman, R.E. Williams, and I. Shapiro, J. Phys. Chem. 63 (1959) 1533. 18. M.J. How, G.R. Kennedy, and E.F. Mooney, J. Chem. Soc., Chem. Commun. (1969) 267. 19. R.K. Momii and N.H. Nachtrieb, Inorg. Chem. 6 (1967) 1189. 20. H.D. Smith and R.J. Wlersema, Inorg. Chem. 11 (1972) 1152. 21. W.G. Henderson, M.J. How, G.R. Kennedy, and E.F. Mooney, Carbohydr. Res. 28 (1973) 1. 22. G.R. Kennedy and M.J. How, Carbohydr. Res. 28 (1973) 13. 23. Experimental data for L = glycol at pH > 6: M. Makkee, thesis, Delft (1985). 24. The stability of the borate esters of the diol type are affected by changes in pH at pH > 13: this thesis, chapter 7. 25. T.L. Paal, Acta Chim. Acad. Scient. Hung. 103 (1980) 181. 26. "Handbook of Chemistry and Physics", CRC Press, West Palm Beach, 52nd edn. (1972). 27. B NMR spectra showed that the amount of esterified glycolic acid is 17 optimum at pH = 4 (Figure 5). 0 NMR (27.12 MHz) spectra of solutions 17 of glycolic acid (5* 0 enriched carboxylic acid and hydroxyl groups;
1.0 M) and boric acid (0-0.5 M) in D?0 were recorded at pH = 4 and 25 °C. The exchange between glycolic acid and its borate esters is slow on 17 the O NMR time scale. The signals (chemical shifts in ppm and between brackets the line widths in Hz) are assigned as follows: H„Ó: 0 (80); free glycolic acid/glycolate: C00H/C00_: 258 (300) and OH: -5 (270); borate ester: C=0: 302 (300), 0=C-0-B: 210 (240), and C-O-B: 20. The 0 chemical shifts resemble those of the ethylboronic acid ester of 28 glycolic acid. 28. B. Wrackmeyer and R. Koster, Chem. Ber. 115 (1982) 2022. 29. In aqueous solution glyoxylic acid (CHO-COOH; pK = 2.9 ) is present in on
its hydrated form (93*: CH(0H)2-C00H) and thus will behave similar to glycolic acid with respect to borate ester formation. The borate mono- -41-
and diester of hydrated glyoxylic acid (6 = -13.3 and -10.4 ppm, respectively) showed pH optima at pH = 7 and 3, respectively. 30. P.E. S0rensen, K. Bruhn, and F. LindelfSv, Acta Chem. Scand. A28 (1974) 162. 31. P.A. Sienkiewicz and D.C. Roberts, J. Inorg. Nucl. Chem. 42 (1980) 1559. 32. With DMSO as solvent borate ester formation is enhanced and the B L„ 5 signal can be observed (6 = -12.0 ppm). 33. W.G. Henderson and E.F. Mooney, Annu. Rev. NMR Spectrosc. 2 (1969) 219. 34. V. Frei and A. Solcova, Coll. Czech. Chem. Commun. 30 (1965) 961. 35. G.L. Roy, A.I.. Laferriere, and J.D. Edwards, J. Inorg. Nucl. Chem. 4 (1957) 106. 36. T.L. Paal, Mag. Kern. Foly. 34 (1978) 12. 37. N. Vermaas, thesis, Delft. (1931). -43-
CHAPTER 3
STRUCTURE AND STABILITY OF BORATE ESTERS OF POLYHYDROXYCARBOXYLATES AND RELATED POLYOLS IN AQUEOUS ALKALINE MEDIUM AS STUDIED WITH 11B NMR*
Introduction
Borate esters of polyhydroxy compounds and their potential for separation and protection are being explored for a long time. In this laboratory Böeseken and coworkers have studied the stability of esters of boric acid and borate using conductometry and polarimetry from 1910 to 1940. The results served as a tool in the configurational analysis of carbohydrates. 2 More recently, Makkee utilized borate to enhance the selectivity of the hydrogenation of D-fructose towards D-mannitol. Further interest in borate esters is derived from our complexation studies on calcium(II) and lantha- 3 4 nide(III) cations with polyoxygen ligands, ' together with the fact that mixtures of boric acid and D-gluconic acid or D-glucaric acid in aqueous alkaline solution have been disclosed in the patent literature as 5 6 triphosphate substitutes in detergent formulations. ' In order to understand the calcium(II) sequestering ability of borate esters of sugar acids, firstly their structures have to be determined and the factors governing their relative stability should be understood. Then in a next stage, the effects of cation addition to the borate-polyhydroxy- carboxylate systems should be investigated. In the present chapter the usefulness of B NMR as an experimental technique for the analysis of borate esters of sugar acids and related polyols is demonstrated. Some general rules for both the assignment of B resonances and the estimation of the relative stability of borate esters are put forward and discussed.
Cf. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 41 (1985) 3411. -44-
The influences of the vicinity (1,2 or 1,3), the configuration (threo or erythro and syn or anti), and the number of hydroxyl groups (2-5) as well as the presence of substituents are studied. In this study we confine ourselves to the high pH area (pH = 11.0), where borate and borate esters of aliphatic diol functions occur predominantly (Figure 1) and the concentrations of boric acid, boric acid esters, and 7 borate esters involving carboxylic acid functions are negligible. In addition, it should be noted that the line width of the borate signal at -17.6 ppm is small (10 Hz) and, therefore, no interference occurs with most of the other signals of borate esters.
l-OH |,-O— UH '« :>»>. £^= EX]
B ^= B'L == B L2
Figure 1. Equilibria between borate (B ) and a diol function (L) at pH > 9.
Results and discussion
General
The exchange rate between borate, its monoesters, and diesters at 25 °Cis slow on the B NMH time scale. This enabled the determination of the chemical shifts, line widths, and intensities of the signals of the various borate esters (Table 1) for a series of sugar acids and related polyols (Figure 2). The assignment of the signals will be discussed in the next section. The association constants for the borate mono- and diesters, defined as:
KB_ = [B L]/([B ][L]) = K, (1) B L x
KB_L = [B L„]/([B L][L]) = K„ (2) BL2 -45-
r-OH r- OH H'J - - OH OH OH OH ■OH HO- HO- OH OH OH •OH -OH -OH b OH £ OH EiO H -OH -OH -OH l-OH
Q OH C OH OH /^-^f HO -f^^T-OH HO^ïKJ/ OH8 O H OH1 0
e e C B COOB e coo coo C00e :oo coo ö HO- -OH -OH COO HO- -OH HO- HO- H0- -OH [-OH -OH -OH HO- -OH -OH HO- L- OH -OH -OH -0H -OH -OH -OH -OH -OH -OH -OH -OH -OH
12 13 15 16 18
e coo coo® COO° COOe COOQ coo° COO° -OH -OH -OH [-OH HO-j -OH -OH HO- HO- HO- (—OH -OH -OH HO- -OH HO- -OH e COOe coo HO- -OH -OH e e c:oo ° coo COO® coo COO®
19 20 21 22 23 24 25
Figure 2. Structures of polyols and polyhydroxycarboxylates. are mean values- (Table 1), determined over a range of total borate
(C = 0-0.15 M) and polyol concentrations (CT = 0-1.0 M). They were D Li calculated using Equations (1) and (2) together with the material balance equations for borate and the polyol:
[B ] + Z[B L] + Z[B L2] (3)
CL = [L] + Z[B L] + 2I[B Lg] (4) Table 1. B chemical shifts, line widths, and association constants for borate esters. polyhydroxy compound ester type chemical shift line width association constant (ppm) (Hz) (M_1)
_ B L B-L2 B~L B-L2 B L B L„
8,c 1 glycol 1,2 -13.9 -10.1 15 15 1.0 0.1 8,c 2 1,2-propanediol 1,2 -14.0 -10.2 10 25 1.8 1.5 3 pinacol ' 2,3 -14.8 -11.9 15 45 3.5 8.5 8,c 4 1,3-propanediol 1,3 -18.3 -18.9 10 - 1.2 0.05 I 5 glycerol 1,2 -13.6 -9.6 20 30 25 3.0 1,3 -18.5 -19.0 10 - 3.7 0.05 1,2 + 1,3 -14.2 15 0.18^ 6 D-mannitol erythra-2,3 -14.6 40 threo-2,4 -13.5 -9.5 50 120 syn-1,3/2,4 -18.2 - 7 D-glucitol threa -13.4 -9.3 50 90 erythro-1,5 -14.4 25 syn-2,4 -18.1 15 8 cis-l,2-cyclopentanediol 1,2 -13.6 -9.4 - - 9 9 cis-l,2-cyclopentanediol 1,2 -14.2 -10.7 - - -47-
oo co o oo
o o O O ^- O CM 05 o co o CM o «t m "* o CM rH CM
O 05 o co CO s
in in O in in o o o o 1 O o o m in in m o CM CM CM m CM co co co CM co co CM
t> co ui co t~ CM «* 00 05 05 05 OJ 05 05 1 1 i 1 1 1 1
i—l*t.—ICMCMini—ICO>3,C0005COCM'3'mCO«3,CMCM OOOTcÖcÓ^COCDCO^COCDntCOCDcÓ^COCO'S'oÓ I I I I I I I I I I I I I I I I I I I I
m co co CM co CM <* <3" *r t 4> \ t, co m co Ni» I{>s +0 >, & co -t? CO 0 •Cl I <; 1" ■s. t O !" ?■> m t f-, v. q- c's *, 's «s Is *, ■s ■■s 1* •<5 's i-H i-H CM { cu ^r CQ vU). CU CM •U
i- -l-> m co
r-\ 1 CU § X ■o CU -aG CU 3 O ■p CU c r~i rH cd ■p • H O O u o 4) CU +J +J CU c CU •p -p c ü>> ■H o o -u co co o E cd co c c o 4, o3 i->H> • H c c o 0 c bO J3 o o s ü 1 'r0j • H 1 co .n 3 • H £ 5 i—l <—( •ii cj cd k, rH B bO ■»41 0, I
18 D-gulonate erythro-2,3 -14.6 30 65 threo -13.5 -9.5 40 80 540 79 syn-3,5 -18.2 20 17 19 weso-tartrate erythro-2,3 -13.0 -8.7 55 120 2.2 0.36 20 (S, 5)-tartrate threo-2,3 -12.6 -7.7 60 160 11 17 21 meso-3,4-dihydroxyadipate erythro-3,4 -13.9 -10.4 30 75 3.3 0.42 22 rac. -3,4-dihydroxyadipate threo-3,4 -13.8 -10.1 25 85 15 3.2 23 L-idarate threo -13.2 -9.1 55 120 120 20 syn-2,4 -18.0 -18.4 10 20 - - 24 galactarate threo-2,3 -13.3 -9.1 30 95 260 7.7 erythro-3,4 -14.4 25 42 25 D-glucarate threo -13.4 -9.5 45 110 180 31 erythro-4,5 -14.0 20 syn-2,4 -17.9 11
a 64.19 MHz; CD = 0-0.5 M; CT = 0-1.0 M; Do0; pH = 11.0; 25 °C. Relative to 0.1 M boric acid as — rl — — c external reference. Corrected for S(B ) = -17.1 ppm. Kg = [B (1^ 2)(L1 3)]/{[B 1^ 2][L]}. -49-
Chemical shifts
The chemical shifts of the borate esters of the diols 1-4, 8, 9, 12, and 19-22 can be assigned in a straightforward fashion, since these compounds can bind borate just in a single way. The H NMR spectrum of the borate ester of aii-cj>-cyclohexane-l,3,5-triol (10) unambiguously showed that this compound forms a tridentate borate ester, which is in agreement with the 13 results observed for epi-inositol (11). In both cases, borate diesters could not be detected. On the basis of the assignments of the borate esters of these 13 compounds, some general rules are derived which serve for the further assignment of the other borate esters in Table 1. Firstly, borate esters can be divided into groups with a characteristic chemical shift range, depending upon the type of ester involved (Table 2), o n as has been noted before by Henderson et al. and by us. The substantial
11 Table 2. Characteristic B chemical shift ranges for various types of borate esters.
11 ester type B chemical shift range (ppm)
B L B L„
1,2-bidentate 12.6 to -14.9 -7.7 to -11.9 1,3-bidentate 17.9 to -18.5 -18.4 to -19.0 1,3,5-tridentate 18.1 to -19.4
OR OR °y OR Ö NOR £^°f
•P (°) 104 (± 2) 107 B-0 (A) 1.47 (± 0.05) 1.49 ring geometry half chair/envelope/planar chair
Figure 3. Mean O-B-0 valency angles (?) and B-0 bond distances, and ring geometries for borate esters of 1.2- and 1,3-diols (standard 14 deviations between brackets). -50- difference in chemical shifts between borate esters of 1,2- and 1,3-diols should be traced back to differences in the geometry of the borate ester ring (Figure 3). Secondly, it may be noted that for 1,2-diols the difference in B chemical shift between the borate monoester and borate (A.) roughly equals that between the borate diester and the monoester (A_) as shown in Figure 4:
(5) Al = *2
Al - 8(B L) - 8(B ) (6)
Ag = 6(B L2) - 6(B L) (7)
A 2 / [ppm]5 /. / / /.
/ /
/ 1/ I
A,[ppm]
Figure 4. 4, as a function of A. for 1,2-diol type borate esters.
Equation (5) does not hold for borate esters of a-hydroxycarboxylic 7 acids, which is probably due to resonance effects. Although for borate esters of 1,3-diols only a few experimental data are available and A, and A„ are small, Equation (5) seems to be applicable there too. Thirdly, borate esters of tAreo-diols have chemical shifts which are more downfield than those of erythra-diola (cf. compounds 19-22). With the aid of these three general rules the B NMR signals of the borate esters of 5-7, 15-18, and 23-25 are assigned. A comparison of the -51- chemical shifts enables us to determine characteristic shift ranges for borate esters of threo-, erythro-, and terminal 1,2-diols. In this way the signals of the borate esters of D-arabinonate (13) and D-ribonate (14) are fully assigned. The regularities observed in the B chemical shifts of borate esters of 1,2-diols [6(B~L )] can be summarized by the following empirical equation:
8(B L ) = S(B ) + n(A + i) (8) n in which 8(B~) is the chemical shift of borate [S(B ) = -17.6 ppm], n the number of diols bound by the borate anion (n = 1 or 2), A the shift induced by one bound glycol molecule (A = 3.7 ppm), and i an increment depending upon substituents on the glycol moiety and the diol configuration. The use of Equation (8) and the increments i, given in Table 3, allow the prediction of B chemical shifts of 1,2-diol borate esters with an accuracy of ± 0.2 ppm (± 0.6 ppm for borate esters of erythro-diols). This additivity is also — R valid for mixed borate diesters such as B (glycol)(1,3-propanediol) and B (1,2-glycerol)(1,3-glycerol) (Table 1). Mixed borate diester formation is also plausible for D-ribonate (14), because of the rather broad borate diester signal as shown in Figure 5.
Table 3. Configuration and substituent increments [Equation (8): i].
configuration sub:stituent ;3
X-CHOH-CHOH-Y X/Y = CH2/CH2 CHOH/CHOH coo~/coo~ CHOH/COO" CHOH/CHOH and CHOH/COO-
threo 0.1 0.3 1.3 0.5 0.5 erythro -0.1 -0.6 0.8 -0.2 -
C00~ X-CH0H-CH„0H X = CH2 CHOH
0.0 0.4 0.8
In ppm. -52-
B R2 4 -18-O
COO®
20 ppm 11 Figure 5. 64.19 MHz B NMR spectrum of D-ribonate (R: 0.2 M) and borate
(0.1 M) in D20 at pH = 11.0 and 25 °C.
In this respect it has to be noted that borate esters of tAreo-diols are more stable than those of erythro-diols. The same holds for borate 19 esters of sj7?-diols in comparison with those of anti-diols. The relative intensities of the various B signals gave a further confirmation of the assignments made. Since B NMR is not adequate to distinguish between the borate esters of different threo-diol functions in a given polyol, complete assignment requires additional techniques, such as H and C NMR. Although more research is necessary for the further refinement of Equation (8), Figure 5 once again demonstrates the versatility of B NMR as a tool for the structural analysis of borate esters.
Line widths
The line width of the B signal is dominated by the quadrupolar 20 relaxation. The quadrupolar relaxation rate in the case of rapid tumbling can be approximated by:
3(21+3) _ . n2 4nr ^s 21 1/T2 = 2 (2neZqQ/h)^(l+-)-—— (9) 401^(21-1) J Jkl -53- in which 2ne qQ/h is the quadrupole coupling constant, Ti the electric field gradient asymmetry, T| the solution viscosity, and in which the molecule under study is regarded as a rigid sphere with radius r. The other symbols have their usual meaning. Borate itself gave rise to a sharp line (10 Hz), as is expected since this ion possesses a strictly regular tetrahedral structure and, therefore, 22 a near zero field gradient. The line widths of borate esters were larger, (Table 1: 10-170 Hz) and were independent of C_ and C., i.e. the influence of exchange between free borate and its mono- and diesters is negligible. One exception was observed, viz. epi-inositol (11). For borate esters of the 1,2-diol type, the coordination of the central boron deviates more from an ideal tetrahedron than for those of the 1,3-diol type (Figure 3). Therefore, the electric field gradient q in Equation (9) is larger for borate esters of the 1,2-diol type. As a result, the line widths of the borate monoesters of the 1,2-diol type (10-60 Hz) are broader than those of the 1,3-diol (10-30 Hz). The line widths of the borate diesters varied between 20 and 170 Hz. An increase of the line width with a factor of about 1.5 is expected, as a result of the increase of the molecular radius. Overlap of signals of parent borate diesters is caused by signals of mixed borate diesters (Figure 5). The temperature dependence of the line widths was demonstrated for a solution of boric acid (0.1 M) and galactaric acid (24: 0.2 M) at pH = 11.0. Two signals were observed and assigned to the borate mono- and diester of the tAreo-2,3-diol function. Increasing the temperature from 20 to 95 °C resulted in a decrease of the line widths from 30 to 15 and from 90 to 30 Hz, respectively.
Association constants
The effects which determine the stability of the various borate esters will be discussed in the order of decreasing importance. Tridentate borate 13 23 esters are known to exist, ' but require polyols with specific config urations. y4iJ-cis-cyclohexane-l,3,5-triol (10) forms a tridentate ester with a relatively low association constant compared with epi-inositol(ll). This phenomenon can be understood by redefining K. as:
K: = [B~L]/([B"][L]) = ([L-]/[L]){[B"L]/([B~][L-])} = KJ-KJ. (10) -54-
all - cis - 1,3.5 - trihydroxyclohexane epi- inositol
G= 5-4^-L' (a.a.a) L (a.e.a.e.e.e) -fG=4 9
AGi = 5-4 AG1 =->-9 L(e,e,e) -tó=0
Figure 6. Free energy diagrams (kcal/mol) for tridentate borate ester formation of aii-cis^l,3,5-trihydroxycyclohexane (10) and epi- -inositol (11).
23 in which L' is the ring-inversed form of L. Using the data of Stoddart for the calculation of CG and CG' (Figure 6), K, - appears to be nearly constant L l and thus K. depends solely on KT„, the equilibrium constant for the cyclohexane ring inversion. The calculated difference in CG of 2.6 kcal/mol between epi-inositol and aii-cis-l,3,5-trihydroxycyclohexane is close to the experimental value of 3.8 kcal/mol. Although there has been some dispute concerning the relative stability of 24 borate esters of glycol (1) and 1,3-propanediol (4), it is now well o established that these esters are about equally stable. One of the causes of the dispute has been the fact that both substituted compounds and configurational isomers have been used in the comparison, which may change the picture dramatically. As monodentate borate esters are unstable in aqueous medium (log K, < 0), chelating effects seem to be a major factor determining cyclic borate ester stability. The stability of the 1,2-bidentate borate esters of the aldonates and aldarates is enhanced upon increasing the number of hydroxyl groups (n. ). UH To a lesser extent the same holds for 1,3-bidentate borate esters. It may be noted that for n-H > 2, borate esters of 1,2-diols generally are more stable than those of 1,3-diols. We have ascertained that no borate esters were Mforme. Althougd withh twsuco borath estere anions sexis bount d fotro thmannitole sugar ,acid s [(Bth e)„L presenc] at C„e o For the alditol series with nnH varying from 2 to 6, the overall association constants (glycol, glycerol, D-arabinitol, D-ribitol, I O IQ 18 17 D-xylitol, galactitol , D-glucitol, and D-mannitol ) increase upon increasing n-„ (Figure 7). Statistically the number of possibilities for a borate anion to bind an alditol as a 1,2-diol increases with nn„. In glycol there is just one mode, in glycerol two, etc. Introducing the statistic 2R effect in the entropy term of the Gibbs' equation, the increase in association constant going from glycol to glycerol would only be log (2/1) = 0.3. Because this statistic effect is too small to explain the observed increase in log K, an extra effect upon borate ester dissociation 7 - the stepwise hydrolysis of the two B-0 ester bonds - might be operative: a chelation-migration effect. After hydrolysis of the first B-0 bond formation of another B-0 bond, resulting in a new borate ester, competes with total hydrolysis. The escape difficulties of a borate anion upon hydrolysis might be translated into a stabilizing factor. It possibly also explains the difference in borate ester stability between 1,2- and 1,3-diols 29 when n_„ > 2. As suggested by Paal intramolecular hydrogen bonding might lo9 Ki 4 _ OH Figure 7. Log K. as a function of n„„ for borate esters of alditols UH ( V : glycol, : glycerol, A: D-arabinitol, □: D-ribitol, O: D-xylitol, ▲ : galactitol, • : D-glucitol, and ■ : D-mannitol). -56- be an additional stabilizing factor for borate esters of polyols. In the case of borate diesters steric constraints will hinder the formation of these intramolecular hydrogen bridges. The effects discussed above, together with a small substituent effect, are responsible for the influence of n_„ upon borate ester stability. Statistic and steric considerations will be used to explain the observed increase in A log K as a function of nn„: A log K = log Kx - log K2 (11) For a polydentate ligand, complex formation is assumed to be proportional to the number of available binding sites (for borate and the borate monoester this number is six and one, respectively) and dissociation is 30 proportional to the number of bound ligands. For glycol A log K = 1.0, 6/1 = close to the predicted value of log (T";Ö) !•!• With increasing n.u, A log K increases, which might be due to the relatively large enhancement of steric hindrance in the borate diesters. The configurations of the 1,2-dlol ( threo and erythro) and the 1,3-diol {syn and anti) moieties are also of importance. The diastereomeric tartrates (19 and 20) and 3,4-dihydroxyadipates (21 and 22) clearly show that threo- diols form more stable borate mono- and diesters than erytAro-diols. This is in agreement with results for the borate esters of (S,$)~ and meso-2,3- 17 ie lp -butanediol, of D-xylitol, D-arabinitol, and D-ribitol, ' of 1O 1 o lp galactitol, D-glucitol, and D-mannitol, and of l,6-dideoxy-l,6- 24 -dibromogalactitol and l,6-dideoxy-l,6-dibromo-D-mannitol. In addition, 19 syo-diola are known to form more stable borate esters than anti-diols. These differences in stability are mainly caused by differences in steric interactions between the substituents R and R' in the free diol and in the borate ester (Figure 8), which are estimated to be 1.0 and 2.5 kcal/mol for the borate esters of the diastereomeric 1,2- and 1,3-diols, respectively. Thus K., /K ., is about 6.5. This value agrees with experimental ratios varying from 3.4 to 14. Although the reaction enthalpy for the borate ester formation of terminal diols probably is somewhat smaller than that of tAreo-diols, loss of entropy will be more substantial and, therefore, K4.U > Kx • , > K ., , as is demonstrated for D-arabinonate (13) and threo terminal erythro v ' D-ribonate (14). Introduction of alkyl substituents increases the stability of the borate esters, as appears from the association constants for glycol (1), 1,2-pro- panediol (2), and pinacol (3). This is not only caused by inductive effects, -57- threo - diol OH TGT OH AG BT R,TVOH N R-r-°v/0H «"W OH B 'BT Ö NOH syn- diol anti - diol OH R OH GS '7/ OH R R'-/ T GA2^GS-1 AG BS AG BA i R G R' OH BA^GBS.15 OH I -O^/ VOH B- - GBS -O vOH '/» Figure 8. Free energy diagrams (kcal/mol) for borate ester formation of threo- and eryt/rro-diols and of syn- and anti-diols. 29 as has been suggested by Paal, because similar stabilities have been 31 observed for rac.-glycerate, 3-methoxy-l,2-propanediol, and 3-chloro-l,2- 24 —propanediol. Furthermore, the decrease of reaction enthalpy in the series glycol, 1,2-propanediol, 2,3-butanediol, 2-methyl-2,3-butanediol, and 17 pinacol does not parallel log K, because of entropy effects. So the variation of K, (2-20) and K„ (0.5-2.5) for substituted glycols will be due to both inductive and steric effects. We have started a series of empirical force field calculations for both free diols and the corresponding borate 32 monoesters, using Allinger's MM2 force field, to quantify the substituent 15 effects as well as some of the other effects dealt with in this section. A special substituent effect, that plays a secondary role in the overall picture, is observed upon introduction of negatively charged carboxylate groups. Generally, a decrease of the stability of a borate ester is -58- observed, as a result of electronic repulsion between the negatively charged COO and BO. moieties. Thus, the stabilities of the threo borate esters of D-arabinonate (13) and D-gluconate (17) are lower than those of D-lyxonate (15) and D-gulonate (18), respectively, because of smaller distances between the charged groups. The same holds for borate esters of the tartrates compared with those of the 2,3-butanediols (K, = 37 and 2.7 and K„ = 4.4 and 17 l £ 1.7 for threo- and erytAro-2,3-butanediol, respectively). Exceptions are the borate esters of erythro-2,3- and erythro-3,4-D-ribonate (14). The effect of temperature on the stability of borate esters was studied for the formation of the borate diester of galactarate (24): AH„ = -3 kcal/mol and C£„ = -6 kcal/mol.K were obtained. These values are in 17 the same region as those reported by Conner and Bulgrin for other diols and result in lower borate ester stability with increasing temperature, 33 which is in agreement with early results of Coops. Conclusions B NMR enables the distinction and direct identification of a variety of borate esters and, simultaneously, the determination of the corresponding association constants. This technique has definite advantages over the commonly used techniques, such as potentiometry and polarimetry. The present results, together with data from the literature, allow the formulation of empirical rules. For the B chemical shifts of the borate esters this is shown in Tables 2 and 3 and with Equation (8). The general rules for the relative stabilities of the borate esters can be summarized as follows: tridentate > bidentate > monodentate increase n0„ —«- more stable threo > terminal > erythro-diol syn > anti-diol Coulomb repulsion —►■ less stable log Kx - log K2 > 1.0 -59- These general rules will be helpful in the study of the interaction of borate with polyhydroxy compounds. It allowed us, for instance, to tackle some of the problems when dealing with the calcium(II) sequestering 12 34 abilities of borate-polyhydroxycarboxylate mixtures. ' Experimental All B NMH spectra were recorded at 25 °C on a Nicolet NT-200 WB spectrometer at 64.19 MHz using a 12 mm sample tube and 0.1 M boric acid in D„0 as external reference. Base line correction was applied to suppress the broad signal of the boron incorporated in the glass sample tube and in the insert. Sometimes it was necessary to use a deconvolution program to obtain all the signal characteristics. C and C. were 0-0.15 M and 0-1.0 M, respectively. Measurements were performed with D„0 as solvent at pH = 11.0. The total volume of each sample was 5 ml. Potassium D-lyxonate (15) and rac- and jneso-3,4-dihydroxyadipic acid (21, 22) were synthesized according to Moore and Link, Posternak and Susz, and Linstead et al., 38 respectively. L-Iditol, obtained by the reduction of D-sorbose, followed 39 by removal of D-glucitol with pyridine was converted into L-idaric acid 37 (23), using the procedure for the preparation of D-mannaric acid. References and notes 1. J. Böeseken, Adv. Carbohydr. Chem. 4 (1949) 189 and references cited therein. 2. M. Makkee, A.P.G. Kieboom, and H. van Bekkum, Carbohydr. Res. 138 (1985) 225. 3. M.S. Nieuwenhuizen, A.P.G. Kieboom, and H. van Bekkum, J. Am. Oil Chem. Soc. 60 (1983) 120. 4. J.A. Peters and A.P.G. Kieboom, Reel. Trav. Chim. Pays-Bas 102 (1983) 381 and references cited therein. 5. H. Peters, Neth. Pat. 99,202 (1961); Chem. Abstr. 56 (1962) 12682. 6. J.G. Heesen, Neth. Pat. 7,215,180 (1972); Chem. Abstr. 81 (1974) 176040. 7. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 40 (1984) 2901; this thesis, chapter 2. 8. W.G. Henderson, M.J. How, G.R. Rennedy, and E.F. Mooney, Carbohydr. Res. 28 (1973) 1. -60- 9. M. Makkee, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav.'Chim. Pays-Bas 104 (1985) 230. 10. Recently, the B chemical shifts, line widths, and association constants of borate esters of six other polyols were determined. fl?eso-2,3-butanediol: B L„ „: -14.2 ppm, 15 Hz, and 3.2 M ; B (L2 „)2: -10.7 ppm, 35 Hz, and 1.4 M . rac.-2-methylglycerate: B L9 „: -13.5 ppm and 45 Hz; B (L„ „)„: -9.4 ppm, 120 Hz, and 5.5 M . 2,4-dihydroxybutanoate: B L„ .: -18.1 ppm, 35 Hz, and 0.3 M . For D-mannarate, 2-keto-D-gluconate, and 2-carboxy-D-gluconate these data are given in references 11 and 12. 11. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav. Chim. Pays-Bas, in press; this thesis, chapter 4. 12. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Carbohydr. Res., submitted; this thesis, chapter 6. 13. P.J. Garegg and K. Lindström, Acta Chem. Scand. 25 (1971) 1559. 14. The mean O-B-0 valency angles and B-0 bond distances for the five membered borate ester rings were calculated using crystal structures from the Cambridge Data File; for the six membered borate ester rings these are obtained from reference 15. 15. M. van Duin, J.M.A. Baas, and B. van de Graaf, to be published; this thesis, chapter 13. 16. J.M. Furnée, thesis, Delft (1938). 17. J.M. Conner and V.L. Bulgrin, J. Inorg. Nucl. Chem. 29 (1967) 1953. 18. W.J. Evans, E.J. McCartney, and W.B. Carney, Anal. Biochem. 95 (1976) 383. 19. J. Dale, J. Chem. Soc. (1961) 922. 20. H. Nöth and B. Wrackmeyer, NMR:Basic Princ. Prog. 14 (1978). 21. A. Abragam, "The Principles of Nuclear Magnetism", Clarendon Press, Oxford (1961). 22. J.W. Akitt and W.S. McDonald, J. Magn. Res. 58 (1984) 401. 23. J.F. Stoddart, "Stereochemistry of Carbohydrates", Wiley Interscience, New York (1971) 58. 24. T. Paal, Magy. Kem. Foly. 34 (1978) 12 and references cited therein. 25. L. Petterson and I. Andersson, 'Acta Chem. Scand. 27 (1973) 1019. 26. R. Montgomery, Adv. Chem. Soc. 117 (1973) 197. 27. T. Paal, Acta Chim. Acad. Scient. Hung. 91 (1976) 393. 28. H. Sigel, Angew. Chem. 87 (1975) 391. 29. T. Paal, Acta Chim. Acad. Scient. Hung. 95 (1977) 31. -61- 30. R. Pizer, Inorg. Chem. 23 (1984) 3027. 31. G.L. Roy, A.L. Laferriere, and J.D. Edwards, J. Inorg. Nucl. Chem. 4 (1957) 106. 32. N.L. Allinger and Y.H. Yuh, QCPE 395 (1980). 33. J. Coops, thesis, Delft (1924). 34. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, J. Chem. Soc, Perkin Trans. II, in press; this thesis, chapter 5. 35. S. Moore and K.P. Link, J. Biol. Chem. 133 (1940) 297. 36. T. Posternak and J. Susz, Helv. Chim. Acta 39 (1956) 2032. 37. R.P. Linstead, N. Owen, and R.F. Webb, J. Chem. Soc. (1953) 1225. 38. M. Abdel-Akher, J.K. Hamilton, and F. Smith, J. Am. Chem. Soc. 73 (1951) 4691. 39. L. Wright and L. Hartmann, J. Org. Chem. 26 (1961) 1588. -63- CHAPTER 4 STRUCTURAl ANALYSIS OF BORATE ESTERS OF POLYBYDROXYCAHBOXYLATES IN WATER USING 13C AND XH NMR* Introduction Mixtures of borate and polyhydroxycarboxylates have good cation sequestering properties in aqueous alkaline solution and are applied in the galvanic, glass, and cement industry and as pharmaceuticals. In addition, these systems have been claimed as triphosphate substitutes in synthetic 2 3 detergent formulations. ' In aqueous medium boric acid and borate form cyclic esters with poly- hydroxycarboxylic acids, in which dicarboxylic acid, a-hydroxycarboxylic acid, and diol functions may be involved. At pH > 9 borate esters of the 4 diol functions are predominant (Figure 1). In C_- and CR-polyhydroxycarboxylates several diol functions are present, resulting in a large number of possible borate esters. Despite the high 7 -1-1 5 rates of borate ester formation at 25 °C (k„ s: 10 M s ), the exchange 1 11 13 between free ligand/borate and borate esters is slow on the H, B, and C NMR time scales. B NMR is a valuable tool in the study of these esters, because it enables the identification and the quantitative determination of threo-, erythro-, and terminal-l,2-diol and of 1,3-diol borate mono- and 4 6-9 diesters. ' The tAreo-diol functions are the preferred borate binding C p Q 1 1 sites. ' ' However, B NMR did not allow the distinction between borate esters' of different threo-diol functions, which for instance are present in D-gluconate (6), D-gulonate (7), D-glucarate (16), and L-idarate (17) (Figure 2), between borate monoesters (B L) and diborate esters [(B )_L], and between different diastereomeric borate diesters (B L„) (Figure 3). This 11 is probably due to the small differences in B chemical shifts with respect p to the line widths. * M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav. Chim. Pays-Bas, in press. -64- ■OH ■OH •OH ■OH B(OH\ ■OH O^© ^B(OH), OH l-O B- B"L OH r- OH ■OH HO- OH -OH + ■OH HO- O © -OH O^e^O- ^B(OH), O^ 2 -OH B"L + L B-Lc OH ^B(OH), OH 9 h-O^ B(OH)4 -o_ © ;B(OHI ;B(OHL -O' _ B"L B" (B )2L Figure 1. Borate ester formation for a polyol fragment of a polyhydroxy- carboxylate at pH > 9. Addition of boric acid, phenylboronic acid, and diphenylborinic acid to 1 13 solutions of polyols at varying pH is known to result in complex H and C 9-23 NMR spectra, containing a large number of new resonances. Small up- and downfield shifts with respect to the free ligands as well as changes in vicinal H coupling constants have been observed. This may be explained by conformational changes upon borate ester formation. In addition, primary shielding changes due to the inductive effect of the borate group may play a role 10 These phenomena have found use in the application of boric acid as a po pe 1 I NMR shift reagent. Heteronuclear coupling with B has not been 1 13 observed in H and C NMR spectra of borate esters. In the carbohydrate field protection of hydroxyl groups or blocking of the anomeric interconversion have been used in NMR investigations to limit the number of 9-11,13-17 borate binding sites. -65- coo" cooc coo"1 cooc COOs COO® -OH HO- HO- HO- — OH OH b-OH •— OH — OH HO — — OH HO — OH OH — OH r-OH OH "— OH — OH OH OH 2 6 coo" COOe COO"3 COO6 COOc COO® — OH HO- OH -OH HO- — OH HO- OH HO- -OH -OH HO — OH COO® COO€ COOfc OH OH -OH I—OH OH COO® 8 9 10 11 12 c e COO COO COO® cooe COO® COO® — OH OH —OH HO — OH HO- HO HO- HO- HO HO- — OH HO - OH I—OH (-OH OH OH HO- OH COOE COOe COO® COOe COOs COO® 13 14 15 16 17 18 Figure 2. Structures of polyhydroxycarboxylates. 26 The presence of a chiral axis in the spiro borate diesters may result in diastereomers or enantiomers, depending on the substitution of the parent diols (Figure 3). This is in agreement with previous observations of peak doubling and line broadening in H and C NMR spectra of borate esters. ' It should be noted that for borate diesters of enantiomerically pure polyols, as shown in Figure 3, the various nuclei of one of the polyol moieties are always equivalent to the corresponding nuclei of the other polyol moiety, due to the presence of a two-fold symmetry axis in these borate diesters. -66- polyol borate diesters X .O. X x ■OH ^ •OH TV> TV "6 X * Y pair of diastereomers X = Y pair of enantiomers x Y -OH Y°\/V Y°V°Y HO- X t Y pair of diastereomers X = Y a single isomer X x c HO- OH 'Y°W rV ■OH HO- / k / X^o \A Y^ O \ X t Y pair of enantiomers X = Y a single isomer Figure 3. Stereoisomeric borate diesters. 13 This chapter firstly describes the results of a C NMR study of the polyhydroxycarboxylates 1-4, 8-15, and 18 and the corresponding borate 11 esters, for which the structure has been elucidated earlier using B O O1? "I o NMR. ' These data result in a set of C chemical shift increments for borate ester formation, which is used to determine the structures of borate esters of other polyhydroxycarboxylates in which two different frAreo-diol functions are present. Furthermore, vicinal H coupling constants of both the free polyhydroxycarboxylates and the borate esters are used to investigate con- formational changes upon borate ester formation. -67- Results and discussion Spectral assignment Upon addition of borate to an aqueous solution of a polyhydroxycarboxy- 1 13 late at pH = 11.0, new sets of signals showed up in the H and C NMH spectra. Signals of the borate esters could be distinguished from the free polyol signals, because exchange between the free compound and the various 1 13 borate esters usually is slow on the H and C NMR time scale. Signals could be assigned to the borate monoesters (B L), the borate borate diesters (B L„), and the diborate esters [(B )„L] by a study of the variation of the intensities as a function of the ratio CD/CT. When several binding sites for the borate anion are of importance, a corresponding number of borate ester spectra appeared. Loss or conservation of C„ symmetry, as present in compounds 15, 17, and 18, upon borate ester formation are important features. The former resulted in a number of borate ester signals twice as large as that of the free polyol (cf. references 9 and 14). 13 C chemical shifts for the polyhydroxycarboxylates and their borate esters are compiled in Table 1. The data of the free aldonates agree with the results of Bock and Pedersen. For galactarate (15), L-idarate (17), and D-mannarate (18) the borate diester signals were rather broad while the borate monoester signals were not observed, probably as a result of exchange 13 phenomena. For D-ribonate (5) the large number of small C signals upon addition of borate, resulting from four borate esters of comparable 11 8 stability as determined with B NMR, devoided further interpretation. When peak doubling occurred for diastereoraeric borate diesters, the separation of the peaks was small (< 0.4 ppm), as would be expected. No attempt was made to assign the individual COO and HCOH carbon resonances of 3-8, 15, 17, and 18. The H NMR spectra of solutions containing borate and a polyhydroxy- carboxylate are very complex due to overlap of multiplets of borate mono- esters, diesters, and diborate esters in combination with line broadening caused by exchange phenomena. For compounds 1, 2, 11, and 15-18 spectra of the borate esters could be analyzed (Table 2). Peak doubling due to the presence of a chiral axis in the borate diester was observed only in the 29 1 case of D-glucarate. The H NMR spectra of the free polyhydroxycarboxy- 30 lates will be discussed in another chapter. Table 1. C chemical shifts3 of polyhydroxycarboxylates and corresponding borate esters. 13. polyhydroxycarboxylate species C chemical shifts COO CHOH CH20H CH0 1 (.fi^-glycerate L 178.8 73.4 64.2 B~L 182.4 74.0 65.6 B"L2 182.4 73.7 66.1 1+2 rac. -glycerate L 178.9 73.4 64.2 B_L 182.5 74.0 65.7 B~L2 182.5 73.8 66.2 L 179.3 72.3 71.7 71.3 63.2 3 D-arabinonate 05 03 B~L 182.6 74.2 72.5 72.0 64.4 B V 182.1 77.2 76.1 74.2 63.2 181.5 77.3 76.0 74.0 63.0 (B")2L 183.2 79.2 76.0 74.4 63.9 4 D-lyxonate L 178.7 73.7 71.9 71.3 63.0 B~L 178.1 75.6 74.3 72.8 65.1 e B"L2 178.0 75.6 73.7 73.2 64.9 177.9 75.6 73.6 73.0 64.7 5 D-ribonate L 178.2 73.6 73.4 71.7 63.0 6 D-gluconate L 178.7 74.2 72.7 71.3 71.0 62.7 B"L 179.6 76.6 75.0 74.9 74.5 63.2 BV 182.5 78.0 75.7 72.4 - 63.4 B L 75.9 73.8 71.9 - 66.2 Table 1 - continued: B V 179.6 76.9 74.9 74.6 74.4 63.2 179.5 76.7 74.8 74.4 74.4 63.2 BV' 181.9 75.9 75.4 72.2 - 63.1 181.7 75.9 75.3 72.0 - 63.1 (B")2L 180.0 77.2 76.3 75.5 74.5 64.3 7 D-gulonate L 178.9 73.7 72.8 72.5 70.6 62.7 B~L 178.1 75.9 74.6 73.7 72.3 63.8 B"L 178.0 75.7 73.8 73.0 72.4 63.9 - f BL2 - 75.0 74.1 73.3 - 64.3 (B")2l 178.3 75.9 75.4 75.4 74.3 63.7 8 D-mannonate L 179.2 73.9 71.0 70.7 70.6 63.1 i B~L 178.3 75.9 75.8 74.2 74.0 62.7 CO 1 e B"L2 178.4 76.1 75.4 74.4 74.4 62.7 178.1 76.1 75.0 74.2 74.0 62.5 (B")2L 178.7 76.4 75.6 74.9 74.9 63.3 9 jffeso-tartrate L 177.6 177. .6 74.9 74.9 B~L 180.1 180. .1 77.6 77.6 10 (.ff,.fl)-tartrate L 178.7 178. .7 73.9 73.9 B~L 182.1 182. ,1 78.2 78.2 B"L2 182.1 182. ,1 78.0 78.0 11 (S, 5)-tartrate L 178.5 178. 5 73.9 73.9 B_L 182.0 182. 0 78.3 78.3 B~L„ 182.1 182. 1 78.0 78.0 Table 1 - continued: 10+11 rac-tartrate L 178.7 178.7 73.9 73.9 B~L 182.1 182.1 78.3 78.3 B-L2 182.1 182.1 78.0 78.0 12 ineso-3,4-dihydroxyadipate L 180.4 180.4 71.9 71.9 40.2 40.2 B~L 180.9 180.9 73.0 73.0 39.7 39.7 13+14 rac. -3,4-dihydroxyadipate L 180.3 180.3 71.6 71.6 41.1 41.1 B~L 180.6 180.6 76.1 76.1 43.5 43.5 B"L2 180.6 180.6 76.1 76.1 43.8 43.8 15 galactarate L 179.5 179.5 71.8 71.8 71.5 71.5 B"L/B"L2 182.6 179.8 76.7 76.4 74.7 71.6 (B")2L 183.4 183.4 79.3 79.3 75.4 75.4 i o 16 D-glucarate L 178.5 178.4 73.7 73.7 73.6 71.7 B~L 179.6 178.2 76.1 74.6 74.4 74.0 e B-L2 179.7 178.1 75.7 74.2 73.9 73.7 179.7 177.9 75.4 74.1 73.7 73.6 17 L-idarate L 178.6 178.6 73.4 73.4 72.1 72.1 B~L/B~L9 179.6 179.6 76.3 76.3 73.7 73.7 - f BL2 182.4 179.0 75.7 75.3 73.9 72.9 (B )2L 182.7 182.7 78.6 78.6 76.0 76.0 18 D-mannarate L 179.1 179.1 73.9 73.9 71.7 71.7 B~L/B~L9 178.5 178.5 75.7 75.7 75.6 75.6 a b In ppm, relative to y>-dioxane as internal standard (6 = 66.6 ppm). C. = 0.2-0.5 M; C„ = 0-0.5 M; D90; COG pH = 11.0; 25 °C. 20.00 MHz. 50.31 MHz. The presence of a chiral axis results in two diastereomeric borate diesters. Borate ester with relatively low stability. Table 2. H NMR spectral parameters of polyhydroxycarboxylates and corresponding borate esters. polyhydroxycarboxylate species H chemical shift vicinal H coupling constant H2 H3 H4 H5 H2,H3 H3,H4 H4,H5 1+2 rac. -glycerate L 4.09 3.72 3.82c 6.0 Z.ld -11.8e C d e B"L2 4.25 3.58 3.98 7.4 1.2 8.1 11 (S, S)-tartrate L 4.35 4.35 1.6' B~L 4.20 4.20 B~L2 4.17 4.17 4.4' ~ 15 galactarate L 4.22 3.90 3.90 4.22 1.1 7 1.1 | B~L 4.17 3.74 3.75 4.22 < 2 ~ 7 < 2 1—|' B~L2 4.18 3.80 3.85 4.22 < 2 ~ 7 < 2 (B~)2L 4.13 3.75 3.75 4.13 < 2 ~ 8 < 2 16 D-glucarate L 4.10 4.03 3.90 4.08 3.0 4.7 4.6 B~L/B~\ 3.64 4.12 4.13 4.18 1.2 < 0.7 2.6 3.60 4.11 4.10 4.15 1.2 < 0.7 3.3 17 L-idarate L 4.16 4.03 4.03 4.16 < 5 - < 5 B~L/B"\ 4.15 3.90 3.90 4.15 < 6 - < 6 18 D-mannarate L 4.06 3.89 3.89 4.06 5.6 ~ 2 5.6 B~L/B"\ 4.04 3.95 3.95 4.04 /v 5 - ~ 5 a 1 200.07 MHz; H chemical shifts in ppm, relative to £-butanol as internal standard (S = 1.20 ppm) and b C d 3 coupling constants in Hz. C^ = 0.1-0.2 M; C = 0-0.5 M; DgO; pH = 11.0; 25 °C. 8(H3-). J(H2>H3-). e2 13 l 1 J(H3,H3,). 'using C satellites; J( U, C) = 145.9 and 149.2 Hz, respectively. -72- Structure determination of borate esters using 13 C NMR 11 With the use of B NMR we have previously determined the structure of p 0*7 the borate esters of compounds 1-4, 8-15, and 18. ' Minor differences 13 between the C chemical shifts of borate mono- and diesters (Table 1) suggest that for a particular polyhydroxycarboxylate the borate binding sites are the same in both esters. In the case of D-arabinonate (3), 13 D-lyxonate (4), and D-mannonate (8) peak doubling of the borate diester C signals was observed, as should be expected. For D-arabinonate (3) the ratio of the intensities of the two diastereomeric borate diesters was about 0.6. The borate diester with the lower stability will be (ff)-B (D-arabinonate)„, since for this diastereomer the proximity of the two C„C„ ends is sterically unfavourable, whilst the proximity of the two 4 5 carboxylate groups is electrostatically unfavourable in the absence of 29 coordinating cations. 13 The average C NMR substituent effects (AS) for borate ester formation obtained from compounds 1-4, 8-15, and 18 are given in Table 3. The most important feature is that relatively large downfield shifts are observed, both for the carbons in the five-membered borate ester ring and for the adjacent carbons. Substituent effects for more remote carbons are small 13 (AS < 1.5 ppm) and often upfield. The C substituent effects for borate esters of tAreo-diols generally are larger than those of erythro- and terminal diols. 13 In those cases where the C NMR spectra could not be fully assigned, the changes in the chemical shifts of the COO and CH„0H carbons are still 13 Table 3. Average C substituent effects (AS) upon borate ester formation using compounds 1-4, 8-15, and 18. position of carbons threo-diol erytJiro-diol terminal 1,2-diol carbons in borate ester ring 4.4 ± 0.3 (4) 1.9 ± 0.8 (2) 1.1 ± 0.8 (4) neighbouring carbons 2.7 ±1.1 (12) 1.0 ± 1.5 (2) 3.6 ± 0.0 (2) more remote carbons -0.2 ± 1.4 (18) 0.5 (1) In ppm; the symbol ± denotes the range of experimental substituent effects; the number of experimental values is given between brackets. -73- indicative for the position of the borate binding site. As a result, a more detailed structural analysis of the borate esters of D-gluconate (6), D-glucarate (16), L-idarate (17), and D-gulonate (7) is possible, using both the substituent effects of Table 3 and earlier B NMR results which showed that threo-diol moieties are preferentially involved in borate ester formation. For D-gluconate (6) two sets of borate diester signals were observed with 13 an intensity ratio of about 90/10. The substituent effects on the C chemical shifts of the COO and CH„0H carbons of the major diester are small (AS, _ < 1.1 ppm), thus borate ester formation occurs at the threo-3,4- -position. The COO carbon signal of the minor borate diester shows a downfield shift of 4.0 ppm with respect to the free D-gluconate, which demonstrates that here D-gluconate is esterified at the £A.reo-2,3-position. This D-gluconate is assumed to belong to a mixed borate diester with one D-gluconate bound at the threo-2,3- and the other at the tA/-e»-3,4-position, since the stability of this mixed borate diester will be relatively larger than that of the borate diester with both D-gluconates bound at the threo— 2,3-positions. Probably the nuclei of the 3,4-bound D-gluconate of the mixed 13 borate diester (20%) are in fast exchange on the C NMR time scale with those of the borate diester with both D-gluconates bound at the threo—3,4- positions (80%). In addition to the spectra of the corresponding threo-3,4 and threo-2,3 borate monoesters, signals were identified belonging to a small amount of a third borate monoester. In this borate monoester D-gluconate is bound at the ery£Aro-4,5-position (A8R = 3.5 ppm), which is in agreement with earlier B 8 NMR results. Analogously it is shown that borate esters of D-glucarate (16) involve the £Areo-3,4-diol function (AS, _ < 1.2 ppm). l,b For L-idarate (17) two borate diesters were observed. In the more stable borate diester (80%), L-idarate has conserved its C„ symmetry and the COO carbon resonances are only 1.0 ppm downfield with respect to free L-idarate. Therefore, this compound is the threo-3,4 borate diester. In the less stable borate diester (20%), L-idarate has lost its C„ symmetry and the induced carboxylate shifts are 3.8 and -0.6 ppm. Here, L-idarate is probably part of a mixed borate diester and will be bound at the £Areo-2,3/4,5-positions. As in the case of galactarate (15) six signals were observed, showing that the interconversion between the borate diesters with borate bound at the threo— 13 2,3- and at the equivalent £Areo-4,5-position is slow on the C NMR time scale. -74- For D-gluconate (6), D-glucarate (16), and L-idarate (17) borate is preferentially bound at the £Areo-3,4-positions whereas, for instance, in g D-glucitol both the threo-2,3- and £Areo-3,4-positions are involved. This difference might result from the electrostatic repulsion between the negatively charged BO. moiety and carboxylate groups, which is in agreement 11 8 with previous B NMR results. The results on the borate esters of D-gulonate (7) do not allow an unam biguous structure determination. The somewhat higher chemical shift of the CH„OH carbon in the minor mixed borate diester (20*) suggests that the £Areo-4,5 ester is involved, whereas the major compound (80*) probably is 31 the threo-3,4 ester. This is in agreement with results of Moore et al., who have demonstrated that borate ester formation occurs more readily near the centre of polyhydroxy compounds. For D-gulonate (7) electrostatic repulsion cannot account for the four fold higher stability of the borate diester with borate bound at the threo— 3,4-position with respect to that of the mixed borate diester, which also involves the £Areo-4,5-position. Other effects, such as differences in hydration or changes in conformation in order to avoid sy/f-l,3-interactions might be of importance. 13 Recalculation of the substituent effects after analysis of the C data of all compounds resulted in the values as given in Table 3 within the standard deviations. In some cases also diborate esters [(B )„L] were observed; There is only one configurational possibility for the diborate esters of D-arabinonate (3), galactarate (15), and L-idarate (17), viz. with the two borate anions bound at the 2,3- and 4,5-positions. As a result, relatively large downfield shifts are found for all carbons. For the diborate esters of D-gluconate (6), D-gulonate (7), and D-mannonate (8) this phenomenon was also observed, with the exception of the COO resonances. Thus the two borate anions occupy the 3,4- and 5,6-positions in these compounds. Diborate esters only occur when the non-esterified diol functions in a borate monoester have a tAreo-configuration or are terminal (compounds 3, 6-8, 15, and 17). The existence of these esters demonstrates that Coulomb repulsion between negatively charged groups is only of secondary importance with respect to the stability of borate esters. In this respect, it may be 11 8 noted that our previous B NMR investigations have been performed at lower borate concentrations (C_ < 0.15 M) and, consequently, diborate ester forma- tion was of'minor importance. -75- Conformational changes upon borate ester formation as studied with ff NMR 13 1 Contrary to the C NMR results, we observed no regular patterns for H NMR chemical shift changes upon borate ester formation (AS = -0.5 to 0.2 ppm; Table 2). Changes in vicinal H coupling constants may give information about conformational changes. Coupling constants for the free polyhydroxycarboxylates without sj77-l,3-interactions (11, 15, and 18) point 3 to the predominance of the planar zig-zag conformation [ J(H,H., ) < 3 Hz and J(H,H ., ) > 5 Hz]. On the other hand, free polyhydroxycarboxylates with s.*77-l,3-interactions (16, cf. reference 30) had J(H,H., ) > 3 Hz or J(H,H .. ) < 5 Hz, which suggests the existence of equilibria between planar, bent, and sickle conformations. This is in agreement with literature 30 32-40 data on various related systems. ' For rac.-glycerate (1+2) the vicinal coupling constants increased upon borate ester formation from 6.0 to 7.4 and from 3.1 to 7.2 Hz. For the free rac.-glycerate the coupling constants correspond with a conformation with 41 the torsion angle 0„C9C„0„ estimated to be 60°, which is in agreement with 42 stabilization of the gauche conformations of vicinal diols in water. For the borate diester the 0„C„C„0„ torsion angle is about 20°. 3 For (5,5)-tartrate (11) the increase in J(H„,H3) from 1.6 to 4.4 Hz corresponds with a conformational adaptation upon borate diester formation, viz. a change of the torsion angle 0„C9C_0„ from -70 to about 0°. For D-glucarate (16) the decrease of J(H„,H4) from 4.6 to < 0.7 Hz illustrates the change of the conformational equilibrium around the C„C, bond in the free system towards a more rigid system in the borate diester. 3 From J(H„,H.) the torsion angle OqC„C.O. in the borate diester is estimated to be 30-60°, the lower value being more likely. The changes in the other coupling constants upon borate ester formation indicate that the C.C. part of D-glucarate is predominantly in a planar zig-zag conformation, whereas the torsion angle C„C.C,.CK changes to about -60 or 50°, the former value being more likely for steric reasons (Figure 4). Finally for galactarate (15), L-idarate (17), and D-mannarate (18) no significant changes in coupling constants were observed upon borate ester formation and, therefore, the free compounds and the borate diesters have similar zig-zag conformations (Figure 4). This has to be expected since the O.C.C.O. moieties of the free compound (the threo-i,j-position being preferred for borate ester formation) are already in a gauche conformation due to steric interactions in the carbon chain. -76- Figure 4. Structures of the borate diesters of L-idarate (17; a) and D-mannarate (18; b) and of the {ft)- and (S)-borate diesters of D-glucarate (16; c and d). Conclusions 11 13 In addition to B NMR, C NMR chemical shift increments are very helpful in the determination of the binding site of the borate anion in polyhydroxycarboxylates. In this way it is established that D-gluconate (6), D-glucarate (16), L-idarate (17), and probably D-gulonate (7) preferentially bind borate at the £Areo-3,4-positions. H NMR gives insight into the conformational changes of the polyhydroxy carboxylates upon borate ester formation. The value of the OCCO torsion angle of the borate ester ring ranges from 30 to -30°, which will be 43 compared with results of an empirical force field study. -77- In the next chapter we will present a detailed NMR study of the interesting calcium(II) coordinating properties of the D-glucarate-borate . 29 system. Experimental NMR spectra were measured for solutions of the polyhydroxycarboxylate (C. = 0.2-1.0 M) and borate (Cfl varied between 0 and 0.5 M) in D„0 (galactarate: D-O/HgO = 50/50: v/v) at pH = 11.0 (NaOD) and 25 °C. 1H NMR spectra were recorded with a Nicolet NT-200 WB spectrometer at 200.07 MHz using t-butanol as internal reference (5 = 1.20 ppra). H chemical shifts and coupling constants were determined using the LAOCOON spin simulation 1 13 program. H decoupled C NMR spectra were recorded with a Varian CFT-20 or a Nicolet NT-200 WB spectrometer at 20.00 and 50.31 MHz, repectively, using p-dioxane (8 = 66.6 ppm) as internal standard. D-Ribonate (5), D-gluconate (6), D-mannonate (8), and D-mannarate (18) were obtained by hydrolysis of the corresponding lactones. D-Lyxonate (4), the 3,4-dihydroxyadipates (12, 13+14), and L-idarate (17) were prepared as o described previously. D-Mannaric acid dilactone and (.ff)-glyceric acid were 44 45 prepared according to Linstead et al. and Baer et al., respectively. In order to avoid ethyl ester formation, the former compound was not recovered with ethanol/diethyl ether but with acetone/diethyl ether. References and notes 1. W. Kliegel, "Bor in Biologie, Medizin und Pharmazie", Springer-Verlag, Berlin (1980). 2. H. Peters, Neth. Pat. 99,202 (1961); Chem. Abstr. 56 (1961) 12682. 3. J.G. Heesen, Neth. Pat. 7,215,180 (1972); Chem. Abstr. 81 (1974) 176040. 4. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 40 (1984) 2901; this thesis, chapter 2. 5. R. Pizer and L. Babcock, Inorg. Chem. 16 (1977) 1677. 6. W.G. Henderson, M.J. How, G.R. Kennedy, and E.F. Mooney, Carbohydr. Res. 28 (1073) 1. 7. K. Yoshino, M. Kotaka, M. Okamoto, and H. Kakihana, Bull. Chem. Soc. Jpn. 52 (1979) 3005. -78- 8. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 41 (1985) 3411; this thesis, chapter 3. 9. M. Makkee, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav. Chim. Pays-Bas 104 (1985) 230. 10. R.W. Lenz and J.P. Heeschen, Polymer. Sci. 51 (1961) 247. 11. M. Mazurek and A.S. Perlin, Can. J. Chem. 41 (1963) 2403. 12. J. Knoeck and J.K. Taylor, Anal. Chem. 41 (1969) 1730. 13. W. Voelter, C. Bürvenich, and E. Breitmaier, Angew. Chem. 84 (1972) 589. 14. P.A.J. Gorin and M. Mazurek, Carbohydr. Res. 27 (1973) 325. 15. P.A.J. Gorin and M. Mazurek, Can. J. Chem. 51 (1973) 3277. 16. S. Aronoff, T.C. Chen, and M. Cheveldayoff, Carbohydr. Res. 40 (1975) 299. 17. G. de Wit, thesis, Delft (1979). 18. Th. Posternak, E.A.C. Lucken, and A. Szente, Helv. Chim. Acta 50 (1967) 326. 19. P.J. Garegg and K. Lindstrttm, Acta Chem. Scand. 25 (1971) 1559. 20. S.J. Angyal, J.E. Klavins, and J.A. Mills, Aust. J. Chem. 27 (1974) 1075. 21. J. Liu and C. Jiang, Youji Huaxue 428 (1984); Chem. Abstr. 102 (1984) 149645. 22. W.B. Smith, J. Org. Chem. 44 (1979) 1631. 23. H. Asaoka, Carbohydr. Res. 118 (1983) 302. 24. F. Fernandez-Gadea, M.L. Jimeno, and B. Rodriguez, Org. Magn. Res. 22 (1984) 515. 25. F. Fernandez-Gadea and B. Rodriguez, J. Org. Chem. 49 (1984) 4721. 26. J. Rigaudy and S.P. Klesney, "Nomenclature of Organic Chemistry", Pergamon Press, Oxford (1979) 489. 11 8 27. The B cemical shifts, line widths, and association constants of the borate esters of D-mannarate (18) are: _ _1 B L3 4: -13.2 ppm, 30 Hz, and 71 M _1 B~(L3 4)2: -9.1 ppm, 90 Hz, and 4.2 M . 28. K. Bock and C. Pedersen, Adv. Carbohydr. Chem. Biochem. 41 (1983) 63. 29. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, J. Chem. Soc, Perkin Trans. II, in press; this thesis, chapter 5. 30. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Magn. Res. Chem., in press; this thesis, chapter 10. 31. R.E. Moore, J.J. Barchi Jr., and G. Bartolini, J. Org. Chem. 50 (1985) 374. -79- 32. S.J. Angyal, D. Greeves, and J.A. Mills, Aust. J. Chem. 27 (1974) 1447. 33. A.P.G. Kieboom, T. Spoormaker, A. Sinnerna, J.M. van der Toorn, and H. van Bekkum, Reel. Trav. Chim. Pays-Bas 94 (1975) 55. 34. S..T. Angyal and R. Le Fur, Carbohydr. Res. 84 (1980) 201. 35. D. Horton, Z. Walaszek, and I. Ekiel, Carbohydr. Res. 119 (1983) 263. 36. D. Horton and Z. Walaszek, Carbohydr. Res. 105 (1982) 95. 37. T. Taga, Y. Kuroda, and K. Osaki, Buil. Chem. Soc. Jpn. 50 (1977) 3079. 38. G.A. Jeffrey and R.A. Wood, Carbohydr. Res. 108 (1982) 205. 39. G.K. Ambady, Acta Crystallogr. B24 (1968) 1548. 40. N.C. Panagiotopoulos, G.A. Jeffrey, S.J. la Place, and W.C. Hamilton, Acta Crystallogr. B30 (1974) 1421. 41. C.A.G. Haasnoot, F.A.A.M, de Leeuw, and C. Altona, Tetrahedron 36 (1980) 2783. 42. M. van Duin, J.M.A. Baas, and B. van de Graaf, J. Org. Chem. 51 (1986) 1298; this thesis, chapter 11. 43. M. van Duin, J.M.A. Baas, and B. van de Graaf, to be published;this thesis, chapter 13. 44. R.P. Linstead, L.N. Owen, and R.F. Webb, J. Chem. Soc. (1953) 523. 45. E. Baer, J.M. Grosheintz, and H.O.L. Fischer, J. Am. Chem. Soc. 61 (1939) 2609. -81- CHAPTKR 5 THE AQUEOUS D-GLUCARATE-BORATE-CALCIUM(II) SYSTEM AS STUDIED WITH 1H, 11B, AND 13C NMH* Introduction The cation sequestering capacities of aqueous solutions of polyhydroxy carboxylic acids are known to increase substantially upon the addition of (per)boric acid at pH > 9.5. Mixtures of borate and D-glucarate (G: Figure 1), for example, are disclosed in the patent literature as potential sodium 1 2 triphosphate substitutes in detergent formulations. ' This prompted us to study the structure and stability of both boric acid esters and borate esters of polyhydroxycarboxylic acids in aqueous medium with multinuclear 3-5 NMR. Formation of borate esters takes place instantaneously in water at 25 °C, but the exchange on the NMR time scales generally is slow. Although both the carboxylic acid and hydroxyl functions may be involved in ester formation, above pH 9 borate mono- and diesters of diol functions 3 are predominant (Figure 2). TAreo-diol functions are preferred as borate c,ooe D-gluconate H—C2 —OH end / I HO —C3—H I H-C4-OH D-mannonate I H —CI 5 —OH end I | c6oo° Figure 1. D-Glucarate (G) containing a D-gluconate (C,C„C„) and a D-manno nate end (C.CgCg). M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, J. Chem. Soc, Perkin Trans. II, in press. -82- r-OH pOH e B(OH), 4=^ ^B(OH)2 •—o . L L B B'L B'L Figure 2. Equilibria between borate (B ) and a diol function of a polyhy- droxycarboxylate (L) at pH > 9. binding sites, while Coulomb repulsion between the carboxylate group(s) and the borate anion may be a secondary directing effect with respect to the 4 5 stability of the borate esters. ' The aim of the present investigation is to elucidate the structural origin of the pronounced calcium(II) sequestering properties of the D-glucarate-borate system with the use of a combination of H, B, and C NMR. Concentration, pH, and temperature effects are included. Results and discussion The system D-glucarate-borate 11 4 Previous B NMR experiments have shown that upon addition of boric acid to a solution of D-glucaric acid in D„0 at pH = 11.0, borate mono- and diesters of tAreo-diol functions are formed preferentially. Borate esters of the eryfcAro-4,5- and sj7?-2,4-diol functions are less stable (Table 1). In 13 1 this chapter C (Table 2) and H NMR (Table 3) are used to obtain more detailed structural information on these borate esters, in particular to determine whether the main borate binding site is the tJireo-2,3- or threo- -3,4-diol function. 13 The C NMR signals of free D-glucarate, with the exception of the carboxylate resonances, were assigned using 2D heteronuclear shift 13 correlation. Separate C NMR signals for the borate mono- and diesters occured, since the exchange between free D-glucarate and the borate monoester and between the borate monoester and the borate diester is slow on 13 13 the C NMR time scale. The various carboxylate and hydroxymethylene C signals of each ester could not be assigned unambiguously. -83- Table 1. 11B NMR data and association constants of borate esters of D-glucarate. a borate binding site 6** Avv, Vi" (ppm) (Hz) (M *) _ B~L B L2 B~L B~L2 B~L B~L2 £/?reo-2,3/3,4-diol -13.4 -9.5 45 110 180 30 eryt/iro-4,5-diol -14.0 30 20 syn-2,4-diol -17.9 - 10 threo-2,3/3,4-diol (+ phenylboronate ) -12.3 305 240 ot-hydroxycarboxylic acid -12.7 -9.4 170 210 64.19 MHz; CG = 0-0.2 M; C = 0-0.1 M; DgO; 25 °C. Relative to 0.1 M c — boric acid in D„0 as external reference. Association constant for B L — — it n defined as K„- = [B~L ]/([B L J[L]). Phenylboronate: 6 = -16.2 ppm and o lTi n n—x n flv,, = 100 Hz. / z a Table 2. 13 C chemical shifts for D-glucarate and its borate esters. compound C C l /c 6 C2 C3 C4 5 D-glucarate 178.5 178.4 73.7 71.7 73.7 73.6 borate monoester 179.6 178.2 76.1 74.6 74.4 74.0 borate diester 179.7C 178.1 75.7C 74.2 73.9 73.7 179.7C 177.9 75.7C 74.1 73.7 73.6 50.31 MHz; in ppm; p-dioxane as internal standard (6 = 66.6 ppm); b CQ = 0-0.2 M; CB = 0-0.5 M; DgO; pH = 11.0; 25 °C. The assignments of C^ and of C, , . 5 may be interchanged. Broad signals. -84- For the main borate mono- and diesters 6 and 12 resonances were observed, respectively. The close resemblance of the spectra for these borate mono- and diesters indicates that D-glucarate is bound to borate in a similar way in these esters. Upon borate ester formation the carboxylate signals under went small shifts (-0.6 < _A6 < 1.5 ppm). As such small shift differences are 13 characteristic for C atoms at the p- or y-position with respect to the borate binding site, the main binding site of borate in D-glucarate is the 13 tAreo-3,4-position. The observation of 12 C resonances for the borate 5 diester of D-glucarate is due to the occurrence of a pair of diastereomers. Threo-2,3 borate esters of D-glucarate could not be excluded using B NMR. 1 *? Since in the C NMR spectra no extra signals were observed besides those of the threo-3,4 borate esters, the stability of the threo-2,3 borate esters appears to be substantially smaller than that of the tJireo-3,4 borate esters. The H NMR spectrum of D-glucarate was assigned using selective labelling of the 2-position with deuterium. The results confirm that H9 is the most 6 7 deshielded oe-proton. ' Addition of boric acid to a solution of D-glucaric 1 9 Table 3. H NMR data for D-glucarate and its borate esters. compound H chemical shift 3J(H,H) (ppm]1 (H2) H ,H H2 H3 H4 H5 H2,H3 H3,H4 4 5 D-glucarate 4.073 3.998 3.876 4.061 2.7 4.6 4.6 borate diester 3.623 4.077 4.099 4.146 1.3 < 1.2 3.1 3.594 4.061 4.060 4.112 1.4 < 1.2 3.2 phenylboronat e monoester 3.63 4.25 4.17 4.28 1.0 < 1 2.8 3.70 4.25 4.27 4.31 1.0 < 1 3.2 diphenylborinate monoester 3.64 - - - < 3 — - a C_ = 0-0.2 M; C = 0-0.5 M; D„0; 25 °C. ISButanol as internal standard u an c (8 = 1.20 ppm). C 500 MHz; pH = 9.0; flv, = 1.2 Hz for all signals. d 'z 200.07 MHz; pH = 11.0; Av,. = 0.8 Hz for the free D-glucarate signals and / z about 3 Hz for those of the esters. -85- acid at pH = 11.0 (C_/C_ < 1) resulted in two additional sets of signals, a u besides the signals of free D-glucarate. This indicates slow exchange on the H NMR time scale between D-glucarate and its borate esters of the preferred iAreo-3,4-dlol function. The two sets of signals were quite similar and their intensity ratio (0.9/1.0) was independent of C-/CL,. This phenomenon again demonstrates the occurrence of two diastereomeric borate diesters of D-glucarate. This was further confirmed using phenylboronate and diphenylborinate as the esterifying agents (Table 3). In the case of phenyl boronate, a boronate monoester (Table 1) with a chiral center atom is formed and the two diastereomers gave rise to two sets of H signals. In contrast, the boron center of the borinate monoester of diphenylborinate is achiral and no peak doubling was observed. 11 13 B (Table 1) and C NMR (Table 2) spectra demonstrated the presence of appreciable amounts of borate monoester of the £Areo-3,4-diol function. Since for this species no separate H NMR signals were observed, the exchange between the borate mono- and diester nuclei is probably fast on the H NMR time scale. This might be supported by the small upfield shifts (< 0.01 ppm) observed upon increasing C_/C_. For C_ > C„ only a few broad H resonances were observed, probably due to a change in chemical exchange rates. Broad signals were also obtained for samples with lower C_ upon increasing the temperature. Conformational changes of D-glucarate upon borate ester formation were studied with the use of vicinal H coupling constants (Table 3). Torsion angles HCCH were estimated using the semi-empirical relation of Haasnoot et 8 al. For free D-glucarate, equilibri6,7 a between two or three linear and bent conformations have been suggested Upon borate ester formation a decrease Figure 3. Diastereomeric (It)- and (5)-borate diesters of D-glucarate in water (symbols as in Figure 5). -86- of J(H„,H-) was observed, which is in agreement with the formation of a borate ester ring including 0„ and 0.. The torsion angle C,C„C„C. of D-glucarate in the borate esters is about 170°, which demonstrates that the C.C,. part is in the planar zig-zag conformation. The torsion angle C-C.C-C,. is estimated to be either -60 or 50°, the former value being more likely for steric reasons. The resulting solution structures of the diastereomeric (ft)- and (,S)-borate diesters of D-glucarate with borate bound at the threo- -3,4-position are given in Figure 3. Here (R)~ and (5)- represent the g configuration at the central boron atom. The system D-glucarate-borate-calcium(II) The effects of stepwise addition of calcium(II) chloride to a solution of boric acid (0.1 M) and D-glucaric acid (0.1 M) at pH = 10.5 up to C„ = 0.08 M, where precipitation occurred, were studied with B NMR. The 11 exchange of borate remained slow on the B NMR time scale, whereas the exchange between the various borate esters and the corresponding calcium(II) complexes was fast on the B NMR time scale, as no separate B signals were observed for the calcium(II) complexes. Upon calcium(II) chloride 006 [M] 004 002 O 0025 005 0075 01 * CCa HJ Figure 4. Effect of calcium(II) upon the concentration of boron containing species for a solution of boric acid (0.1 M) and D-glucaric acid U (0.1 M) in D20 at pH = 10.5 and 25 °C as determined with B NMR. -87- addition up to C_ = 0.04 M, the total amount of the borate diester containing species (borate diesters and their calcium(II) complexes) increased about one mol per two mol of calcium(II), whereas the concentrations of the borate monoester and of free borate decreased (Figure 4). The total concentration of the erytAro-4,5 and syn-2,4 borate ester remained < 0.01 M. So the borate diesters of D-glucarate are the predominant calcium(II) coordinating species, which was supported by a small calcium(II) induced shift (CalS) of the B resonance of the borate diesters (0.5 ppm). Furthermore, each borate diester contains two calcium(II) coordinating sites. The line widths of the borate mono- and diester signals increased, from 60 to 100 and from 170 to 250 Hz, respectively, which may be ascribed to exchange phenomena or to an increase of the electric field asymmetry upon calcium(II) coordination. The synergic calcium(II) sequestration in solutions of borate and D-glucarate thus finds its origin in the good calcium(II) coordination by the borate diesters of D-glucarate. The borate anion brings two D-glucates, each of which coordinates calcium(II) only moderately, together and thus creates two new calcium(II) coordinating sites. Each site consists of two carboxylate oxygens (each of a different D-glucarate molecule), two oxygens of the five membered borate ester rings, and up to two non-esterified a-hydroxyl oxygens, depending on the a-CHOH configuration (Figure 5). In the solid state some related structures are known, viz. the borate 11 12 diesters of malic acid and rac.-tartrate, KB (malic acid)„.H„0 and Figure 5. Calcium(II) coordination in the diastereomeric (Jt)- and (5)-borate diesters of D-glucarate in water. -88- Figure 6. Solid state coordination sites in borate diesters of malie acid (K ) and rac. -tartrate (Na ) (symbols as in Figure 5). Na-B (rac.-tartrate)o.8Ho0, respectively (Figure 6). Here the coordination polyhedron of the alkali ions consists of two carboxylic acid or carboxylate oxygens, each belonging to a different polyhydroxycarboxylic acid of the borate diester, one oxygen of the borate ester ring, and two other oxygens. 13 14 In the natural borate esters boromycine and aplasmomycine, two oxygen atoms (each of a different five membered borate ester ring) contribute to the coordination of the monovalent cations. Cooperation of two or more carboxylate groups is known to result in relatively good calcium(II) coordinating sites, as has been shown for relatively small ligands such as 15 oxalate, oxydiacetate, citrate, and carboxymethyloxysuccinate, but is even 1 fi more evident for larger molecules, such as oxidized polysaccharides and 17 calcium(II) binding proteins. To elaborate the structural changes of the borate diesters of D-glucarate upon calcium(II) coordination, calcium(II) chloride was added to solutions containing boric acid and D-glucaric acid at elevated pH until precipitation 1 13 occurred. The H and C NMR chemical shifts (Figures 7 and 8) confirm that the borate diesters are the main calcium(II) coordinating species, since only the borate diester signals showed a significant CalS. After addition of 13 calcium(II) chloride all diastereomeric borate diester C signals were separated. Comparison of the conformations of the two diastereomeric borate diesters of D-glucarate (Figure 3) with the corresponding calcium(II) coordination compounds (Figure 5) shows that, upon coordination of the 6-carboxylate a rotation of the torsion angle CC..C..C., from 60 to 180° is required. o o ** O O Accordingly J(H4,Hg) increased upon calcium(II) chloride addition, whereas the other vicinal coupling constants remained constant. Thus both D-gluca- -89- ppm] O O-05 0 10 O-15 * CCQ [M] Figure 7. Calcium(II) induced H NMR shifts for a solution of boric acid (0.1 M) and D-glucaric acid (0.2 M) in DgO at pH = 9.0 and 25 °C. rates probably are in a planar zig-zag conformation in the dicalcium(II) complexes of the borate diesters (Figure 5). Molecular models show that oc-hydroxyl groups belonging to the D-gluconate ends (C„) are able to participate in the calcium(II) coordination, contrary to those of the D-mannonate ends (C,). This contribution was reflected by the relatively large CalS of the H„ signals of D-glucarate in the borate diesters, viz. 0.17 and 0.10 ppm at C 0.11 M (Figure 7). Ca As a consequence, three different calcium(II) coordinating sites exist in the borate diesters. Because of the required C.C_ rotation upon calcium(II) coordination and the lack of coordination of the 5-hydroxyl in the case of a D-mannonate end, the calcium(II) coordination strength is assumed to decrease in the order of sites composed of two D-gluconate ends, of one D-gluconate and one D-mannonate end, and of two D-mannonate ends. Distinction between the two sets of four H signals for each of the diastereomeric borate diesters was possible, because the CalS curves of one -90- 6 [ppm] 7CO 13 Figure 8. Calcium(II) induced C NMR shifts for a solution of boric acid (0.15 M) and D-glucaric acid (0.2 M) in D„0 at pH = 10.5 and 25 °C. set of signals were concave vs. C_ whereas those of the other set were 1 13 convex (Figure 7). The intensity ratio of both the H and the C signals of the two diastereomeric diesters was about 1.0 and was independent of the amount of calcium(II) present. Thus the overall calcium(II) coordinating strength of the (#)- and (S)-borate diesters of D-glucarate are comparable. This is probably due to the fact that the (V^-borate diester contains two equal pentadentate coordination sites, while the (5)-borate diester contains one tetra- and one hexadentate coordination site. Additional evidence for the cooperation of two carboxylate groups upon borate diester formation was obtained from D-arabinonate. Borate ester formation occurs at the £Areo-2,3-position, which for the borate diester results in two diastereomers. Upon addition of calcium(II) chloride -91- Figure 9. Calcium(II) coordination in the diastereomeric (ff)- and (5)-borate diesters of D-arabinonate in water (symbols as in Figure 5). 13 considerable CalS for one set of borate diester C resonances was observed, whereas the other signals did not shift at all. Furthermore, the intensity ratio between the shifted and non-shifted borate diester signals increased from 0.6 (C_ = 0) to 4 (C_ = 0.1 M) and the signals of free D-arabinonate uB LB and its borate monoester almost disappeared. Obviously, preferential calcium(II) coordination by the (/Q-borate diester, acting as a tetradentate ligand, is favourable (Figure 9). For free D-glucarate the CalS of H, and H- were larger than those of H„ and H., viz. 0.025 and 0.024 vs. 0.018 and 0.011 ppm (C. = 0.11 M). This H Ca agrees with the general observation that in calcium(II) coordination compounds of polyhydroxycarboxylates the carboxylate and the oc-hydroxyl oxygens form the calcium(II) coordinating site. ' Plotting the CalS of H„, H,, and H. as a function of the CalS of H, for free D-glucarate gave straight lines, whereas plots of the CalS vs. C. (Figure 7) were convex. oa These data suggest that D-glucarate as such binds just one calcium(II) ion, only when the relatively strongly coordinating sites in the borate diesters are fully occupied. Effect of concentration, pH, and temperature on the D-glucarate~borate- -calcium(II) system Upon dilution of a solution with boric acid (0.1 M) and D-glucaric acid (0.1 M) at pH = 11.0, B NMR spectra demonstrated that the concentrations of the borate mono- and diesters of D-glucarate decrease as should be -92- expected. At C_ = C_ < 0.025 M the borate diester signal was no longer observed. The association constants as given in Table 1 did not change significantly upon dilution. In the presence of calcium(II) (0.05 M) dilution also resulted in dissociation of the borate esters, but a remaining concentration of the borate diester species of about 0.5C_ was observed, oa even in the mM-range. Once more this shows that the borate diesters of D-glucarate strongly coordinate two calcium(ll) ions, which has been 20 quantified by calcium(II) ion selective electrode measurements. The effect of pH was studied using B NMR for the system D-glucaric acid-boric acid in the absence and presence of calcium(II) (Figure 10). The 01 c [M] 005 0 0 25 5 7-5 10 12-5 -pH 0-1 c [M] 005 0 Figure 10. Distribution of boron containing species as a function of the pH for a solution of boric acid (0.1 M) and D-glucaric acid (0.1 M) in the absence and presence of calcium(II) (0.06 M) in D„0 at 25 °C as determined with B NMR. -93- curves for the borate esters include both esters of oc-:hydroxycarboxylic acid and diol functions (Table 1). The pH optima for the borate mono- and diesters of the a-hydroxycarboxylic acid functions without calcium(II) were at pH = 5.5 and 3.5, respectively, which is in agreement with the pH rule of 3 thumb postulated previously. In the presence of calcium(II) these maxima were at pH= 5.0 and 3.0, respectively, which demonstrates the decrease of pK upon cation coordination. The concentration of the borate esters of diol functions were independent of pH at pH > 11.5 and 9.0, in the absence and presence of calcium(II), respectively. The relatively high concentration of borate diester species in the presence of calcium(II) is due to the high calcium(II) coordinating strength of the borate diesters, as discussed before. The temperature dependence of the borate ester equilibria as studied with B NMR (Figure 11) was small, in particular when calcium(II) was present. This contrasts the destabilizing effect of temperature increase usually 4 observed and favours the application of the present system as builder in detergent formulations. 006 c[M] /. 0 04 002 0 j i i 20 40 60 80 100 > T[.C] Figure 11. Distribution of boron containing species as a function of the temperature for a solution of boric acid (0.1 M) and D-glucaric acid (0.1 M) in the absence and presence of calcium(II) (0.06 M) in D„0 at pH = 11.4 as determined with B NMR. -94- Experimental The NMR spectra were measured for solutions of boric acid (0-0.2 M), D-glucaric acid (0-0.2 M), and calcium(II) chloride (0-0.12 M) in D„0 at 1 z pH = 9.0-11.5 and 25 °C (unless stated otherwise). 200.07 MHz H NMR spectra were recorded with a Nicolet NT-200 WB spectrometer using fr-butanol (6 = 1.200 ppra) as internal standard. The H_ signals of D-glucarate and its 2 borate esters were assigned using 2- H-D-glucarate. The coupling between H„ and H0 and between H. and H- of the borate esters was established with the 1 4 5 21 aid of H homonuclear shift correlation (COSY) of solutions of boric acid (0.1 M), D-glucaric acid (0.2 M), and calcium(II) chloride (0 and 0.08 M) at pH = 9.0 with a 300 MHz spectrometer built at the Department of Applied 22 Physics. A spectrum of the sample without calcium(II) was also recorded at 500 MHz on a Bruker WP 500 spectrometer of the SON NMH facility at the 3 University of Nijmegen. Since J(H0,H/)) < 1 Hz, coupling between H„ and H. 11 13 in the borate diester manifested itself only as line broadening. B and C NMR spectra were recorded on a Nicolet NT-200 WB spectrometer at 64.19 and 50.31 MHz, respectively. 0.1 M boric acid in D„0 (6 = 0.0 ppm) and p-dioxane (6 = 66.6 ppm) were used as external and internal reference, respectively. The reproducibility of the intensities of the B signals was about 5*. A 1 13 21 H- C heteronuclear shift correlation spectrum was recorded for a sample 2 of D-glucarate in D„0. Potassium hydrogen 2- H-D-glucarate was synthesized 2 2 23 by oxidation of a mixture of 2- H-D-glucitol and 2- H-D-mannitol, obtained 24 by NaBD. reduction of D-fructose, followed by selective precipitation 25 using K2C0o. References and notes 1. H. Peters, Neth. Pat. 99,202 (1961); Chem. Abstr. 56 (1961) 12682. 2. J.G. Heesen, Neth. Pat. 7,215,180 (1972); Chem. Abstr. 81 (1974) 176040. 3. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 40 (1984) 2901; this thesis, chapter 2. 4. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 41 (1985) 3411; this thesis, chapter 3. 5. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav. Chim. Pays-Bas, in press; this thesis, chapter 4. 6. T. Taga, Y. Kuroda, and K. Osaki, Bull. Chem. Soc. Jpn. 50 (1977) 3079. -95- 7. D. Horton and Z. Walaszek, Carbohydr. Res. 105 (1982) 95. 8. C.A.G. Haasnoot, F.A.A.M, de Leeuw, and C. Altona, Tetrahedron 36 (1980) 2783. 9. J. Rigaudy and S.P. Klesney, "Nomenclature of Organic Chemistry", Pergamon Press, Oxford, (1979) 489. 10. The free borate signal shifted from -17.1 to -17.6 ppm and its line width decreased from 40 to 25 Hz. This can be explained by a small increase in the borate/boric acid ratio due to some calcium(II) coordination by borate. 11. R.A. Mariezcurrena and S.E. Rasmussen, Acta Cryst. B29 (1973) 1035. 12. H. van Koningsveld, M. van Duin, and J.C. Jansen; refinement of the structure is in progress. 13. J.D. Dunitz, D.M. Hawley, D. Miklós, D.N.J. White, Yu. Berlin, R. Marusic, and V. Prelog, Helv. Chim. Acta 54 (1971) 1709. 14. H. Nakamura, Y. Iitaka, T. Kitahara, T. Okazaki, and Y. Okami, J. Antibiotics 30 (1977) 714. 15. A.E. Martell and R.M. Smith, "Critical Stability Constants", Plenum Press, New York III and IV (1977). 16. M.S. Nieuwenhuizen, A.P.G. Kieboom, and H. van Bekkum, Starch 37 (1985) 192. 17. B.A. Levine and D.C. Dalgarno, Biochem. Biophys. Acta 726 (1983).187. 18. C.A.M. Vijverberg, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav. Chim. Pays-Bas 99 (1980) 403. 19. C.A.M. Vijverberg, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 42 (1986) 167. 20. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Carbohydr. Res., submitted; this thesis, chapter 6. 21. A. Bax, "Two-dimensional Nuclear Magnetic Resonance in Liquids", Kluwer Boston Inc., Hingham (1981). 22. A.F. Mehlkopf, thesis, Delft (1978). 23. R.P. Linstead, L.N. Owen, and R.F. Webb, J. Chem. Soc. (1953) 523. 24. M. Abdel-Akher, J.K. Hamilton, and F. Smith, J. Am. Chem. Soc. 73 (1951) 4691. 25. B.S. Furniss, A.J. Hannaford, V. Rogers, P.W.G. Smith, and A.R. Tatchell, "Vogel's Textbook of Practical Organic Chemistry", Longman Group Ltd., London (1978) 454. -97- CHAPTKH 6 SYNERGIC CALCIUM(II) COORDINATION IN AQUEOUS BORATE-POLYHYDROXYCARBOXYIATE SYSTEMS* Introduction The application of sodium triphosphate (STP) as a builder in synthetic 1 2 detergent formulations ' contributes to eutrophication in stagnant surface 3 water. In a search for STP substitutes, various inorganic and organic compounds have been screened, in particular with respect to their cal- 4-7 cium(II) sequestering abilities. We have synthesized polyhydroxycar- 8 9 boxylates ' and have studied their calcium(II) coordinating behaviour using g calcium(II) ion selective electrode measurements and multinuclear NMH techniques. Sometimes the calcium(II) coordinating strength of poly(hydr)oxycarboxy- lates can be improved by addition of a second ligand. Such synergic effects 11 12 can be attributed to interactions between the two different ligands. ' In this respect, mixed ligand systems (MLS) with polyoxygen ligands have been studied. ' Zeolites with carboxylates as cobuilder might be regarded as 19 a special class of MLS. Mixtures of (per)boric acid and polyhydroxycar- boxylic acids at pH > 9.5 have been disclosed in the patent literature as 20-22 promising cation sequestering systems. Borogluconates and -glucohepto- nates are commercially available sequestering agents. In aqueous medium at pH > 9, borate forms borate mono- and diesters with 23 the diol functions of polyhydroxycarboxylates (Figure 1). We have established the preferred borate binding sites and the stability of the 11 13 borate esters for a series of polyhydroxycarboxylates using B and C 24 25 NMH. ' Also with the use of NMH, it has been demonstrated that the diastereomeric borate diesters of D-glucarate, bound at the tAreo-3,4- M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Carbohydr. Res., in press. -98- OH OH c OH O. o E B (0H)4 ^B(OH) -OH_ rosS/0 [ U/B-o ] B B L B"L Figure 1. Equilibria between borate (B ) and a diol function of a polyhydroxycarboxylate (L) in water at pH > 9. -position, form stable dicalcium(II) complexes. The calcium(II) coordination sites are composed of two carboxylate oxygens, two borate ester ring oxygens, and - depending on the oc-CHOH-configuration - up to two ?fi a-hydroxyl oxygens (Figure 2). This chapter deals with the calcium(II) coordinating properties of mixtures of borate and various poly(hydr)oxycarboxylates (Figure 3) in aqueous alkaline solution. The extent and structural origin of the synergic calcium(II) binding is determined using B NMH and free hydrated calcium(II) concentration ([Ca]) measurements. In this way the synergic effect can be explained in terms of the stability of the borate diester and the number and the nature of the calcium(II) coordinating sites. Figure 2. Calcium(II) coordination sites in borate diesters of polyhydroxy- carboxylates with borate bound at C„C3 (a) and C„C. (b) are composed of two carboxylate oxygens and two borate ester ring oxygens. In the case of a ^Kio-2,3,4-configuration [as in the left carbon chain of (b)] the 2-hydroxyl oxygen also participates. -99- coo® coo® COO3 COO® COO° COO® b=0 I—OH HO—I HO — HO- •OH '—OH '—OH — OH HO- OH — OH — OH — OH — OH — OH -OH 2 3 4 5 6 e COO'3 coo COO® COO® COO® COO® — OH — OH HO — — OH — OH O HO- — OH HO — HO — HO- HO- -OH HO — — OH HO — — OH -OH -OH — OH — OH — OH — Oh 1 1 -OH -OH —OH —OH = o = o -OH 7 8 9 10 11 12 COO® COO® COOe COO® COO® COO® — OH 1—OH HO — HO — |—OH — OH — OH HO- e -OH OH COO® COO — OH — OH HO — =o COO® COO® — OH COO^ 14 15 16 17 18 13 COO® COO® COO® COO® COO® COO® — OH — OH HO s OOP /"iU OH Un HO — HO — HO — HO — HO- HO- ■COO* HO- —OH — OH — OH — OH OH —OH HO — — OH — OH COO® COO® COO® COO® COO® — OH 19 20 2 1 2 2 23 24 Figure 3. Structures of polyhydroxycarboxylates. Results and discussion Calcium(II) sequestering capacities A way to demonstrate synergic calcium(II) sequestration in a borate- -polyhydroxycarboxylate mixture is via the determination of the calcium(II) 20-22 sequestering capacities (CaSC), using a titration procedure with oxalate as indicator. With the exception of citrate (24), the addition of borate led to substantially higher CaSC (Table 1). Although this method has the advantage of being rather practical, it does not always give reliable results. This was observed in the system borate-galactarate (19): precipitation of a calcium(II) borogalactarate defined the turbidity point. -100- Table 1. Calcium(II) sequestration capacities (CaSC) for polyhydroxycar- boxylates in the absence and presence of 0.5 molar equivalent borate. polyhydroxycarboxylate CaSC (g calcium(II)/100 g L) without borate with borate 7 D-gluconate 2.9 6.8 8 D-gulonate 1.4 5.2 14 üreso-tartrate 2.5 8.6 19 galactarate 0.7 2.5 (2.5C) 20 D-glucarate 1.5 10.8 (> 15C) 20 D-glucarate 1.5 1.9 24 citrate 5.5 5.6 a 8 g polyhydroxycarboxylate/1; pH = 11.0; 25 °C. Taken from reference 20; c d pH = 9.5. Without oxalate as indicator. Phenylboronate instead of borate. Furthermore, it may be noted that (i) the ligands may inhibit the precipi- 27 tation and the crystal growth of calcium(II) oxalate, (ii) the change of the ionic strength affects the various equilibrium and solubility constants, and (iii) interactions between boric acid and oxalate result in additional 23 problems at pH < 7. Origin of the synergic calcium(II) coordination in the borate-polyhydroxy- carboxylate system The effects of increasing amounts of calcium(II) chloride on the composition of the MLS were studied using B NMR until precipitation occurred at C_ (Table 2). Formulations were chosen such as to ensure an oa,max excess of borate monoester with respect to the borate diester before calcium(II) chloride addition. For dicarboxylates C„ was relatively 0a, max low, because the corresponding calcium(II) salts are less soluble than those of monocarboxylates, probably as a result of self-association. -101- The exchange between the borate an ion and the borate monoester and between the borate mono- and diesters remained slow on the B NMR time scale, but the exchange of the borate esters with the corresponding calcium(II) complexes was fast. The calcium(II) induced shifts were negligible, but all signals were broadened upon calcium(II) chloride addition. Consequently, the spectral resolution decreased and the error in the intensity of the B NMR signals increased. This, in combination with the sometimes small changes in intensities, particularly when precipitation occurred at low C, , did not allow an accurate quantitative analysis of Ca,max the complex MLS on the basis of HrB NMR data only. Upon increase of C_ the total concentration of the borate diester t*a containing species (borate diesters and their calcium(II) complexes) generally increased, whereas that of both the borate monoester and free borate decreased (Table 2; Figure 4). This indicates that the borate diesters are the predominant calcium(II) coordinating species, which is in agreement with previous observations. In addition, this is supported by the negligible effects both of calcium(II) chloride addition to a sample containing phenylboronate and D-glucarate (20) as studied with B NMR and of phenylboronate on the CaSC of D-glucarate (Table 1). In the phenylboronate-D-glucarate system only boronate monoesters can be formed. The synergic effect, therefore, can be rationalized by the good cal- 0-10 C M4 ] ^^ 005 sD >-^ 0 1 005 0-10 -CcaM Figure 4. Effect of calcium(II) on the borate ester equilibria for a solution of boric acid (0.1 M) and /nesn*,d *B(Ll,2>2fc,e D JL 03 f IDELX (M) (M) (M) 'Ca,0 Ca,max Ca,0 Ca,max Ca,0 Ca,rnax Ca,0 Ca,max 2+3 rac. -glycerate 0.1 1.0 10.5 0.41 17 5 54 36 29 59 4 D-arabinonate 0.1 0.2 11.0 0.54 9 3 65 21 2 2 34 74 5 D-lyxonate 0.15 0.2 11.0 0.09 20 14 57 52 1 2 22 32 6 D-ribonate 0.1 0.2 11.0 0.70 12 15 52 33 26 15 12 37 7 D-gluconate 0.2 0.2 11.0 0.15 16 21 62 49 2 6 20 25 8 D-gulonate 0.2 0.2 11.0 0.04 19 10 58 37 1 0 23 54 9 D-mannonate 0.15 0.2 11.0 0.13 4 4 55 36 2 6 40 54 12 2-keto-D-gluconate 0.1 0.2 11.0 0.13 5 4 65 53 0 0 30 43 14 iseso-tartrate 0.1 1.0 11.0 0.09 32 9 55 24 13 67 15 D-tartrate 0.1 0.1 10.5 0.05 77 69 22 10 1 21 16 meso-3,4-dihydroxyadipate0. 1 0.5 11.0 0.05 39 35 54 50 7 16 17+18 rac. -3,4-dihydroxyadipate 0.05 0.25 11.0 0.05 22 21 50 54 28 25 19 galactarate 0.1 0.1 10.5 0.05 15 26 70 42 0 0 15 24 Table 2 - continued: 20 D-glucarate 0.1 0.1 10.5 0.075 21 16 59 35 4 4 16 43 21 L-idarate 0.1 0.2 11.0 0.05 22 21 55 45 3 10 21 24 22 D-mannarate 0.1 0.2 10.5 0.06 29 21 53 40 0 0 19 39 64.19 MHz; D-O; 25 The composition is given in * of C_ in the absence (C_ _) and presence of calcium(II) (C„ ). Sum of the borate monoesters of the 1,2-diol functions, including the corresponding calcium(II) complexes. , o a,max Sum of the borate esters of 1,3-diol functions (n = 1,2), including the corresponding calcium(II) complexes. Sum of the borate diesters of the 1,2-diol functions, including the corresponding calcium(II) complexes. Table 3. Association constant for CaL, overall association constant for B L„, and denticity of calcium(II) coordination sites in the borate diesters. polyhydroxycarboxylate log K_ . ' log p_-. denticity in the borate diester H-diastereomer S-diastereomer 1 glyoxylate 1.6 2+3 rac. -glycerate 1.6 (1.2)e 0.6 4 D-arabinonate 1.6 2.8 4 5 D-lyxonate 1.6 3.8 4 Table 3 - continued: 6 D-ribonate 1.5 1.8 2 7 D-gluconate 1.6 (1.2)e 3.9 6 8 D-gulonate 1.6 4.6 2 9 D-mannonate 1.6 4.7 4 10 D-galacturonate 1.3 (0.7-1. 8)' - - 11 D-glucuronate 1.1 (0.7-1. 5/ - - 12 2-keto-D-gluconate 1.2 3.3 - 14 iseso-tartrate 2.5 -0.1 4+4 4+4 15 D-tartrate 2.0 (1.8)* 2.3 4+4 4+4 o 16 mesa-3,4-dihydroxyadipate 1.6 0.1 4+4 4+4 17+18 rac. -3,4-dihydroxyadipate 1.6 1.7 4+4 4+4 20 D-glucarate 2.2 3.7 5+5 6+4 21 L-idarate 2.1 3.4 6+6 6+6 22 D-mannarate 2.3 2.6 4+4 4+4 23 2-carboxy-D-gluconate 3.2 2.3 6 3+3 borate 1.4 (1.1)* 5.0 mM; C, = 10.0 mM; pH = 10.0; I = 0.1; 25 °C. Values taken from the literature for other Ca c d ionic strength and temperature between brackets. Reference 24 and 28. Two sites in borate diesters of dicarboxylates, with exception of (/fl-B L„ of 23. Reference 29. Reference 30. ^Reference 31. -105- cium(II) coordinating properties of the borate diesters. The borate an ion brings two polyhydroxycarboxylates together, resulting in one or two new calcium(II) coordinating sites. The denticity (number of coordinating donor atoms) of these sites ranges from 4 to 6 (Table 3). Participating donor sites are two carboxylate oxygens - one of each polyhydroxycarboxylate - and two borate ester ring oxygens. Moreover, the non-esterified 2-hydroxyl oxygen of a Ay7o-2,3,4-configuration can participate in the calcium(II) coordination, when borate is bound at the iAreo-3,4-position (Figure 2b). 5r Ca)|mM] 100 Figure 5. Free calcium(II) concentration as a function of the molar fraction poly(hydr)oxycarboxyli)oxycarboxylic acid for various MLS ((CC _ + C. = 10.0 mM and C. 5.0 mM at pH = 10.0, I = 0.1, and 25 °C) Ca -106- To determine the number of calcium(II) ions bound by the borate diesters, calcium(II) complexation was studied with a CalSE. For the dicarboxylates D-glucarate (20) and L-idarate (21) [Ca] < 2.5 mM, when CCQ = Cfi = CL = = 5.0 mM (Figure 5) and thus > 2.5 mM calcium(II) is coordinated. Since the maximum concentration of the borate diesters under these conditions is 2.5 mM, these species must be able to bind two calcium(II) ions, which is in ■I 1 0£ agreement with previous B NMR results. In borate diesters of monocar- boxylates only a single calcium(II) coordination site is present in one of the two diastereomers and, as a result, [Ca] > 2.5 mM for monocarboxylates under the present conditions (Figure 5). Quantitative analysis of the calcium(II)-borate-polyhydroxycarboxylate MLS The CalSE measurements do not suffer from the problems of the CaSC determinations and allow a more quantitative analysis of the MLS than the B NMR results. The experiments were carried out at pH = 10.0, since both the equilibria of borate ester formation and those involving calcium(II) coordination (Figure 6) are then independent of pH. Furthermore, the experimental pH = 10.0 is in the pH-range of the standard washing process of 4 9.0 to 10.5 and in the optimum pH-region with respect to the CalSE sensitivity. The measurements were performed at C_ = 5.0 mM, which is the upper level of the Dutch tap water hardness and at CR + C. = 10.0 mM. |Co]mM 12 — pH Figure 6. Effect of pH on the free calcium(II) concentration for a solution of boric acid (3.33 mM), D-glucaric acid (20: 6.67 mM), and calcium(II) (5.00 mM) at I = 0.1 and 25 °C. -107- [Ca] was determined for the various MLS (Figure 5) as a function of the molar fraction polyhydroxycarboxylate xr: XL = V(CL + CB> (1) The accuracy of the experimental method was demonstrated by the excellent overlap of the two partial curves, constructed from results of experiments starting at x = 0.0 and 1.0, respectively. For galactarate (19) and 5-keto- L -D-gluconate (13) clear starting solutions could not be prepared due to precipitation of calcium(II) salts. For 2-carboxy-D-gluconate (23) always a calcium(II) borate ester precipitate was observed with the present procedure. As to the species in the MLS (Figure 7), the concentrations of Ca(B )„, CaL„, Ca„B , Ca„L, and (B )„L were neglected. The overall association constants of CaL„ and Ca(B )„, obtained by fitting the curves for titration of free D-glucarate and borate with calcium(II) are only about 20 and 1 M , respectively. Those of Ca„L and Ca„B are expected to have similar or lower values. The overall association constant of (B )„L for L = D-mannitol is 4 -2 32 33 relatively large (2.10 M ). ' In the case of L = polyhydroxycarboxy late, however, the concentration of (B )„L can be neglected even at C_ = C. = 0.1 M, due to the smaller number of hydroxyl groups and to Coulomb Ca ^ ^ Ca2B" Ca2L CaB" CaL Ca(B-)2 ^ CaL, ^ Ca2B L2 CaB"L2 . CaB~L V X (B")2L B"L2 B"L Figure 7. Species in the aqueous calcium(II)-borate-polyhydroxycarboxylate (Ca-B~-L) MLS. -108- 24 repulsion between the BO. moiety and the carboxylate group(s). As a result, our mathematical model includes the three material balance equations for calcium(II), borate, and the polyhydroxycarboxylate and the association constants for the following species: Ca, B , L, CaL, CaB , B L, B L„, CaB L, CaB L„, and Ca^B L„. The K values are defined as: — — ?4 2R Vl = tB\J/(tB Ln-l][I,]) (n = 1<2) (2) KCflZ = [CaZ]/([Ca][Z]) (Z = L, B , B L,. B L^ or CaB L2) (3) K with Z = B" or L was determined from [Ca] at x = 0.0 or 1.0, respec tively (Figure 5) and the relation: K = (C c CaZ Ca ' [ «])/{[Ca](Cz - CCa + [Ca])} (4) The agreement with literature values is good (Table 3). In addition, two assumptions were made: KCaB~L " KCaL (5) and for dicarboxylates: K _ = (6) Ca2B L2 ««CaB-Lg with a = 0.25 on statistical grounds. When [Ca] is measured for a MLS our mathematical model reduces to a set of three equations with three variables, viz. [B ], [L], and K_ „-. . Although accurate fitting of the experimental data (Figure 5) was not possible, this model gave log K_ _-T and log K_ _-T values of 3.8-5.0 and 3.3-3.6, respectively. These values are comparable with those of other calcium(II) coordinating ligands with four oxygen donor atoms, such as Q citrate or carboxymethoxysuccinate (log K_ „ = 3.4 and 4.1, respectively ). Both the imposed proximity of the carboxylate groups in the borate diester and the relatively large partial charge on the coordinating oxygens of the borate ester rings (-0.37 in a borate ester ring vs. -0.25 in a free diol, 34 as obtained with CNDO calculations ) contribute to this. Variation of a [Equation (6)] did not improve the fit and increase of K„ „-. only resulted -109- Figure 8. Calculated distribution of species in the system calcium(II) (5.0 mM), borate, and D-glucarate (C„ + CQ = 10.0 mM) at pH = 10.0 with log h-Q = 2.3, log KB-Q2 = 1.4. log KCaB- = 1.4, log K^ = = l0g K 1 l0g K 4 2 rad lo 3 8 The CaB-G = 2- ' CaB-G2 = " ' * «Ca^G,, = ' - concentrations of the calcium(II), borate, and D-glucarate species are expressed as p[Ca (B ) G ], q[Ca (B ) G ], and r[Ca (B~) G ), respectively. -110- in a better fit, when K~ _-. > K_ _-, , which can be rejected on the basis 11 ^ of the B NMR and CaSC results. For D-glucarate (G: 20) as the ligand, Figure 8 shows the concentrations of the various species calculated with the model described above as a function of x_. Most of the coordinated calcium(II) is bound as Ca_B G„. Calculations for x_ = 0.5 (C„ = C~ = 5.0 mM) demonstrate that in the absence G D Ca _ of calcium(II), the concentration of B G~ is 0.05 mM, whereas for C = 5.0 mM the concentrations of B~G2> CaB~G2> and Ca2B~G2 are 0.01, 0.25, and 1.39 mM. So the amount of borate diester containing species in dilute solutions is only significant when calcium(II) is present. This agrees with previous 11 2fi — B NMR experiments and stresses the high stability of CaB G2 (n = 1,2). Supporting evidence for this phenomenon is obtained from ion exchange 19 experiments in the presense of borate- D-glucarate. The calcium(II) coordinating system generated in the presence of calcium(II) resembles the 35 ternary calcium(II)-calmodulin-enzym system. More concentrated solutions (> 0.1 M) of borate and a polyhydroxy- carboxylate (as in the case of NMR experiments) in the absence of cal- cium(II) generally contain substantial amounts of borate diesters. Upon calcium(II) addition the induced equilibrium changes will be relatively small (Table 1 and Figure 4) compared with the more diluted solutions. Synergic calcium(II) coordination as a function of the polyhydroxycar- boxylate K„ „-, and K-, n-r could not be calculated with the required accuracy for a discussion of the effect of the polyhydroxycarboxylate in the MLS. In order to quantify the synergic effect of borate and a polyhydroxycar boxylate, the experimental calcium(II) concentrations ([Ca] ) are compared with values obtained by calculation, in which only equilibria with CaB and CaL were taken in account ([Ca] ), i.e. discarding all extra non-syn interactions such as borate ester formation. The synergic effect (SE) is then defined as: SE = [Ca] - [Ca] (7) non-syn L Jexp v ' The SE appeared to be maximum at x, = 0.45 - 0.65 (Figure 9). Theoretically, this optimum is at x = 0.67 (C-/C, equals the ratio B /L in B_L„), although the curve of SE vs. x is rather flat at x = 0.5-0.7. -111- 20 1 00 Figure 9. Synergic effect (SE) as a function of the molar fraction polyhy- droxycarboxylate for various MLS (C(C__ + C. = 10.0 mM and C_ =5.0 oa Ij L»a mM at pH = 10.0, I = 0.1, and 25 °C). The SE is determined by both the overall stability constant of the borate diester: = VL2 [B-L2]/ÜB-][L]<) =VLVL2 (8) and the calcium(II) coordinating strength of the borate diester: P n Ca B~L = [CanB~L2]/([Ca] [B~L2]) (n = 1, 2) (9) n 2 which depends on the denticity of the coordination sites (Figure 2, Table 3). Combination of Equations (8) and (9) shows that the SE is related with: B + 2 L ü B L„ nSa Ca B L„ P n 2 Ca B-L, = [CanB-L2]/([Ca] [B-][L] ) - *„- fè fi- (10) n Z £ n £ Borate esters of glyoxylate (1) and citrate (24) involve the carboxylic acid functions and are not stable at pH > 10, according to the pH rule of 23 thumb derived earlier. For both compounds only the free borate signal was observed in the B NMR spectra at pH = 10.0. As a result [B L ] = 0 and thus SE = 0 at pH = 10. -112- Calculations demonstrate that no significant SE occurs (SB < 0.2 mM) if pD-T < 60, assuming log K n-T = 4.2. This is the case for rac.-glycerate, areso-tartrate, and aeso- and rac.-3,4-dihydroxyadipinate (2 + 3, 14, 16, 17 + 18: 0D-T < 60). Furthermore, the denticities of the calcium(II) B L2 coordinating sites are only two or four for the diastereomeric borate dies- ters. For borate- ineso-tartrate (14) the calculated curve (assuming no synergy) follows the experimental one (Figure 5) closely and, therefore, the calcium(II) coordinating properties of this system are entirely due to the calcium(II) coordination by a?eso-tartrate itself. D-ribonate (6) is a border case with pn-T = 66 and SE < 0.24 mM. B L2 For the aldonates with borate bound at C„C„ (D-arabinonate and D-ribonate: 4 and 6) and for the aldarates (D-glucarate, L-idarate, and D-mannarate: 20-22) the value of p_-T seems to determine SE: 4 > 6 and B L2 20 > 21 > 22, respectively. But for the aldonates with borate bound at C„C4 (D-lyxonate, D-gluconate, D-gulonate, and D-mannonate: 5, 7-9) differences in the denticity of the calcium(II) coordinating site seem to be of major importance, 7 > 5=8=9. With the exception of D-mannarate (22), the C_-aldarates have a larger SE than the C„-aldonates, since both diastereo- b b meric borate diesters of the former are able to bind two calcium(II) ions. Discussion of the SE of 2-keto-D-gluco-nate (12) and the uronates is complicated due to acetal formation. The antagonistic effect for D-glucuro- nate (11) and the maximum SE for D-galact-uronate (10) at xT = 0.35 are exceptional. Experimental The carboxylic acids were commercial products or were prepared as described in reference 24 and 25. Sodium(l) 2-keto-D-gluconate, calcium(II) 5-keto-D-gluconate, and disodium(I) 2-carboxy-D-gluconate were gifts from Akzo. The B spectra of solutions of boric acid (0.05-0.20 M), a polyhydroxy- carboxylic acid (0.1-1.0 M), and increasing amounts of calcium(II) chloride (until precipitation occurred) were recorded with a Nicolet NT-200 WB spectrometer at 64.19 MHz and 25 °C using a 12 mm sample tube. The total volume of each sample in D„0 at adjusted pH (NaOD) was 5 ml. B chemical -113- shifts were measured against external 0.1 M boric acid in D„0. Base line correction was applied for all spectra and when necessary a deconvolution program was used to obtain all signal characteristics. Calcium(II) sequestering capacities were determined according to Wilham and Mehltretter at pH = 11.0 (NaOH). Free calcium(II) concentrations were measured at 25 °C with a Radiometer F2112 Ca or a Philips IS 561-Ca CalSE, a HNU ISE-40-01-100 single junction reference electrode, and a Corning digital 112 pH meter. The CalSE was calibrated as a function of the pH. The desired MLS were obtained by mixing solutions with C_, = 5.0 mM, pH = 10.0 (NaOH), I = 0.1 (KC1), and Cn = 10.0 mM or CT = 10.0 mM, respectively, and were flushed with nitrogen. The measurements were performed under a nitrogen atmosphere. Linear drift correction was applied using standard solutions with CCa = 10.0 mM at pH = 10.0 and I = 0.1, and 25 °C. References and notes 1. Henkel & Cie. GMBH, "Waschmittelchemie", Dr. Alfred Hüthig Verlag, Heidelberg (1976). 2. M. Sittig, "Detergent Manufacture Including Zeolite Builders and Other New Materials", Noyes Data Corporation, Park Ridge (1979). 3. A. Taylor, J. Am. Oil Chëm. Soc. 57 (1980) 859A. 4. P. Berth, G. Jakobi, E. Schmadel, M.J. Schwuger, and C.H. Krauch, Angew. Chem. 87 (1975) 115. 5. K. Henning, J. Handler, and H.D. Nielen, Seifen-Ole-Fette-Wachse 103 (1977) 571. 6. G.C. Schweiker, J. Am. Oil. Chem. Soc. 58 (1981) 170A. 7. M.K. Nagarajan and H.L. Paine, J. Am. Oil Chem. Soc. 61 (1984) 1475. 8. M.S. Nieuwenhuizen, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav. Chim. Pays-Bas 101 (1982) 339. 9. M.S. Nieuwenhuizen, A.P.G. Kieboom, and H. van Bekkum, J. Am. Oil Chem. Soc. 60 (1983) 120. 10. J.A. Peters and A.P.G. Kieboom, Reel. Trav. Chim. Pays-Bas 102 (1983) 381 and references cited therein. 11. R.P. Martin, M.M. Petit-Ramel, and J.P. Scharff, in H. Sigel (ed.), "Metal Ions in Biological Systems 2", Marcel Dekker Inc., New York (1973) 1. 12. H. Sigel, Advances in Solution Chemistry (1981) 149 and references cited therein. -114- 13. S. Matsumara, Yukagaku 28 (1979) 403. 14. S. Ramamoorthy and P.G. Manning, J. Inorg. Nucl. Chem. 37 (1975) 363. 15. Y. Abe and S. Matsumura, Yukagaku 29 (1980) 748. 16. S.V. Vaeck and V. Merken, Tens. Det. 17 (1980) 25. 17. S.V. Vaeck and G.V. Merken, Tens. Det. 18 (1981) 177. 18. P. Berth, M. Berg, and K. Hachmann, Tens. Det. 20 (1983) 276. 19. M.S. Nieuwenhuizen, A.H.E.F. Ebaid, M. van Duin, A.P.G. Kieboom, and H. van Bekkum, Tens. Det. 21 (1984) 221 and references cited therein. 20. H. Peters, Neth. Appl. 99,202 (1961); Chem. Abstr. 56 (1962) 12682. 21. J.G. Heesen, Neth. Appl. 7,215,180 (1972); Chem. Abstr. 81 (1974) 176040. 22. P. Suhac, N. Hafner-Milac, and B. Dolenc, Eur. Pat. 14939 (1980); Chem. Abstr. 94 (1981) 103784. 23. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 40 (1984) 2901; this thesis, chapter 2. 24. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 41 (1985) 3411; this thesis, chapter 3. 25. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav. Chim. Pays-Bas, in press; this thesis, chapter 4. 26. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, J. Chem. Soc., Perkin Trans. II, in press; this thesis, chapter 5. 27. H.H. Zinsser and I. Light, J. Polym. Sci. 58 (1962) 1153. 11 24 28. The B chemical shifts, line widths, and association constants of the various borate esters of 2-keto-D-gluconate (12) are: ; 12,5 p m 50 Hz and 150 M_1; B~(L1 2-dioP ~ P ' > B_(L1 2-diolV ~7,9 ppB' 12° Hz* and 9 M_1' _1 B^L^ 2_diol): -13.6 ppm, 60 Hz, and 200 M ; _8-6 ppm 90 Hz and 2 M_1; B~(L'1 2-diolV * * B"(Ll,3-dioI): -18-1 ppra' and of 2-carboxy-D-gluconate (23) are: B~L„ .: -13.1 ppm, 30 Hz, and 60 M_1; - ' -1 B (L3 4)2: -8.8 ppm, 110 Hz, and 9 M ; _1 B~L4 5: -14.4 ppm, 50 Hz, and 13 M ; _1 B~L4 6: -18.1 ppm, 50 Hz, and 5 M . 29. A.E. Martell and R.M. Smith, "Critical Stability Constants", Plenum Press, New York (1977) III and IV. 30. J.A. Rendleman, Food Chemistry 3 (1978) 47. 31. R.H. Byrne and D.R. Kester, J. Mar. Res. 32 (1974) 119. -115- 32. L. Petterson and I. Andersson, Acta Chem. Scand. 27 (1973) 1019. 33. R. Montgomery, Adv. Chem. Ser. 117 (1973) 197. 34. J.A. Pople and D.L. Beveridge, "Approximate Molecular Orbital Theory", McGraw-Hill, New York (1970). 35. T.G. Spiro, "Calcium in Biology", John Wiley and Sons, New York (1983) 8. 36. CA. Wilham and C.L. Mehltretter, J. Am. Oil Chem Soc. 48 (1971) 682. -117- CHAPTER 7 INTERACTIONS OF CATIONS WITH OXYACID ANION BRIDGED ESTERS OF D-GLUCARATE IN ALKALINE MEDIUM* Introduction Aqueous alkaline solutions of borate and polyhydroxycarboxylates possess good cation sequestering abilities and are applied in the galvanic, glass, and cement industries and in pharmaceuticals. In addition, these systems 2 3 have potentials as triphosphate substitutes in detergents. ' We have deter mined the stability and structure of borate mono- and diesters of a series 4 5 of polyhydroxycarboxylates (Figure 1) using multinuclear NMR. ' The synergic calcium(II) coordination in these systems finds its origin in the high calcium(II) coordinating strength of the borate diesters of the fi 7 polyhydroxycarboxylates. ' This effect is most pronounced for D-glucarate 2 3 7 (G; Figure 2) as the polyhydroxycarboxylate. ' ' Formation of the £Areo-3,4 borate diesters of D-glucarate results in the creation of new multidentate calcium(II) coordinating sites. Each of these sites is composed of two carboxylate oxygens, two borate ester ring oxygens, and - depending on the fi 7 configuration - up to two hydroxyl oxygens (Figure 3). ' i-OH OH e S LOH. c B (OH)4 ^B(OH)2 OH r °^ /° L o L B B L B'L, Figure 1. Equilibria between borate (B ) and a diol function of a polyhy droxycarboxylate (L) at pH > 9. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, J. Chem. Soc., Dalton Trans. , submitted. -118- c,ooe I H-C, —OH I HO —C,—H I H-C« —OH H—C5 —OH csoo° Figure 2. D-Glucarate (G). Figure 3. Calcium(II) coordination in the diastereomeric (ff)- and (5)-borate diesters of D-glucarate in water. Borate [B(III)] is not unique in forming oxyacid anion esters (or com plexes) with diol functions. Other oxyacid anions (X ) such as aluminate [Al(III)], silicate [Si(IV)], germanate (Ge(IV)], arsenite [As(III)], selenite [Se(IV)], stannate [Sn(IV)], stibate [Sb(V)], tellurate [Te(VI)], 8—18 and periodate [I(VII)] are also capable to do so. It may be noted that synergic calcium(II) sequestration has been reported for aluminate- D-gluco- heptonate mixtures. As an extension of our work on borate esters and their calcium(II) 4-7 coordination, this chapter is dealing with the (synergic) cation coordination phenomena in different oxyacid anion- D-glucarate systems. Firstly, the affinity of the cation coordination sites in the borate diesters of D-glucarate (Figure 3) at high pH is screened using B NMR for a series of cations: M = Na(I), Mg(II), Al(III), K(I), Ca(II), Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Sr(II), Ag(I), Cd(II), Ba(II), Pr(III), and Pb(II). Secondly, several oxyacid anion- D-glucarate systems are investi- -119- gated with respect to their calcium(II) coordinating ability in the pH range 6-12, using callcium(II) ion selective electrode (CalSE) measurements: B(III), Al(III), Si(IV), Ge(IV), As(III), As(V), Se(IV), Sn(IV), Sb(III), Sb(V), Te(VI), and I(VII) are studied as oxyacid anions. The complexation phenomena in the cation-oxyacid anion- D-glucarate systems are rationalized in terms of differences in the charge/radius density and the polarizing ability of the cations, as quantified with the D 20 2 21 values of Marks and Drago and the g,(z/r + g„) values of Brown et al. In addition, it is demonstrated that the various oxyacid anion- D-glucarate 22 systems obey the pH rule of thumb, formulated previously for borate. Results and Discussion Cation addition to the boric acid- D-glucaric acid system at pJf = 10.5 The effects of various cations (0.05 M) added to solutions of boric acid (0.1 M) and D-glucaric acid (0.1 M) in D„0 at pH = 10.5 were studied with 11 B NMR (Figure 4). In all cases the exchange between borate and the borate monoester and between the borate monoester and the borate diester was slow on the B NMR time scale, whereas the exchange between the borate esters 23 11 and the corresponding cation complexes was fast. The changes in B chemical shifts upon cation addition were small (< 0.5 ppm). The cations can be classified into three groups, according to their effect on the borate ester equilibria (Figure 4): (i) hardly any effect, (ii) increase of the borate diester concentration, and (iii) decrease of the borate diester concentration. This distinction between the cations is related to the charge/radius density and the polarizing ability. One way of 20 quantifying these properties is the D&O equation of Marks and Drago, which relates the acid(A)-base(B) reaction enthalpy (AH.B) with terms for electro static (D) and covalent interactions (0): 'ÜHAB= »DA-V2 + 0A°B]1/2 In the case of oxygen donor atoms only electrostatic interactions are of importance, so that -ÜH._ is largely determined by the D values. Another way no n of quantifying the effects of the cations are the g,(z/r + g„) values of 21 Brown et al., which are calculated measures for electrostatic interactions -120- group (i) group (ii) group (iil) M Na(l) K(l) Ag(lMg(ll) ) Ca(ll) Co(ll) Nl(ll) Sr(ll) Cd (II) Ba(ll)AKIII)Cu(ll ) Zn(ll) Pr(lll) Pb(ll) 31 D" I 113 100 isa 284 213 273 283 200 280 191 300 293 281 >300 233 2.S 1.6 19.4 19.4 12.0 37.2 40.7 10.0 33.0 8.3 67.7 49.6 37.2 43.1 52.2 Figure 4. Effect of cations (0.05 M) on the distribution of boron containing species (including cation complexes) for a solution of boric acid (0.1 M) and D-glucaric acid (0.1 M) in D 0 at pH = 10.5 and 25 °C S as determined with B NMR ( For Pr(III), Cp = 0.01 M and pH = 8.0 to avoid precipitation and excessive line broadening; without Pr(III): [B~] = 0.027 M, [B~G] = 0.040 M, and [B~G2] = 0.033 M, respectively). and polarizing effects: z/r is a charge/radius density, corrected with g, and g„ to obtain an effective charge/radius density. Finally, the value of „ML for: ML MH^L + H (cf. Figure 5) will be used as a more practical measure. ' Group (i): The monovalent cations Na(I), K(I), and Ag(I) (D < 160, gj(z/r + g2) < 20, and pK^ L > 12) did not show preferential coordi nation to one of the borate esters or to the free D-glucarate. This is in agreement with the generally observed weak coordination of these cations by organic 27 2*3 acyclic polyoxygen ligands. However the line width of the Na signal for a solution of boric acid (0.1 M), D-glucaric acid (0.1 M), and NaCl (3.0 M) at pH =10.0 was about 30 Hz, which suggests that the average state of the Na(I) ions differs from the free hydrated form (8 Hz). Na(I) coordination -121- C OH Ov j O O v^ CnOH h n <1HOH c'WC 'OHy / \Ho\HO"Cc, H I C 0\ ^.OHC cHo^ ^oHc I I CM C CC 1r, Hy _ / H'U H'U_ .._NH ! t O ' M C OH B- C OH HO C »B"L2 H H H H C OH " C OH "* C Ov ^0 C CHOH CHOH CH0^ ^0HC o^ j O O. I I II ^ \ / -"C M 1 B-L, 'H ^ ^- H CMO / \ 0 C "Vs- *^ ^ cHo. ,oHc H B H Ln è o/ C0 i c °v I I «B'IK.,1.1, 24 Figure 5. Cation coordination in a borate-polyhydroxycarboxylate system. does not interfere with the Ca(II) coordination, as the line width did not change upon calcium(II) chloride addition. Group (ii): In the presence of divalent cations with moderate polarizing abilities, Mg(II), Ca(II), Co(II), Ni(II), Sr(II), Cd(II), and Ba(II) (190 < 2 < D < 280, 10 < g,(z/r + g„) < 40, and 8 < pK?^ L < 12), the amount of borate diester containing species of D-glucarate (esters and their cation complexes) increased and all B NMR signals were broadened. These results demonstrate that the coordinating strengths of the borate diesters for these fi po cations are of the same order of magnitude as for Ca(II). ' As the ionic 29 radii of the group (ii) cations vary from 0.7 to 1.7 A, these data indicate that the cation coordinating sites of the borate diesters of D-glucarate are rather flexible. This can be understood by the rotational freedom around C(l)-C(2)/C(6)-C(5) and C(2)-C(3)/C(5)-C(4), and the 30 flexibility of the five membered borate ester rings. Group (iii): The polyvalent and strongly polarizing cations, Al(III), Cu(II), Zn(II), Pr(III), and Pb(II)-31 (D > 280, " g^z/r + gg) > 40, and pit!. . < 8) induced dissociation of the borate esters. A comparison of stepwise calcium(II) and copper(II) chloride addition to the borate- D-glucarate system (Figure 6) demonstrates the different behaviour of group (ii) and (iii) cations. Ionization of a-hydroxyl functions upon cation coordination and/or borate substitution are responsible for these phenomena, -122- 006 Ca(Il) CanB"G2 0 04 ~B"G -v-B'G, 005 010 -CCuM Figure 6. Effect of Ca(II) and Cu(II) on the distribution of boron containing species for a solution of boric acid (0.1 M) and D-glucaric acid (0.1 M) in D„0 at pH = 10.5 and 25 °C as 11 determined with B NMR. as will be explained below. The acidity of an acid function increases upon coordination to a cation. The potentiometric determination of the stability constant of a metal com- 33 plex is actually based on this principle. The enhancement of the acidity of an oc-hydroxyl group upon cation coordination increases with higher charge/radius density of the cation. That is, increase of the D and g,(z/r + g„) values results in a decrease in pJvjj, L- In the presence of group (iii) cations , the oc-hydroxyl groups of D-glucarate are ionized at pH = 10.5. The essential equilibria of the cation-borate-polyhydroxycarboxylate _ 24 (M-B -L) system are shown in Figure 5. For group (ii) cations the stability of MB L_ is larger than that of ML and ML„, as shown above. This is in contrast to group (iii) cations, because there MH_,L and M(H_,L)„ have a higher stability than MB (H_.L)„. Several factors may influence the stability of the species involved. Firstly, the stability of borate esters of polyols with ionized hydroxyls adjacent to the borate ester ring is relatively low, due to electrostatic repulsion and the absence of possible stabilizing hydrogen bonds4,34-3 7 between ionized hydroxyls and the B0. moiety. In the absence of multivalent cations this phenomenon was only -123- Table 1. Effect of [OH ] on the concentration8 of boron containing species (C„ = 0.1 M) for D-mannitol (0.1 M) and D-glucaric acid (0.2 M) in 11 D„0 at 25 °C as determined with B NMR. polyhydroxy compound species [OH ] = 0.01 M [OH ] = 0.5 M D-mannitol B~ 0.012 0.046 B~L 0.057 0.054 B"L2 0.031 0.000 D-glucaric acid B~ 0.002 0.030 B~L 0.013 0.070 B"L0 0.085 0.000 3 In M. observed at pH > 13 (Table 1). Secondly, the stability of M(H_1L)n is relatively high, as a result of the deprotonated oe-hydroxyl groups. Thirdly, the behaviour of some group (iii) cations can be explained by competition with borate for diol functions (vide infra). Upon addition of dysprosium(III) chloride, a member of group (iii), to borate solutions of D-gluconate or D-mannonate at pH = 11.0 quite different effects were observed using B NMR, supporting the explanations given above. The oc-hydroxyl functions of the borate diesters of D-gluconate fi 7 participate in the Dy(III) coordination ' and, therefore, the corresponding Dy(III) complexes [MB (H_,L)„] are relatively unstable. Moreover, in the Dy(III) complexes of free D-gluconate [M(H_,L) ] tridentate coordination occurs, which enhances the stability of these complexes. In contrast, the «-hydroxyl functions of the borate diesters of D-mannonate are not able to fi 7 participate for steric reasons ' and, as a result, the borate esters of D-mannonate did not dissociate. Furthermore, the coordination of Dy(III) by 38 11 the free D-mannonate probably is only bidentate. The new B NMR signals observed in the case of D-mannonate upon addition of dysprosium(III) chloride are assigned to Dy(III) complexes of borate esters of D-mannonate. Dissociation of borate esters in the presence of group (iii) cations will be even more pronounced when these cations compete with the borate anion for the diol functions of the polyhydroxycarboxylate. In particular, this will 2 be the case for group (iii) cations with high g,(z/r + &^) values (> 60), -124- such as Al(III), where all coordinated waters are ionized under the present conditions. Oxyacid anions are formed, resulting in oxyacid anion esters 39 [Figure 5: M(H_„L) ], comparable with borate esters. Competition between Al(III) and B(III) for the coordination sites of D-glucaric acid was studied as a function of the pH using B NMR (Figure 7). At pH < 8 both Al(III) and B(III) prefer coordination by the a-hydroxy- carboxylate functions of D-glucarate. Obviously, the M(H_,L) complexes of l n« Al(III) are more stable than those of B(III). Since the gjCz/r + gg) value of B(III) is larger than that of Al(III), B(III) occupies the diol functions at 8 < pH < 11, at which pH Al(III) remains at the a-hydroxycarboxylic acid functions. As a result, mixed binuclear complexes of D-glucarate are probably formed. The stability of the borate esters is affected by Al(III) at pH > 11, when aluminate esters of the diol functions are formed too. Similar effects are expected for Fe(III), also a group (iii) cation with 91.2"1 It explains, for instance, the observation that 2 g1(z/r + g2) increase of pH (> 1* NaOH) decreased the synergic Fe(III) sequestration of borogluconate, a commercially available Fe(III) sequestering agent. At high pH (> 4* NaOH) the Fe(III) sequestering capacity of borogluconate equalled that of D-gluconate. 0 10 r !~~ n CA|.0-1M cM X B°.B 0 05 -v V_ J ^^B"G B G w 1 -^^ |\ " 2 8 pH Figure 7. Distribution of boron containing species for a solution of boric acid (0.1 M) and D-glucaric acid (0.1 M) in D„0 in the absence and presence of Al(III) (0.1 M) as a function of the pH at 25 °C as determined with B NMR. -125- Ca(II) coordination in oxyacid anion- D-glucarate systems The concentration of free hydrated Ca(II) was determined in solutions of Ca(Il) (5.0 mM) and the oxyacid (5.0 mM) in the absence and presence of D-glucaric acid (10.0 mM) at I = 0.1 and 25 °C as a function of the pH using a CalSE (Figure 8). The CalSE was poisoned when I(VII) (only in the absence of D-glucaric acid) and Sb(V) were tested. For Te(VI) precipitation of CaTeO. was responsible for the low [Ca], both with and without D-glucaric 40 acid. All the other oxyacid (anions) as such showed only a moderate Ca(II) binding capacity, typically log [Ca] > -3. The mixed ligand systems demonstrated synergic Ca(II) coordination in the case of B(III), Sb(III), Sn(IV), Al(III), and Ge(IV) oxyacid anions, whereas synergic effects were negligible for Si(IV), Se(IV), As(III), and As(V) (Figure 8). These phenomena will be discussed on the basis of the model K 7 previously derived for B(III). ' (i) At pH > 6 boric acid reacts with D-glucarate with formation of borate esters. The borate diesters of D-glucarate have a high Ca(II) coordinating strength and, as a result, [Ca] decreases, (ii) At pH > 9 boric acid is completely converted into borate and, therefore, both borate ester formation and the Ca(II) coordination equilibria are not affected by the pH anymore. For Al(III), As(III), and Sb(III) oxyacid anions comparable to borate [B(0H)~] are formed, viz. aluminate [A1(0H)~; pH > 11], arsenite [As(0H)~; OK JC Jl * co HJ pH > 9], and stibite [Sb(0H)4; pH > 11] 4 '^°' - These oxyacid anions will form the corresponding esters of D-glucarate. The overall association con stant for the aluminate diesters of polyhydroxycarboxylates (PV~T ) is about 5 4 10 10 times that of the borate diesters, ' whereas (3V-T for As(III) is only 10~2 to 10~3 times that of B(III).4'13,25,26 These differences in 0 - X l2 explain the differences in [Ca] observed for B(III), Al(III), and As(III) (Figure 8), when it is assumed that the Ca(II) coordination of the oxyacid anion diesters of D-glucarate are of comparable strength. If this is the 2 case, 0V- for Sb(III) is 10 times that of B(III). A Lp Silicate [SiO (0H)~n ; pH > 10: n > i25>26] contains at most three n 4-n hydroxyl groups and, consequently, only silicate monoesters of D-glucarate are formed at higher pH. Arsenate (H AsO"~ ; pH > 7: n < 2) and selenite (SeO„ ; pH > 8) do not possess more than one hydroxyl function ' and, therefore, show no oxyacid anion ester formation. As oxyacid anion diesters of D-glucarate are the Ca(II) coordinating species, this explains why no synergic Ca(II) coordination is observed for Si(IV), As(V), and Se(IV). -126- log [Ca] log [Ca] —~—:\*N.si"uv) \>A»(V) [(VII) y ^B(in) V%**h,k-^-So(IV) \\*Klll) \ S»(V[> \.G*(IV) 1 1 1 — pH Figure 8. Influence of the pH on log [Ca] for a solution of Ca(II) (5.0 mM) and an oxyacid (5.0 mM) in the absence and presence of D-glucaric acid (10.0 nM) at I = 0.1 and 25 °C as measured with a CalSE. -127- Finally, germanate [GedlgOJg (OH) n; n > 4] and stannate [Sn(OH)g ] are the predominant species for Ge(IV) and Sn(IV) at pH > 9 and pH > 11, respectively. ' With D-glucarate these hexadentate oxyacid anions may form either triesters, which possibly results in increased cooperation between three D-glucarates with respect to the Ca(II) coordination, or diesters with possible cooperative coordination of two oxyacid anion hydroxyl functions with two D-glucarates. For oxyacid anions exhibiting synergic Ca(II) coordination in the presence of D-glucarate [X~ = B(III), Al(III), Ge(IV), Sb(III), and Sn(IV)), [Ca] was measured at pH = 10.0-11.5, I = 0.1, and 25 °C as a function of the molar fraction of D-glucarate: XG = CG/(CX + CG> (2) 5.Or- -i [CajmM Figure 9. Free Ca(II) concentration as a function of the molar fraction D-glucaric acid for various Ca(II)-oxyacid anion- D-glucaric acid systems (Cy + C~ = 10.0 mM and Cr = 5.0 mM at pH as indicated, I = 0.1, and 25 °C) as measured with a CalSE. -128- The results for B(III), Al(III), and Ge(IV) again demonstrated the synergic Ca(II) coordination (Figure 9). The curve for Ge(IV) was influenced by kinetic effects, because of the very low rate of germanate ester formation, while precipitation occurred at x < 0.2. For Sn(IV) and Sb(III) clear solutions were only obtained in the presence of a substantial amount of D-glucarate. Ca(II) sequestering capacities (CaSC) were measured using a titration procedure with oxalate as the indicator, in order to obtain more practical data for synergic Ca(II) coordination and to check whether for the Al(III) and Ge(IV) systems [Ca] indeed is extremely low. Ba(II) sequestering capacities (BaSC), determined with sulfate as indicator, were included, since sequestration of Ba(II) is of relevance in oil winning and our B NMH data indicated that the oxyacid anion- D-glucarate mixed ligand systems might be of importance in that area. The data in Table 2 demonstrate that addition of oxyacid anions to a D-glucarate solution had a large effect on both Ca(II) and Ba(II) sequestration, in particular at pH = 12.5. The effects of the oxyacid anions upon the MSC seem less spectacular than with the CalSE measurements, since a decrease in [Ca] from 0.10 to 0.01 mM only amounts to an increase in coordinated Ca(II) from 4.90 to 4.99 mM. The MSC Table 2. Ca(II) and Ba(II) sequestering capacities (CaSC and BaSC) in oxyacid anion- D-glucaric acid systems at elevated pH and 25 °C. . , . mol oxyacid anion „„ „„-„ ,,„,« oxyacid anion —, - J, : rr pH CaSC BaSC mol D-glucaric acid B(III) 0.5 11.0 10.9 38.7 0.5 12.5 15.9 Al(III) 0.5 11.0 14.7 31.2 0.25 12.5 21.3 0.5 12.5 23.0 39.8 B(III) + Al(III) 0.25 + 0.25 12.5 27.8 0.5 + 0.5 12.5 26.0 Ge(IV) 0.5 11.0 43.0 Sb(III) 0.5 11.0 11.6 33.6 Sn(IV) 0.5 11.0 14.5 34.9 In g metal ion/100 g D-glucaric acid -129- correspond with cation/D-glucarate ratios of 0.5 to 1.0, which supports the existence of dication(II) complexes. For Al(III) this ratio is > 1, which indicates that other Ca(II) complexes are predominant. It has been briefly mentioned that for Al(III) and Fe(III) the difference between cations and oxyacid anions becomes rather vague. A general coordination-ionization scheme for cation/oxyacid anion-polyhydroxycarboxy- 39 late systems will be presented in the next chapter. Experimental 1 11 17 23 H, B, 0, and Na NMR spectra were recorded with an Nicolet NT-200 WB spectrometer at 200.07, 64.19, 27.12, and 52.92 MHz, respectively, at 25 °C. The samples contained a polyhydroxycarboxylic acid (0-0.2 M), boric acid (0-0.15 M), and a metal salt (0-0.3 M) in DgO at pH > 9 (NaOD) .unless stated otherwise. Free Ca(II) concentrations were determined with a Philips IS 561-Ca CalSE, a HNU ISE-40-01-100 single junction reference electrode, and a Corning digital 112 pH meter. The CalSE was calibrated as a function of the pH and linear drift correction was applied. The aqueous solutions of calcium(II) chloride (5.0 mM), D-glucaric acid (0-10.0 mM), and an oxyacid (0-10.0 mM) at I = 0.1 (KC1) were flushed with nitrogen. The measurements were performed at 25 °C under a nitrogen atmosphere. The pH was adjusted with NaOH. 42 CaSC were determined according to Wilham and Mehltretter, using a titration procedure with oxalate as indicator at pH = 11.0 or 12.5 (NaOH). BaSC were determined in a similar way with sulfate as indicator. Oxalate was tested as indicator, but the solutions turned turbid slowly and the BaSC of a solution without any sequestering agent was 2 g Ba(II)/25 ml. References and notes 1. W. Kliegel, "Bor in Biologie, Medizin und Pharmazie", Springer Verlag, Berlin (1980). 2. H. Peters, Neth. Pat. 99,202 (1961); Chem. Abstr. 56 (1961) 12682. 3. J.G. Heesen, Neth. Pat. 7,215,180 (1972); Chem. Abstr. 81 (1974) 176040. -130- 4. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 41 (1985) 3411; this thesis, chapter 3. 5. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav. Chim. Pays-Bas, in press; this thesis, chapter 4. 6. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, J. Chem. Soc., Perkin Trans. II, in press; this thesis, chapter 5. 7. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Carbohydr. Res., in press; this thesis, chapter 6. 8. H.R. Ellison, J.O. Edwards, and E.A. Healy, J. Am. Chem. Soc. 84 (1962) 1820. 9. H. Weigel, Advan. Carbohydr. Chem. 18 (1963) 61. 10. V. Frei, Coll. Czech. Chem. Comm. 32 (1967) 1815. 11. C.G. Macarovici and M. Volusniuc-Birou, Reel. Roum. Chim. 16 (1971) 823. 12. W. Pigman and D. Horton, "The Carbohydrates", Associated Press, New York, 2nd edn. (1972) 503. 13. P.J. Antikainen and E. Huttunen, Suom. Kemi B46 (1973) 185. 14. P.J. Antikainen, Finn. Chem. Lett. 1974, 159. 15. D.B. Denney, D.Z. Denney, P.J. Hammond, and Y.F. Hsu, J. Am. Chem. Soc. 103 (1981) 2340. 16. S. Sjöberg, A. Nordin, and I. Ingri, Mar. Chem. 10 (1981) 521. 17. R.J. Motekaitis and A.E. Martell, Inorg. Chem. 21 (1984) 23. 18. J. Mbabazi, Polyhedron 4 (1985) 75. 19. P. Suhac, N. Hafner-Milac, and B. Dolenc, Eur. Pat. 14,939 (1981); Chem. Abstr. 94 (1981) 103784. 20. W.B. Jensen, "The Lewis Acid-Base Concepts", Wiley Interscience, New York, (1980) 251. 21. P.L. Brown, R.N. Sylva, and J. Ellis, J. Chem. Soc, Dalton Trans. (1985) 723. 22. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 40 (1984) 2901; this thesis, chapter 2. 23. In the presence of Mn(II) only one broad B NMR signal was observed. 24. Figure 5 is a rather schematic representation. The borate monoester and its cation complexes are not included. The coordination of M is completed with waters and/or hydroxyls. 25. L.G. Sillen and A.E. Martell, "Stability Constants of Metal-Ion Complexes", The Chemical Society, London (1964/1972). 26. A.E. Martell and R.M. Smith, "Critical Stability Constants", Plenum Press, New York III and IV (1977/1982). 27. D. Midgley, Chem. Soc. Rev. 4 (1975) 547. -131- 28. Co(II), Ni(II), and Cd(II) coordination was investigated in more detail. Addition of cobalt(II) and nickel(II) chloride to a solution of boric acid (0.1 M) and D-glucaric acid (0.1 M) in D90 at pH = 10.5, resulted in excessive line broadening in the H NMR spectra. For Cd(II) this phenomenon was less obstructive, but induced shifts were small (< 0.05 ppm at C = 0.1 M) and the vicinal H coupling constants did not change. Co(II) induced shifts were measured for the carboxylate signal 17 17 in 0 NMR spectra of a solution with D-glucaric acid (5* 0 enriched carboxylic acid groups; 0.1. M) in D„0 at pH = 10.5 and 66 °C. The induced shifts were larger in the presence of boric acid (0.1M). 29. R.D. Shannon, Acta Cryst. A32 (1976) 751. 30. M. van Duin, J.M.A. Baas, and B. van de Graaf, to be published; this thesis, chapter 13. 31. For Pb(II) the g.(z/r + g„) value and pKfL . fall in the indicated regions. This is not so for the D value, which is probably too low. 32. From an extrapolation of the data from reference 20 it follows that the D values for trivalent cations are probably larger than 300. 33. H. Rossotti, " Chemical Applications of Potentiometry", D. van Nostrand Company Ltd., London (1969) 126. 34. E.W. Malcolm, J.W. Green, and H.E. Swenson, J. Chem. Soc. (1964) 4669. 35. T. Paal, Acta Chim. Scient. Hung. 95 (1977) 31. 36. J.L. Frahn, J. Chromatogr. 314 (1984) 167. 37. E.Z. Casassa, A.M. Sarquis, and C.H. van Dyke, J. Chem. Educ. 63 (1986) 57. 38. T. Taga, Y. Kuroda, and M. Ohashi, Bull. Chem. Soc. Jpn. 51 (1978) 2278. 39. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, to be published; this thesis, chapter 8. 40. From [Ca] as a function of the pH in the absence of D-glucaric acid _p (Figure 8), the solubility product of CaTeO was calculated to be 2*10 2 M . 41. C.F. Baes and R.E. Mesmer, "The Hydrolysis of Cations", John Wiley Interscience, New York (1976). 42. CA. Wilham and CL. Mehltretter, J. Am. Oil Chem. Soc. 48 (1971) 682. -133- CHAPTKH 8 A GENKHAL COOHDINATION-IONIZATION SCHEME FOB POLYHYDROXYCARBOXYIIC ACIDS IN WATER* Introduction Polyhydroxycarboxylic acids, such as the tartaric acids, citric acid, and 1 2 D-gluconic acid have found important applications as sequestering agents. ' The coordination sites consist of the carboxylic acid and hydroxyl functions, either deprotonated or not. The composition, structure, and stability of the complexes of polyhydroxycarboxylic acids with various 3 inorganic ionic species have been studied extensively. Sawyer and 4 Rendleman have collected a vast amount of data and have used them in attempts to explain the coordination phenomena of polyhydroxycarboxylic acids in a more general way. In this chapter we will discuss and extend these generalizations, while focussing on structural changes of the complexes as a function of the pH. Literature data are used, with the exception of studies on the solid state and on polymerization phenomena. In some cases new structural interpreta- 5 tions of potentiometric data will be proposed. A general coordination-ionization scheme will be presented, showing the importance of pH effects for the polyhydroxycarboxylic acid complexes of some fourty metal cations and oxyacid anions containing non-metal cations. The pH effects are correlated with the acidity of the hydrated cation and 2 fi the oxyacid. The g.(z/r + g„) values of Brown et al. are included in the explanation. Apart from offering fundamental insight, the coordination- -ionization scheme is expected to be of value in reaction and product research concerning polyhydroxycarboxylic acids. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, to be published. -134- Data and discussion Hydrated cations, metal hydroxides, oxyacids, and oxyacid anions in aqueous solution belong to the same class of inorganic cation containing compounds. They only differ in the degree of ionization of waters or hydroxyls coordinated to the cation (Figure 1). Throughout this chapter the cations will be denoted with their formal charges (M ). Sometimes changes in coordination number (en) occur with pH, as observed for hexaaquoalumi- num(III) (en = 6) vs. aluminate (en = 4) and for boric acid (en = 3) vs. 7 borate (en =4). In addition, dehydration can take place, for example from 2- 2- Si(OH). and Ge(OH)g into H2SiO„ and GeO„ , respectively. The nature of the cation determines which of the species from Figure 1 is predominant at a particular pH. For M = alkaline (earth) ions only Z 2-1 Z [M(H20) ] and [M(H„0) -(OH)] are known, for M = AI(III) and Ge(IV) z z—p successive ionization from [M(H„0) ] up to [M(OH) ] have been reported, for Mz = B(III) only [M(OH) ]z_p has been demonstrated, and for MZ = Si(IV), P As(V), and Se(IV) ionization of hydroxyl groups results in formation of Z_ 2< 7 [M(OH) 0 ] P" !. It should be noted that 0 denotes an olate (-0~) and p-q q not an oxy function (=0). The latter occurs only in dehydrated oxyacids. It is well known that the water acidity is increased by coordination to a metal ion, by virtue of (i) electrostatic repulsion between the metal ion and the water protons, particularly in the case of small and polyvalent metal ions, and (ii) weakening of the water 0-H bond as a result of [M(HjO)p] q [M(H20)p.q(OH)q]'" p-qH+ Z p [M(OH)p] - qH* l |M(OH)p.qOql -P-«' Figure 1. Successive ionization of coordinated waters and hydroxyls. -135- polarization by the coordinated metal ion. Hydrolysis of hydrated alkaline (earth) and lanthanide ions has been explained with simple electrostatic 7 R 6 models using charge/radius densities. ' Recently, Brown et al. have extended these models by introducing effective charges and have presented a quantitative relationship describing the hydrolytic behaviour of most hydrated metal ions: PK S + (Z/t 2 + (1) M(H90) (OH) = q Vl " V 2 p-q q Z 8-1 + q = 0: [M(H20)p] ^ [MCHgOp.jfOH)] + H z_1 Z 2 + q = 1: [Md^O) j(OH)] ^ [M(H20)p_2(OH)2] ~ + H g with z is the formal charge, r is the ionic radius, g, and g„ are functions of the charge and the electronic structure of the metal ion, and a and b 2 q q are empiric parameters. In the absence of metal ions g,(z/r + g„) = 0 and the effect of ionization of one water on the ionization of another water is small. Thus a. « a, (14.52 vs. 14.62). In the presence of metal ions the Z_1 hydrolysis of [M(H20) ,(0H)] will be less facile than that of [M(H„0) ] , as a result of the influence of the negatively charged hydroxyl c p ion, and thus b < b (-0.139 vs. -0.127). In Figure 2 the data of Brown et c U 1. are resente£ an< al. for PK^fii 0\ and P^ufu f)1 (r>H1 P l ^ supplemented with z ionization data of oc-hydroxyls in M - oe-hydroxycarboxylic acid systems (pt-, .), which will be discussed below. The acidity of dehydrated oxyacids was shown to be a function of the 11 12 number (hydr)oxy groups and the formal charge of the central cation. ' An attempt to correlate pK for a series of neutral, fully hydrated oxyacids z 2 z (M = non-metal) with g, (z/r + g„) was not successful. When M is a non- -metal, the M-0 bond has a predominant covalent character and the parameters of electrostatic models (formal charge and ionic radius) have no physical significance anymore. A compilation of literature data on the coordination and the ionization of polyhydroxycarboxylic acids in the presence of cations in water as a function of the pH is given in Table 1 and Figure 3. Here ionization as well as a change in coordination site occurs. This coordination-ionization scheme -136- M(HjO)p.,(OH) 100 125 z -g, (z/r +g2) Figure 2. Ionization of [M(H„0) ]Z (o),6 [M(H„0) (0H)]Z 1 (D),6 and z-1 2 P [MH.L] (•) vs. g.(z/r + g„) for a series of metal ions. can easily be extended for higher denticities besides bidentate and for complexes with other M/L ratios. Since the coordination of the central cation in the complexes of polyhydroxycarboxylic acids is completed with waters, hydroxyls, and olate oxygens, a large number of complexes is in 49 principle possible. Li(l) , Nad) , K(l) MgUD.CaUI) ,Sr(II) .Ba(ll) ML)1 ^^ Co(II), Ni(U) ,2n(II),Cd(lI) MH,L La (III). Am (Ml) k^\\\\H Y//////A Al (III).Th(W) Ge(IV) , Sb(V) , Te (VI) Mo(VI) ,Tc(V) , I (Vll) Figure 3. Successive ionization of cation complexes of polyhydroxycarboxylic acids as a function of the pH. Table 1. Successive ionization for complexes of polyhydroxycarboxylic acids with cations from all over the periodic system. ' ,OH ^ [ML]Z ^T [MH^L]2 1 Z^ (MH„L]Z 2 ^ [MH_,L]Z 3 + 1 + + H H H pH region reference us cation -1 I Li(I), Na(I), K(I) < 4 4-12c > 12' 15 Be(II) < 0 0-4° > 4C d d B(III) 4-9 9-13 I6, n Mg(II), Ca(II), Sr(II), Ba(II) < 3 3-10c > 11' Al(III) < 0 0-3 3-10 > 10 18/ 19,e 20d Si(IV) > 9 21* Ti(IV) + + + 22^ V(V) 23d -138- "O f—1 13 CM .-H .-H 00 I I I CO /v. io t» co oo oo «r oo OO i l i i i i i I CM CO -H CM CM CM CM CM CM CO ^H CM CM CM CM "O s M HH S> hH HH > -i u Sb(V) > 4 41 Te(VI) > 5 23/ 34/ 4/ Ln(III) < 1 1-5/6 5/6-11 > 10 3/ 42/ 43,e 44 e W(VI) a 5 23/ 37^ Pb(II) < 2 2-7 7-14 > 14 15/ 45 ^ Bi(III) < 14 > 14 45^ Th(IV) < 2 2-3 3-9 > 9 46" Am(III) < 1 1-6 > 6 I(VII) 2-10 37/ 47/ md a 7 Z ,z-Z— li 7-~ * The coordination of NT in [ML] , [MH_1L] , and generally in [MH__L] is completed by waters; that in to 1 z-3 b [MH_„L] by waters and (hydr)oxy functions. The pH ranges of stability for the various complexes were calculated with stability constants from references 15 and 16 or obtained from the references explicitly c d _ a given. Estimated by comparison with similar cations or using pKw/H n1 vKiu 1 2. Data and 6 f interpretation taken from the literature. Literature data interpreted by the present authors. Literature interpretation reconsidered. -140- The general applicability of the coordination-ionization scheme (Table 1 and Figure 3) is demonstrated by examples from all over the periodic system. Obviously, there is no essential difference between complexes of polyhy- droxycarboxylic acids with metal ions or with oxyacid anions. Not all the species in Table 1 are formed for a given M^, similarly as to the species in Figure 1. Alkaline (earth) ions are coordinated by the oc-hydroxycarboxylic acid moiety ([ML] ) at low pH (pH < 4) and by the oc-hydroxycarboxylate moiety ([MH_,L] z-1 ) in the intermediate pH region (4 < pH < 11). Ionization of the coordinated oc-hydroxyl function occurs at high pH (pH > 11: z-2 [MH_„L] ). For cations with a higher charge and a larger polarization ability, such as Ln(III), Am(III), Fe(III), and Cu(II), all the possible complexes given in Table 1 occur. Small, polyvalent, and strongly polarizing cations such as Mo(VI), Tc(V), and I(VII) are solely coordinated by the z-3 deprotonated diol function ([MH_„L] ). A plot of PK™ T vs. vXy.(u 0\ (M = non-metal) shows a linear relation ship with slope a 1, i.e. ionization of an oc-hydroxyl group is affected by coordination with a metal ion in approximately the same way as that of a water. The ionization of the oc-hydroxyl is determined by electrostatic and polarizing effects, as indicated by the correlation of pK^, T with 2 g,(z/r + g„) according to Equation (1) with a = 11.6 and b = -0.12 (Figure 2: correlation coefficient = 0.90). Since a coordinated oc-hydroxyl function ionizes prior to coordinated waters (pK^, .. - pIC-. a 2), hydroxyl ions 2 p -1 are only coordinated to cations in complexes with ionized oc-hydroxyl groups (i.e. only in [MH_„L]Z~2 and [MH_,L]2"3). 2 In Figure 4 a plot of pK^ . vs. g, (z/r + g„) is compared with the linear relationships for pK^ , pK^ , and pK^ from Figure p p z-3 2. Complexes with the cation bound at an ionized diol function ([MH_„L] ) 2 exist only for cations with g,(z/r + g„) > 40. For the metal ions the experimental points are scattered around an estimated relationship for 50 pKMH L' silnilar to Equation (1), whereas for the non-metal ions there is no correlation at all. The latter is probably due to the inapplicability of the extended electrostatic model for essentially covalent M-0 bonds. We found that for MH_2L (M = non-metal) pK is a linear function of pKM(OH) 0 (FiS"re 5)« Tnis relationship can be seen as a generalization p-q q of the pH rule of thumb, postulated previously for esters of boric acid and -141- 15- pK \, \pb(II\* ) •BHIII ) \ Cu(U)\ Vi *\ tt^ \ «Crdll) l Vl \ Ft(lll) Sn(lV) \ \ AlCIIlX* S**"1 10 ~\ \\» • \ Asdll) SKIV) \ Vaa(IIl) \ • • \ \\ • \ \ U Th(IV>\ \ \\ \ 0»(IV) \ \\ \ * W(VI). T.IVI) \\\ MH-2L \ • ■ \ \\ \ Tc MH_)L\\\M(H2O)P.,(0H) • \\M(H,0)x 2 D I P 1 1 1 100 200 300 400 2 -f g, (z/r + g2) Figure 4. Comparison of the pK of hydroxyl functions coordinated to a cation 2 vs. g,(z/r + g0) for MH oL complexes (points) with the linear K R relationships obtained for MCH-O) , M(H„0) -(OH), and MH.L (cf. Figure 2; the pKan d g,(z/r + g„) values for B(III) and I(VII) are 9.0 and 2000 and 2.0 and G30, respectively). 16 borate. In this way the pH region of optimum stability of a species can now be predicted. Upon ionization of an oxyacid an oxyacid anion is formed, which, subsequently, can react to an oxyacid anion ester. Therefore, oxyacid anion esters are only formed at that pH where sufficient oxyacid anion is present, that is where pH «: pK ... oxyacid 0 P 2q + H z 2q W Va°/" " _lL — [M(H_3L)(0H) 0 ] -P- + 2 H.,0 It should be noted that with the use of Table 1 the pH region of optimum stability of a species can be predicted, but not the stability as such. For instance, [ML] species will occur at low pH, but the stability as defined by the association constant will be small, i.e. somewhat larger than that z-1 of complexes with non-ionized polyols. Obviously, the [MH -.L] , z-2 z-3 [MH_2L] , and [MH_„L] complexes will be more stable. -142- pK MH.2L JfSbdll) /%m\m B(lll) y^SUIV) /Atdll) - / *Gt(IV) • r*(vn Sb(v) / KVII)• / / / i i i 8 12 -pK M(OH)n Figure 5. Ionization of MH„L as a function of pKufou^ 0 • p-q q In conclusion, the coordination-ionization scheme is useful when dealing with complexation phenomena of polyhydroxycarboxylic acids, but also of other sugar derivatives in water. The existence and structure of complexes as a function of the pH can be predicted, which enables the interpretation of potentiometric data and of the reactivity in these systems (for instance, homogeneous catalysis). References and notes R.L. Smith, "The Sequestration of Metals", Chapman and Hall, London (1959) 105. A.L. McCrary and V.L. Howard, in H.F. Mark, D.P. Othmer, C.G. Overberger, and G.T. Seaborg (eds.), "Kirk and Othmer Encyclopedia of Chemical Technology", John Wiley Interscience, New York, 3rd edn., 5 (1979) 366. D.T. Sawyer, Chem. Rev. 64 (1964) 633. J.A. Rendleman, Food Chemistry 3 (1978) 47. -143- 5. From potentiometric data only conclusions with respect to the composition and stability of complexes may be drawn. Structural interpretations should be made with great care. However, papers on this subject often contain a variety of contradicting and farfetched structures. In addition, some structures that are possible on paper or with space filling models still can be unrealistic. As a result, reinterpretation of the literature data is sometimes necessary (cf. Table 1, note f). 6. P.L. Brown, R.N. Sylva, and J. Ellis, J. Chem. Soc., Dalton Trans. (1985) 723. 7. CF. Baes and R.E. Mesmer, "The Hydrolysis of Cations", Wiley Interscience, New York (1976). 8. J.E. Huheey, "Inorganic Chemistry", Harper and Row, New York (1978). 9. The cationic radius is a function of the en. For Th(IV), Pb(II), Hg(II), Cu(II), and Ag(I), Brown et al. have omitted the use of ionic radii, corresponding with the predominant en. In this way a better correlation has been obtained between calculated and-experimental P*WH nl CnHI than with the use of the proper radii. Furthermore, '' P—Q statistic effects with respect to the number of coordinated waters have not been included. 10. R.D. Shannon and C.T. Prewitt, Acta Cryst. 25B (1969) 925. 11. J.E. Ricci, J. Am. Chem. Soc. 70 (1948) 109. 12. L. Pauling, "General Chemistry", W.H. Freeman, San Francisco (1970) 499. 13. L.G. Sillen and A.E. Martell, "Stability Constants of Metal Ion Complexes", The Chemical Society, London (1964/1972). 14. A.E. Martell and R.M. Smith, "Critical Stability Constants", Plenum Press, New York, 3 and 4 (1977/1982). 15. F. Coccioli and M. Vicedomini, J. Inorg. Nucl. Chem. 40 (1978) 2106. 16. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 40 (1984) 2901; this thesis, chapter 2. 17. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, J. Chem. Soc, Dalton Trans., submitted; this thesis, chapter 7. 18. V. Frei, Coll. Czech. Chem. Comm. 32 (1967) 1815. 19. C. Panada and R.K. Patnaik, J. Inst. Chemists (India) 49 (1977) 297. 20. R.J. Motekaitis and A.E. Martell, Inorg. Chem. 21 (1984) 23. -144- 21. S. Sjöberg, L. Ohman, and N. Ingri, 22th Int. Conf. Coord. Chem. (1984) 598. 22. A.N. Glebov and Yu.I. Sal'nikov, Zh. Neorg. Khim. 30 (1985) 3059; Chem. Abstr. 104 (1986) 40695. 23. H. Weigel, Advan. Carbohydr. Chem. 18 (1963) 61. 24. CL. Mehltretter, B.H. Alexander, and CE. Rist, Ind. Eng. Chem. 45 (1953) 2782. 25. W. Kaminski, Rocz. Chem. 46 (1972) 339; Chem. Abstr. 77 (1972) 52912. 26. P. Souchay and A. Hessaby, Bull. Soc. Chim. Fr. (1953) 614. 27. J. Gonzalez Velasco, J. Ortega, and J. Sancho, J. Inorg. Nucl. Chem. 38 (1976) 889. 28. C.G. Macarovici, E. Pertie, and E. Motiu, Rev. Roum. Chim. 12 (1967) 957. 29. C.G. Macarovici and E. Pertie, Rev. Roum. Chim. 14 (1969) 1113. 30. B. Lindberg and B. Swan, Acta Chem. Scand. 14 (1960) 1043. 31. C.G. Macarovici and M. Volusnic-Birou, Rev. Roum. Chim. 12 (1967) 163. 32. C.G. Macarovici and M. Volusnic-Birou, Rev. Roum. Chim. 16 (1971) 823. 33. P.J. Antikainen, Finn. Chem. Lett. (1974) 159. 34. P.J. Antikainen and E. Huttunen, Suom. Kemi B46 (1973) 185. 35. A.N. Ermakov, I.N. Marov, and L.P. Kazanskii, Russ. J. Inorg. Chem. 10 (1967) 1437. 36. C.G. Macarovici and L. Czeglédi, Rev. Roum. Chim. 15 (1970) 1863. 37. W. Pigman and D. Horton, "The Carbohydrates", Academie Press, New York, 2nd edn. (1972) 503. 38. A.M.V.S. Cavaleiro, V.M.S. Gil, J.D. Pedrosa de Jesus, R.D. Gillard, and P.A. Williams, Transit. Met. Chem. 9 (1984) 62. 39. L.L.Y. Hwang, N. Ronca, N.A. Solomon, and J. Steigman, Int. J. Appl. Radiat. Isot. 36 (1985) 475. 40. C.G. Macarovici and M. Volusnic-Birou, Rev. Roum. Chim. 14 (1969) 1231. 41. J. Mbabazi, Polyhedron 4 (1985) 75. 42. L.I. Katzin, Inorg. Chem. 7 (1968) 1183. 43. C. Panda and R.K. Patnaik, J. Ind. Chem. Soc. 56 (1979) 133. 44. K.M. Nirada and R.K. Patnaik, Ind. J. Chem. 22A (1980) 820. 45. D.T. Sawyer and J.R. Brannan, Inorg. Chem. 5 (1966) 65. 46. C.G. Macarovici and L. Czegledi, Rev. Roum. Chim. 9 (1964) 411. 47. B. Sklarz, Quart. Rev. 21 (1967) 3. -145- 48. P. Zuman, J. Sicher, J. Krupicka, and M. Svoboda, Coll. Czech. Chem. Comm. 23 (1958) 1237. 49. V. Frei, Z. Phys. Chem. 223 (1963) 289. 50. An estimated value for a (18.0) is based on pK , . , a 18. Hounding the b values from Figure 2 gives an estimate for b (-0.1). -147- CHAPTEB 9 A 1H, 11B, AND 13C NMR STUDY OF BORATE ESTERS OF 1,3-DIONES, INCLUDING CURCUMIN* Introduction In the presence of boric acid, 1,3-diones (Figure 1) are able to form borate mono- and diesters. Figure 2 shows that borate ester formation of 1,3-diones leads to neutral and positively charged borate esters, as opposed to the negatively charged species obtained from 1,3-diols. In addition, 2 enolization of the 1,3-diones (Figure 1) and ionization of the enol forms have to be taken into account. Borate esters of 1,3-diols probably have a 3 chair conformation, whereas those of 1,3-diones have a distorted chaiir 4 conformation, since the OCCCO part of the molecule is almost planar. Furthermore, the charge distribution in the six-membered borate ester rings 5 differs substantially. Borate esters of diols have found several applications in carbohydrate chemistry and, therefore, are studied quite extensively. We have demonstrated that H and C NMR, and particularly B NMR, are fruitful in the study of the molecular structure and stability of these borate esters. ' H and B NMR, together with infrared and ultraviolet spectroscopy, have been used by others to study borinate and difluoroborate 19—1 fi esters of acetylacetone and some of its derivatives. Dialkoxy borate 17 esters of 1,3-diones have been studied by ultraviolet spectroscopy. With respect to the application of borate esters of 1,3-diones in chemistry, those of curcumin (1, Figure 3) are of special interest. They are obtained as intermediates in the synthesis of curcumin from vanillin I O in (4-hydroxy-3-methoxybenzaldehyde) and acetylacetone and are applied i1n9 the spectrophotoraetric determination of boric acid in nonaqueous solvents. M. van Duin, J.A. Peters, A. Sinnema, A.P.G. Kieboom, and H. van Bekkum, to be published. o o OH O H II II I II o- -o R^SH^R, R^CH^R, denoted as C>—£C^ Figure 1. Enolization of 1,3-diones. OH I B HO \>H OH ♦ OH OH os OH •O r H OH OH^ V V" >oK<" "^^7 Ho\<" HO' N0 o' No- O, ^OH.^O ' 2H,0^^ V OH OO'' V-OH HO © OH ,B HO' VOH Figure 2. Borate mono- and diester formation for 1,3-diones and 1,3-diols. -149- q p H' H,C Figure 3. Structures of compounds 1-5. 20-29 Spectroscopie, polarographic, and synthetic studies have shown that the intensely red coloured rosocyanine, formed in the presence of a mineral acid, is a borate diester. Upon addition of alkali, the phenolic hydroxyl is deprotonated and the colour becomes blue-green. The intensely red coloured rubrocurcumin, formed in the presence of oxalic acid, is a mixed borate diester. 1 13 Although the signals of the H and C NMR spectra of curcumin have been 30 assigned by Unterhalt, borate ester formation of curcumin has not (and of other 1,3-diones has only partly) been studied before by the use of NMH spectroscopy. In this chapter results based on a H, B, and C NMR study of the borate esters of 1,3-diones are presented. The NMR parameters of both the free 1,3-diones and the corresponding borate esters are studied for curcumin (1), acetylacetone (2), benzoylacetone (3), dibenzoylmethane (4), and (phenylacetyl)benzoylmethane (5) with DMS0-c/_ as solvent (Figure 3). b Since our previous NMR studies on borate esters of diols were performed in aqueous solution, some experiments with acetylacetone in D„0 are included for comparison. -150- Results and discussion The B NMR spectra of acetylacetone (2) and boric acid in D,,0 consisted of a signal at 8 = 0 ppm (Av,. = 60 Hz) for free boric acid and a broad resonance with low intensity at 6 = -16.3 ppm. The latter value is within 31 the chemical shift range of tetracoordinated boron compounds. When compared with diols, such as glycol or 1,3-propanediol, the borate ester of 7 acetylacetone in aqueous solution is about 10 times less stable. In water 2 the enol/keto ratio for acetylacetone is about 0.2 and, since only the enol tautomer can form borate esters, this partly explains the difference in stability. Figure 2 shows that for 1,3-diones, increase of the pH will result in (i) dissociation of the borate diester, in agreement with the pH rule of thumb derived earlier and (ii) ionization of both acetylacetone and boric acid, so borate monoester formation also becomes unfavourable. Consequently, at pH > 8 the borate ester signal vanished, while the signal of free boric acid shifted from S = 0.0 to -17.7 ppm, due to the conversion of boric acid into borate. This picture is quite opposite to that for borate esters of 1,3-diols, where an increase of pH favours the borate ester formation (Figure 2). Formation of borate esters of 1,3-diones is more favourable in apolar media because (i) the enol/keto ratio is larger (Table 1), (ii) unlike water the solvent molecules do not participate in the borate ester equilibria, and (iii) higher concentrations of 1,3-diones can be used. Furthermore, the equilibria can be shifted by absorption of water using zeolite NaA. Table 1. Enol/keto ratio for compounds 1-5 at 25 °C. solvent 1,3-dione 1 2 3 4 5 chloroform- d. > 10s'* 4.1a 16* 10s pyridine-dt. 3.3s 0 acetone- rf, 2.8s 10* b DMSO-ci > 10s'* 1,.3, S1. 4" 3.3,S5* 14,S10* 3.3,S5* C D20 0.2 a *H NMR. h 13C NMR. C Reference 2. -151- The B NMR signal of boric acid in DMSO (8 = 0.5 ppm) was much broader 32 (Av.. = 300 Hz) than in D„0 (Av. , = 60 Hz). Upon addition of the 1,3-diones 1-5 to a solution of boric acid in DMSO at 25 °C, the intensity of the boric acid signal decreased and a new, very broad borate ester resonance at 6 = -16 ppm appeared. In the case of curcumin (1) no borate ester signal was observable. So the chemical exchange between boric acid and the borate esters is slow on the B NMR time scale and extensive line widths hamper the detection of the borate ester signals. The molecular volume of the borate esters of the 1,3-diones 1-5 is probably so large that quadrupolar relaxation becomes very fast. Using a coaxial tube assembly with a solution of borate in D„0 at pH = 11.0 (6 = -17.6 ppm; Av,. = 15 Hz) in the inner tube, we demonstrated that one boric acid molecule is bound by two curcumin molecules. Addition of trifluoracetic acid increased the amount of borate diester. This borate diester, rosocyanine, was formed exclusively, even when the total concentration of boric acid was larger than that of curcumin. This behaviour is quite opposite to that of borate ester formation of diols in alkaline medium. Comparison of the pathways given in Figure 2 shows that (i) both borate mono- and diester equilibria of diols at pH > 9 (where borate is predominant) are independent of the pH and a gradual shift occurs from borate mono- to diester upon increasing the diol concentration and (ii) the reaction of boric acid and 1,3-diones towards the borate monoester is pH independent, whereas subsequent reaction of the borate monoester to the borate diester liberates a hydroxyl ion. This immediately explains that the presence of hydroxyl neutralizing species (boric acid, enol species, 22 trifluoracetic acid, and mineral acid ) highly favours the diester formation in the case of 1,3-diones. For the borate esters of 1-5, B NMR spectra were also recorded at 73 °C. This resulted in the observation of relatively sharp signals (Table 33 34 2), due to the decreased rate of relaxation at elevated temperature, ' and in increased borate diester stability. The B NMR chemical shifts of the borate esters of 2-5 are close to that of 1, while the B NMR line widths correlate with the molecular volumes of the borate diesters. We therefore conclude that in DMSO borate diesters are formed exclusively for the 1,3-diones 1-5. Furthermore, the stabilities of the borate diesters of 1-5 in DMSO do not differ significantly, as was demonstrated both with 11 13 B and C NMR. -152- Table 2. B NMR data for the borate diesters of compounds 1-5. C 1,3-dione 8 /; V 1 -16.4 250 6400 2 -16.6 50 800 3 -16.0 70 1700 4 -15.7 100 2700 5 -16.0 105 2800 64.19 MHz; chemical shifts in ppm, relative to external 0.1 M b c boric acid in D„0; line widths in Hz. DMSO-rf,; 73 °C. Calcu li o o lated molecular volume in A . The chemical exchange between the borate diester and the free 1,3-dione 1 13 is slow on both H and C NMR time scales, with the exception of C., C_, Cg, C,,, and H., of curcumin (1) and of C., C_, Cg, C_, and C,, of (phenylacetyl)benzoylmethane (5). The C and H chemical shifts of the borate diesters of 1-5 are relatively close to those of the free enol forms, but differ substantially from those of the free keto forms (Tables 3 and 4 ' ). So the charge distribution in the 1,3-dione moiety of the enol tautomer and the borate diester will be similar, which is in agreement with 37 both INDO calculations and the general observation that chelation of the enolate moiety is more or less independent of the cation. ' Experimental H (60.01 MHz) and B NMR (64.19 MHz) spectra were recorded on a Varian T-60 and a Nicolet NT-200 WB spectrometer, respectively. C NMR spectra were recorded on a Varian CFT-20 (20.00 MHz) or a Nicolet NT-200 WB (50.31 MHz) spectrometer. TMS was used as internal reference for H and C NMR, a 0.1 M boric acid in DgO as external standard for B NMR. The experiments were carried out in DMSO-dg at 25 °C unless stated otherwise. The concentrations of the compounds were varied between 0-0.5 M boric acid and 0-1.0 M 1,3-dione. Viscosities were measured with Ubbelohde tubes. Table 3. C chemical shifts for compounds 1-5 and their borate diesters. 1,3-dione species 13 C chemical shift 1 2 3 4 5 6 7 8 9 10 11 12 1 101.0 183.2 121.1 140.7 126.4 111.3 148.0 149.4 115.8 123.2 55.7 enol B L2 101.2 178.8 118.8 145.9 126.3 112.5 148.3 151.0 116.2 124.8 55.9 2 57.9 203.6 30.8 keto 191.4 24.6 L enoil 100.7 B'L2 101.4 191.5 23.9 53.7 - - 126.2 127.8 - - 30.7 3 keto 97.0 182.8 137.8 127.1 129.0 132.9 194.4 25.6 enol B~L2 97.6 180.6 135.2 129.5* 128.7* 131.6 193.1 24.6 w I 4 50.8 - 136.1 129.1 128.4 133.5 keto 93.1 185.2 134.4 127.3 128.7 132.9 enol B-L2 93.7 182.0 135.1 129.2* 128.8* 131.9 b b b b _b 204.4 50.1 135.2* 134.3* 129.5* 203.4 5 keto 53.2 97.3 196.0 45.8 130.6 130.1 129.7 129.1 183.0 134.7 127.6 129.3 133.6 B"L2 97.8 193.4 44.0 130.5 130.1 129.6 129.1 182.3 135.1 129.5 129.3 132.1 a b 20.00 or 50.31 MHz; in ppm, relative to TMS; DMSO-cL; 25 °C. Assignments may be interchanged. Table 4. H chemical shifts for compounds 1-5 and their borate diesters. 1,3-dione species H chemical shift 11 aromatic H OH .c,d L . 5.95 6.58 7.56 3.89 7.19, 6.83, 7..1 2 - enol BL? 6.29 6.77 7.84 3.90 7.30, 6.87, 7..2 4 5.5-6 3.70 2.13 keto 5.67 2.02 14.6 enol BL? 6.18 2.21 5.5-6 7.4-8.1 keto 4.29 2.24 L . 6.53 2.18 7.4-8.1 15.8 enol Ol BL2 e 2.40 7.5-8.2 5.5-6 4.87 7.5-8.3 keto 7.35 7.5-8.3 17.2 enol BL? e 7.6-8.5 6 4.36 3.97 7.2-8.0 keto 6.60 3.81 7.2-8.0 15.2 enol B I„ . 7.12 4.00 7.2-8.2 5-6 a 60.01 MHz; in ppm, relative to TMS; DMSO-ti.; 25 °C. b Some of the H NMR data of both free 13 14 1,3-diones and their borate diesters differ from those reported by others ' by up to 0.7 ppm, which is probably due to differences in solvent. The aromatic protons are assigned to 3 H^Hg, H_g and H.-H^, respectively. The coupling constants J(H„,H.Ü3,H4) and J(HJ(H9g,H,H.10Q)) of the enol form as well as of the borate diester are 16 and 8 Hz, respectively. Overlap with the aromatic protons. -155- References and notes 1. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 40 (1984) 2901; this thesis, chapter 2. 2. J. Elmsley, Struct. Bonding 57 (1984) 147. 3. M. van Duin, J.M.A. Baas, and B. van de Graaf; this thesis, chapter 13. 4. F.A. Cotton and W.H. Ilsley, Inorg. Chem. 21 (1982) 300. 5. Partial charges on the atoms in the borate ester rings were calculated with INDO: borate monoester of acetylacetone: B: +0.54, 0: -0.31, CO: +0.40, CH: -0.26, CH: +0.04 and borate monoester of 1,3-propanediol: B: +0.54, 0: -0.44, CO: +0.30; CH,: -0.02; CH:„ -0.05. 6. W. Voelter, Chem. Zeit. 98 (1974) 493. 7. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 41 3411 (1985); this thesis, chapter 3. 8. M. Makkee, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav. Chim. Pays-Bas 104 (1985) 230. 9. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav. Chim. Pays-Bas, in press; this thesis, chapter 4. 10. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, J. Chem. Soc., Perkin Trans. II, in press; this thesis, chapter 5. 11. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Carbohydr. Res., in press; this thesis, chapter 6. 12. L.H. Toporcer, R.E. Dessy, and S.I.E. Green, Inorg. Chem. 4 (1965) 1649. 13. J.A.S. Smith and E.J. Wilkins, J. Chem. Soc. (1966) A 1749. 14. A. Trestianu, H. Niculescu-Majewska, I. Bally, A. Barabas, and A.T. Balaban, Tetrahedron 24 (1968) 2499. 15. N.M.D. Brown and P. Bladon, J. Chem. Soc. (1969) A 526. 16. M.E. Gursky, A.S. Shashkov, and B.M. Mikhailov, J. Organomet. Chem. 199 (1980) 171. 17. H.D. Ilge and D. Fassler, Z. Chem. 24 (1984) 218. 18. H.J. Roth and B. Miller, Arch. Pharm. 297 (1964) 660. 19. G.S. Spicer and J.D.H. Strickland, Anal. Chim. Acta 18 (1958) 231. 20. M.E. Schulemberger, Bull. Soc. Chim. Fr. 5 (1866) 194. 21. L. Clarke and C.L. Jackson, Am. Chem. J. 39 (1908) 696. 22. G.S. Spicer and J.D.H. Strickland, J. Chem. Soc. (1952) 4644. 23. G.S. Spicer and J.D.H. Strickland, J. Chem. Soc. (1952) 4650. 24. A.D. Gol'tman, Tr. Khar'kovsk, Farmatsevt. Inst. 2 (1962) 150; Chem. Abstr. 60 (1964) 13889. -156- 25. M. Miyamoto, Bull. Chem. Soc. Jpn. 36 (1963) 1208. 26. H.J. Roth and B. Miller, Arch. Pharm. 297 (1964) 617. 27. H.J. Roth and B. Miller, Arch. Pharm. 297 (1964) 660. 28. F. Umland and F. Pottkamp, Fresenius' Z. Anal. Chem. 241 (1968) 161. 29. P. Quint, F. Umland, and H.D. Sommer, Fresenius* Z. Anal. Chem. 285 (1977) 356. 30. B. Unterhalt, Z. Lebensm.-Unters. Forsch. 170 (1980) 425. 31. H. Nöth and B. Wrackmeyer, NMR Basic Princ. Prog. 14 (1978). 32. Differences in viscosity (2.11 and 1.00 cP for DMSO and water, respectively at 25 °C) explain only part of this effect. Solvation of boric acid in DMSO probably is stronger than in water, which is supported by the observation at elevated temperature of a small B NMR signal (0.1%) at 8 - -17.9 ppm, which is attributed to a boric acid-DMSO adduct. 33. A. Abragam, "The Principles of Nuclear Magnetism", Clarendon Press, Oxford (1961). 34. Upon temperature increase from 25 to 73 °C the line widths of the signals of boric acid and the borate diester of acetylacetone decreased from 300 to 110 and from 170 to 50 Hz, respectively. A decrease in line width by a factor 2.6 was calculated, since the viscosity of DMSO decreased from 2.11 cP at 25 °C to 0.94 cP at 73 °C, respectively. 35. When the aromatic rings are in conjugation with the 1,3-dione moiety, as 13 in 1, 3, 4, and 5 (benzoyl ring only), the changes in C NMR chemical shifts of the o~ and p-carbons are larger than those of the ürcarbons due to mesomeric effects. 36. For 2-5 the chemical shifts of C, and H. for the keto, enol, and borate 11 diester species, the B chemical shift of the borate diesters, and the enol/keto ratio of the free compounds follow the order 2, 3=5, and 4. This is explained by the difference in conjugation between the 1,3-dione moiety and the aromatic rings and is in agreement with literature 12 14 15 data. ' ' Curcumin can not be fitted in this series. 37. Partial charges on the carbons in the OCCH CO-moiety were calculated with INDO: keto: CO: +0.31, CH„: -0.06, enol: CO: +0.36, CH: -0.27, and borate diester: CO; +0.40, CH: -0.26. -157- CHAPTBH 10 *H NMR SPECTRA OF CARBOHYDRATE-DERIVED POLYHYDROXYCARBOXY1ATES* Introduction Borate esters of sodium polyhydroxycarboxylates are applied as cation sequestering systems. The structures of several of such esters in aqueous 11 13 2 3 solution have been determined in this laboratory using B and C NMR. ' The conformational changes of the polyhydroxycarboxylates upon borate ester formation can be deduced from H NMR experiments. We here present the H NMR data of the free polyhydroxycarboxylates in water. The definition of the various diol configurations is demonstrated in Figure 1. c, oo c. oo r H—c,—-O oH HO—C, —H threo - dio^ iin erythro-diol I L HO — C3— H syn-diol <- HO— C,— H I I H — Ct— OH -J H —C4 —OH T I. H —C5—OH H — C5— OH 1 © I e c6oo c6oo 10 12 Figure 1. Structures of D-glucarate (10) and D-mannarate (12). M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Magn. Reson. Chem., in press. -158- Results and discussion The assignment of the H signals of the polyhydroxycarboxylates 1-12 (Table 1) was straightforward with the exception of those of D-glucarate 2 (10), in which case a comparison with 2- H-D-glucarate was required. The data in Table 1 allow the determination of mean H chemical shifts and vicinal H coupling constants as a function of the proximity of the carboxylate group and of the configuration at and around the hydroxymethylene group under consideration (Table 2). With respect to the H chemical shifts the following may be noted. The presence of an electron-withdrawing carboxylate group results in a downfield shift: &(H ) > 6(H ). ^Area-configurations give rise to deshielding a pa & H relative to erytAro-configurations, i.e. &(H., ) > ( ~rv4-ur )• The vicinal H coupling constants for polyhydroxycarboxylates without syn-l,3-interactions (1-3, 7-9, and 12) point to a preference for the planar 3 3 zig-zae g conformation, viz. J(H,H)., < 3 Hz and J(H,H) ,, > 5 Hz. ° \ threo ? erythro Intermediate coupling constants [ J(H,H, ) > 3 Hz or J(H,H ., ) < 5 Hz] for polyhydroxycarboxylates with sy/j-l,3-interactions (4-6, 10, and 11) Table 2. Effects of position with respect to the carboxylate group and of configuration on mean H chemical shifts and vicinal H coupling constants. &(H ... ) 4.15 ± 0.06 (5) a; threo &(H ., ) 4.08 ± 0.02 (2) a; erythro &(H 4 01 +1 0 03 3 P;threo/threo> " ' < > 8(Hp;other) 3.86 ± 0.06 (8) J(H H ) 2A 4l 2 4 ' a' P;threo - < > J(H H 5 ±0 7 6 3 a' P;erythro> -° - < > J( H 2 9 4l 3 ? V y;threo> " ' ^ ^^.«yierythro) 7"5 ± °"7 (3) Chemical shifts in ppm relative to (Sbutanol (& = 1.20 ppm) and coupling constants in Hz; the symbol ± denotes the standard deviation; the number of experimental values is given between brackets. Table 1. H NMR spectral parameters of polyhydroxycarboxylates. polyhydroxycarboxy late h'. chemical shi ft 3J(H,H) 2J(H,H) H ,H H .H H H H2 H3 H4 H5 H6 H6' H2,H3 3 4 4 5 5' 6 H5*H6' 1 rac. -glycerate 4.09 3.72 3.82C 6.0 3.1" -11.8 2 D-arabinonate 4.19 3.80 3.68 3.81 3.62e 1.7 8.3 2.6 6.3^ -11.6 3 D-lyxonate 4.07 3.75 3.84 3.62 3.58e 5.1 2.8 4.6 7.6/ -11.6 4 D-ribonate 4.12 3.85 3.78 3.77 3.60e 3.6 7.2 2.9 6.9^ -11.9 5 D-gluconate 4.08 3.98 3.71 3.72 3.78 3.62 3.6 4.1 7.4 3.1 6.5 -11.8 Ol 6 D-gulonate 4.08 3.83 3.75 3.75 3.66 3.57 5.2 3.0 0.5 4.0 6.5 -11.7 CD 7 D-mannonate 4.08 3.95 3.70 3.68 3.79 3.60 5.6 0.8 8.5 2.1 6.3 -11.6 8 D-tartrate 4.35 4.35 1.6^ 9 galactarate 4.22 3.90 3.90 4.22 1.1 ~ 7 1.1 10 D-glucarate 4.10 4.03 3.90 4.08 3.0 4.7 4.6 11 L-idarate 4.16 4.03 4.03 4.16 < 5 < 5 12 D-mannarate 4.06 3.89 3.89 4.06 5.6 ~ 2 5.6 Chemical shifts in ppmi (± 0.0 1 ppm) relative to i!*-butano l as iriterna l standard (8 = 1. 20 ppm) and coupling C d e constants in Hz 0. 1 Hz). * C = 0 .2 M; D 0; pH = 11.0 ; 25 °C. 6(H2 . 3J(H H (± 2 2' 3 .). 6(H50- /3 13 '1 1 13 J(H4,H5-). *Us ing C satellites; J( H, C) = 145.9 Hz. -160- suggest the existence of equilibria between linear, bent, and sickle conformations. This is in agreement with literature data on some related 4 5 systems. ' Vicinity of a carboxylate group results in a decrease of the vicinal coupling constant as should be expected for electronegative substituents: 3J(H ,H.) < 3J(H.,H ). <* P P V The data in Table 1 and 2 may be useful, for example in the analysis of oxidation products of carbohydrates. Experimental The 200 MHz H NMR spectra were measured for solutions (0.5 ml) of the polyhydroxycarboxylate (0.2 M) in D„0 at pH = 11.0 (NaOD) and 25 °C, using (^■butanol as internal reference (S = 1.20 ppm). The spectrometer was a Nicolet NT-200 WB headed with a 5 mm probe with internal locking from D„0. The number of data points was 16 K, the spectral width 500-1000 Hz, the pulse width 5-6 fis (90° pulse), the repetition time > 5 s, and the number of transients 10-100. The H chemical shifts (± 0.01 ppm) and H coupling constants (± 0.1 Hz) were determined using the LAOCOON spin simulation 2 program. D-Lyxonate (3), 2- H-D-glucarate, L-idarate (11), and D-mannarate (12) were synthesized as described elsewhere. ' ' References 1. W. Kliegel, "Bor in Biologie, Medizin und Pharmazie", Springer Verlag, Berlin (1980). 2. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 41 (1985) 3411; this thesis, chapter 3. 3. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav. Chim. Pays-Bas, in press; this thesis, chapter 4. 4. G.A. Jeffrey and H.S. Kim, Carbohydr. Res. 14 (1970) 207. 5. S.J. Angyal, Carbohydr. Res. 84 (1980) 201 and references cited therein. 6. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, J. Chem. Soc., Perkin Trans. II, in press; this thesis, chapter 5. -161- CHAPTEH 11 THE CONFORMATIONS OF THE SIMPLE VICINAL DIOLS AS STUDIED WITH MOLECULAR MECHANICS CALCULATIONS* Introduction Dihydroxy compounds react with boric acid and borate in aqueous medium with formation of boric acid esters, borate monoesters, and borate diesters 1 2 (Figure 1). ' These have been of importance in the configurational analysis 3 3 of carbohydrates and are applied in various separation techniques and in 4 5 the sequestration of cations by mixtures of borate and sugar acids. ' An experimental study of the relative stability of the borate esters for a series of pplyhydroxy compounds is presented in a previous chapter. In .OH OHe HO^s/OH HO-BC -OH HO xOH -OH OH -OH OH O e^OH 0 ;B— OH -c OH OH r-o^e^o- l-O' "o-J Figure 1. Equilibria between boric acid, borate, and dihydroxy compounds in aqueous medium. M. van Duin, J.M.A. Baas, and B. van de Graaf, J. Org. Chem. 51 (1986) 1298. -162- addition, a molecular mechanics study was carried out to elucidate the steric and electrostatic interactions in the diols and in the borate monoesters. 1,3-Dioxolanes were studied as model compounds for the borate monoesters. In this chapter we present the results of our calculations for a series of diols: 1,2-ethanediol, 1,2- and 1,3-propanediol, and meso- and rac.-2,3- -butanediol. We also present some results on 1,2-dimethoxyethane to illumi nate the so-called gauche effect. The results of the calculations are compared with data from the literature. Calculations The calculations were performed using Allinger's MM2 empirical force 7 R field and DELPHI, the Delft molecular mechanics computer program. As dielectric constant (E) 1.5 and 80 were used. The former is the standard value used in the force field, the latter is more relevant to the aqueous medium of the study on borate ester stability. The calculations for 1,2-pro- panediol and for meso- and r-ac.-2,3-butanediol were carried out for the (5)-, (,R,S)-, and (S, .SO-configurations, respectively. The various conformers were found starting from the corresponding staggered conformations. In some 9 cases torsion angle driving with the Lagrange multiplier method was used to locate a particular conformer. Because of symmetry it is not necessary to perform calculations for all rotational isomers around the C-C and C-0 bonds. Depending on the OCCO backbone three forms are distinguished, viz. the anti (a), the right handed gauche (g ), and the left handed gauche (g ) forms (Figure 2); each form includes the various conformers resulting from all possible CCOH torsion angles. Note that the designations g and g interchange when (R)- and (^-configurations are interchanged. OH OH OH anti gauche♦ gauche - Figure 2. A, g , and g forms of vicinal diols. -163- The steric energy and the characteristic torsion angles of all relevant conformers are compiled in Tables SI to S6 (supplementary material). The mean steric energies of the anti and gauche forms, E and E , were calcu lated at 25 °C with the Boltzmann equation. In the same way the mean steric energy Ë was calculated for each compound. AE is defined as E - E ; AE o values are given in Table 1 along with the heats of formation AH. calcu- 7 lated from the increments of the NW2 force field. Table 1. Energetic data for the simple vicinal diols, obtained with the MM2 force field. compound form 1.5 t = 80 AE AHX AE 0.00 0.00 1,2-ethanediol a -91.65 + - g ,g 0.91 -0.42 (5)-l, 2-propanediol a 0.00 + g -0.74 g~ -0.40 c a o.oo' (R, S)-2,3-butanediol o.oo -109.73 + - g ,g •0.79 -0.07 (5, S)-2,3-butanediol a 0.00C 0.00' + g •2.12 -110.16 -0.94 g~ 1.56 -1.16 1,3-propanediol a/a 0.00 . + a/g , a/g~, i 0.30 e /g . g~/g~ 0.60 i It ,, g_/g+ 0.86 1,2-dimethoxyethane a 0.00 + g >g -0.59 CE (E - Ea) and AH- are given in kcal/mol. Each form includes the various CCOH conformers; a and g refer to the OCCO backbone. CE [(/?, 5)-2,3- -butanediol] - Ê [(S, S)-2,3-butanediol] is -0.78 (e = 1.5) and -0.69 a , kcal/mol (f = 80), respectively. a and g refer to the OCCC backbone. -164- In Table 3 energy increments for gauche vs. anti Me/Me, Me/OH, and OH/OH interactions are presented. These were obtained by a least squares fit on all AË values at t - 1.5 and 80. Discussion General Before dealing with each compound in detail we, want to discuss the effect of higher energy conformers upon the mean energy (E) of a set of conformers In the case of n higher energy conformers (E = E.) besides the conformer of lowest energy (E = 0) we obtain: E = nE. exp(-E./RT)/[n exp(-E./RT) + 1] (1) 0-7 É (kcal/mol i 06 - 12 3 4 —E, [kcal/mol] Figure 3. Effect of n higher energy minima (E = E.) upon E. Figure 3 shows E as a function of E. for n = 1-3, 5, and 10 at 25 °C. For n = 1 the maximum value of Ë is only 0.16 kcal/mol for E. = 0.87 kcal/mol. With other E.^ values the contribution of higher energy conformers diminishes rapidly. For n > 1 the maximum value of I shifts to higher values of E.. -165- 1,2-Ethanediol The gauche forms are calculated to be more stable than the anti form at e = 1.5 (AÊ =-0.91 kcal/mol). The conformer of lowest energy of the two gauche forms has one CCOH torsion angle of nearly 180°, while the other angle is about +60 or -60°. These confonners are stabilized by large dipole- dipole interactions (-1.28 kcal/mol) between the hydroxyl groups, which can be regarded as intramolecular hydrogen bonds (Figure 4, Table 2). Energetically, hydrogen bonds can. be seen as the sum of both electrostatic and charge transfer effects. Only the former ones are included in the MM2 force field. Figure 4. Gauche form of a vicinal diol stabilized by an intramolecular hydrogen bond in the gasphase and apolar media. Table 2. Characteristic dimensions of the intramolecular hydrogen bonds stabilizing the gauche conformation of diols at t - 1.5. 1,2-ethanediol (R, 5)-2,3-butanediol (S, S)-2,3-butanediol 0 0 2.84 2.83 2.78 0 H 2.48 2.45 2.41 0 H-0 102 104 103 Bond distances in A and valency angles in °. The dipole-dipole attraction term becomes very small at i = 80 and the intramolecular hydrogen bonds vanish. However, the gauche forms remain preponderant (üË = -0.42 kcal/mol) due to the stabilizing V_ term of the OCCO torsion angle energy function. The difference between the torsion energies of the most stable gauche and anti conformers at e = 80 is -0.47 kcal/mol and almost equals AE. The V_ term is incorporated in the MM2 force 7 11 field to cope with the gauche effect. This will be discussed below in -166- connection with the results for 1,2-dimethoxyethane. The gauche conformer of lowest energy at t - 80 has two CCOH torsion angles of about 180° thereby reducing the van der Waals interactions. The results calculated for E = 1.5 agree well with experimental data. In 12 the gas phase the gauche forms are known to be predominant and for 13 solutions in apolar solvents AH is -0.4 to -0.6 kcal/mo]. The existence of intramolecular hydrogen bonds has been demonstrated for both phases. 17 The small difference between the calculated and the experimental values of CM-0, -91.7 and -93.9 ±1.5 kcal/mol, respectively, can be explained with the tendency of 1,2-ethanediol to dimerize to some extent in the gas I Q _ phase. AH values for 1,2-ethanediol in aqueous solution and as pure liquid 13 19 20 are almost equal, viz. -0.8 and -0.7 kcal/mol. ' ' The calculations are in agreement with experimental results, which show that intramolecular 19 21 hydrogen bonds are absent for 1,2-ethanediol and polyols in polar protic environments. The shift of the calculated values of AE from -0.91 at t = 1.5 to -0.42 kcal/mol at t = 80 is opposite to the shift of the experimental values of AH „ from about -0.5 for apolar solvents to about -0.75 kcal/mol for polar protic solvents. This gives evidence for a solvent effect in polar protic solvents of about 0.75 kcal/mol stabilizing the gauche forms. Part of this effect can be explained by the stabilization of the forms with the largest dipole moment, i.e. the gauche forms of 1,2-ethanediol, through intermolecular dipole-dipole interactions with polar solvents. Experimentally this effect only amounts to 0.08 kcal/mol for 1,2-dimethoxy- 22 23 ethane when t is changed from 2 to 8. ' Therefore, a specific solvent Figure 5. Gauche form of a vicinal diol stabilized by two intermolecular hydrogen bonds with a hydroxyl function in polar protic media. -167- effect is probable. We suggest a cyclic structure containing two hydrogen bonds (Figure 5). Preliminary calculations demonstrated that such a 24 structure is energetically favoured. Finally, it should be noted that the anti form is predominant in a diluted solution of 1,2-ethanediol in DMSO, a 20 solvent forming hydrogen bonds only by accepting protons. To study the effect of the negative V„ torsion term, we performed calculations on 1,2-dimethoxyethane. A comparison of AE for 1,2-ethanediol and its dimethyl ether at e = 80, -0.42 and -0.59 kcal/mol, respectively, shows that substitution of the hydroxyl groups with methyl groups has little effect upon the gauche/anti preference. The explanation is that the ener getically preferred gauche and anti conformers of both compounds have CCOH and CCOC torsion angles of about 180°, thus keeping the differences in steric energy to a minimum. Experimentally, the gauche preference of rye op 07 OR 1,2-dimethoxyethane ' as well as that of polyethylene glycol ' has been well established. For the conformers of 1,2-dimethoxyethane we calculated a decrease in stability in the series a/g/a, a/a/a, a/g/g, and a/a/g (supplementary material), which is in excellent agreement with 25 literature data. Thus the gauche effect can be a determining factor in the absence of other stronger effects and is justly incorporated in Allinger's 29 force field for the present compounds. (15 ) -1,2-propanedi ol For this compound the g and the g forms are different (Figure 6). Only calculations at t = 80 were carried out. Both the g and the g forms are preferred over the a form (AË = -0.74 and -0.40 kcal/mol), due to the negative V„ torsion term. The energy difference between the g and the g forms is caused by unfavourable Me/OH interactions (Table 3) in the g form. A comparison with experimental data is not possible, because these concern the gas phase and apolar solvents. Intramolecular hydrogen bonds have been 30 31 + - proved to exist in both phases ' stabilizing the g and g forms. As OH OH OH 0H HO„ "xk ^c / éc** OH Me T anti gauche» (jauche - Figure 6. A, g , and g forms of (5)-l,2-propanediol. -168- discussed for 1,2-ethanediol, the preference for the gauche forms will be enhanced in polar protic environments by specific solvation. 1,3-propanediol Calculations at t = 80 demonstrate that the conformational energy decreases when the number of anti CCCO and CCOH torsion angles increases. This is reflected in the average conformational energies of the four forms, viz. 0.0, 0.30, 0.60, and 0.86 kcal/mol for a/a, a/g , g /g , and g /g~, respectively (Figure 7). The preferred conformer is that with all four torsion angles equal to 180°, i.e. a fully extended conformation. Studies on the conformation of 1,3-propanediol have only been concerned with solutions 30 32 in CC1,, and have shown the presence of intramolecular hydrogen bonds. ' 'A OH HO Figure 7. A/a, a/g , g /g , and g /g forms of 1,3-propanediol. (R.SJ-2,3-but.anediol Calculations at e = 1.5 show the gauche forms (Figure 8) to be favoured (AE = -0.79 kcal/mol). The somewhat smaller stabilization of the gauche forms relative to 1,2-ethanediol is due to unfavourable steric interactions caused by methyl substitution (Table 3). The two gauche conformers of lowest energy are stabilized with intramolecular hydrogen bonds (Figure 4, Table 2). At E = 80 the strong dipole-dipole interactions disappear and steric interactions are the determining factors. Due to the negative V_ torsion term the gauche forms remain slightly favoured (AË = -0.07 kcal/mol). -169- OH OH OH Me Me. 1. .OH HO. Me^ Tf ^ Me J ^ Me OH ' Me anti gauche* gauche- Figure 8. A, g , and g forms of (R, 5)-2,3-butanediol. Quantitative data on conformational equilibria of this compound are not available. In diluted CC1- solutions the presence of both free and intra- lfi *^0 molecularly hydrogen bonded hydroxyl groups has been demonstrated. ' The 33 latter give evidence for the presence of gauche forms. Levy et al. have 13 interpreted the change in the C chemical shift of the methyl groups, going from apolar solvents (CCl.and CHC1„) to nonprotic polar solvents (DMSO, HMPO, DMF, and pyridine), as a shift of the conformational equilibrium from 19 gauche to anti. This is comparable with the results for 1,2-ethanedlol. 33 For water as solvent such a change has not been observed. We conclude that an appreciable amount of gauche forms will be present in aqueous solution. Just as in the case of 1,2-ethanediol we rationalize this by specific 34 solvation (Figure 4). Finally,. Grenier-Loustalot et al. also have 13 published a paper on the changes of the C chemical shifts. We object to their analysis of the data and conclude that the conformational equilibria 13 for this compound in both CDC1_ and D_0 are comparable, because the C chemical shifts do not differ significantly. (S, S ) -2,3-bu tanedi ol Calculations at e = 1.5 show a stabilization of the g and g forms (Figure 9) due to intramolecular hydrogen bonding (Figure 4, Table 2), AE = -2.11 and -1.56 kcal/mol, respectively. Apparently the gauche Me/Me interaction is less than twice the gauche Me/OH interaction (Table 3). AH. is smaller than that of the (./?, S) -compound (-110.2 vs. -109.7 kcal/mol), due to decreased steric interactions. At t = 80, all intramolecular hydrogen bonds disappear and the three forms have conformers of lowest energy with CCOH torsion angles of about 180°. The g and g forms remain preponderant (AË = -0.94 and -1.16 kcal/mol). -170- OH OH OH Me^ v OH HOx ,Me AY ïir rTY Me' Me' Me' S. OH Me f anti gauche» gauche- Figure 9. A, g , and g~ forms of (S, S)-2,3-butanediol. These results agree with experimental data in apolar solvents so far that an appreciable amount of intramolecularly hydrogen bonded species is i K *?n 33 present. According to Levy et al. the change from apolar to polar 13 nonprotic solvents has a shielding effect upon the C chemical shifts of the methyl groups, which has been interpreted as a change in the equilibrium from g to a. For an aqueous solution the shielding effect was larger and we explain this with a conformational change from g to g . These two equilibrium shifts both agree with the different intermolecular hydrogen bonding in both nonprotic and protic polar solvents. Steric interactions in the series of vicinal diols AË values in the present series of diols can be seen as the sum of gauche interactions between the substituents on the ethane backbone (Table 3). For example, AË for 1,2-ethanediol is explained by a gauche OH/OH interaction. As can be expected the Me/Me interaction is independent of e and is close to 35 the experimental Me/Me interaction in .n-butane. The Me/OH interaction decreases upon increase of t, because the CCOH torsion angles in the con formations of lowest energy change from +60 or -60 to 180°. Finally, the OH/OH interaction becomes less favourable when e is increased, due to Table 3. Energy increments for various gauche interactions. e Me/Me Me/OH OH/OH 1.5 0.69 0.61 -0.88 80 0.68 0.25 -0.50 In kcal/mol. -171- breaking of the intramolecular hydrogen bonds; this interaction remains stabilizing due to the gauche effect. The data in Table 3 can be used topredict AE values for other alcohols in the gas phase and in apolar solvents (E = 1.5) or polar noninteractive solvents (E = 80). Conclusions Summarizing the experimental data for the vicinal diols, we can distinguish several types of environments, each with characteristic influences upon the conformational preferences. Diols in the gas phase or dissolved in apolar solvents are able to form intramolecular hydrogen bonds. These hydrogen bonds stabilize the gauche forms relative to the anti form. Intermolecular hydrogen bonds exist in polar solvents. In polar nonprotic solvents this results in stabilization of the anti form, in polar protic environments in stabilization of the gauche forms. Our calculations at t = 1.5 for 1,2-ethanediol and the 2,3-butanediols show stabilization of gauche forms, due to large dipole-dipole interactions and a negative V„ torsional term. The results are generally in good agreement with the experimental data. Increasing t diminishes the dipole— dipole interactions. Going from apolar to polar solvents not only does t increase, but intermolecular hydrogen bonds can be formed. These are not incorporated in the MM2 force field. Therefore, our calculations at t = 80 cannot result in a good description of compounds dissolved in polar interactive solvents. The difference between the calculated results and the available experimental data points to a specific solvation of gauche forms in polar protic environments. Energy increments for gauche Me/Me, Me/OH, and OH/OH interactions rationalize the AE values in the series of the vicinal diols and may be used to predict AE for other alcohols. Supplementary material available from author: characteristic torsion angles, point group, and conformational energy of all conformers of the diols as calculated with the MM2 force field (8 pages). -172- References and notes 1. J. BBeseken, Adv. Carbohydr. Chem. 4 (1949) 189. 2. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 40 (1984) 2901; this thesis, chapter 2. 3. R.J. Ferrier, Adv. Carbohydr. Chem. Biochem. 35 (1978), 31. 4. H. Peters, Neth. Appl. 99,202 (1961), Chem. Abstr. 56 (1961) 12682. 5. J.G. Heesen, Neth. Appl. 7,215,180 (1972), Chem. Abstr. 81 (1974) 176040. 6. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 41 (1985) 3411; this thesis, chapter 3. 7. N.L. Allinger and Y.H. Yuh, QCPE 13 (1981) 395. 8. B. van de Graaf, J.M.A. Baas, and A. van Veen, Reel. Trav. Chim. Pays- -Bas 99 (1980) 175. 9. B. van de Graaf and J.M.A. Baas, J. Comput. Chem. 5 (1984) 314. 10. H. Umeyama and K. Morokuma, J. Am. Chem. Soc. 99 (1977) 1316. 11. A.J. Kirby, "Concepts in Organic Chemistry", Springer Verlag, Berlin, 15 (1983) 75. 12. 0. Bastiansen, Acta Chem. Scand. 3 (1949) 415. 13. K.G.R. Pachler and P.C. Wessels, J. Mol. Struct. 6 (1970) 471. 14. H. Buckley and P.A. Giguere, Can. J. Chem. 45 (1967) 397. 15. H. Frei, T. Ha, R. Meyer, and H.H. Günthard, Chem. .Phys. 25 (1977) 271. 16. L.P. Kuhn, J. Am. Chem. Soc. 80 (1958), 5950. 17. J.D. Cox and G. Pilcher, "Thermochemistry of Organic and Organometallic Compounds", Academic Press, New York (1970). 18. N.L. Allinger, S.H. Chang, D.H. Glaser, and H. Honig, Isr. J. Chem. 20 (1980) 51. 19. S. Maleknia, B.R. Friedman, N. Abedi, and M. Schwartz, Spectrosc. Lett. 13 (1980) 777. 20. M. Schwartz, Spectrochim. Acta 33A (1977) 1025. 21. J. Dale, "Stereochemistry and Conformational Analysis", Universitet Forlaget, Oslo (1978) 111. 22. V. Viti, P.L. Indovina, F. Podo, L. Radics, and G. Nemethy, Mol. Phys. 27 (1974) 521. 23. F. Podo, G. Nemethy, P.L. Indovina, L. Radics, and V. Viti, Mol. Phys. 27 (1974) 541. 24. Calculations yielded energy minima for one molecule of 1,2-ethanediol with one molecule of methanol. At « = 1.5 a cyclic structure with 1,2-ethanediol in a gauche conformation is favoured by 0.65 kcal/mol -173- over a 1,2-ethanediol in an anti conformation with only one hydrogen bond to methanol. The MM2 force field does not contain explicit functions for hydrogen bonding. Therefore, this energy difference is considered to be a lower limit. 25. Y. Osawa, M. Ohta, M. Sakakibara, H. Matsuura, I. Hirada, and T. Shimanouchi, Bull. Chem. Soc. Jpn. 50 (1977) 650. 26. R.G. Snyder and G. Zerbi, Spectrochiin. Acta 23A (1967) 391. 27. R. Iwamoto, Spectrochim. Acta 27A (1971) 2385. 28. K. Matsuzaki and H. Ito, J. Polym. Sci., Polym. Phys. Ed. 12 (1974) 2507. 29. Burkert (U. Burkert, Tetrahedron 35 (1979) 1945), however, sees no justification to add this type of low periodicity torsion energy term, because the influence of the gauche effect in energetic terms might only be in the order of 0.03 kcal/mol. 30. D.J. Morantz and M.S. Waite, Spectrochim. Acta 27A (1971) 1133. 31. W. Caminati, J. Mol. Spectr. 86 (1981) 193. 32. H. Buc, Ann. Chim. 8 (1963) 409. 33. G.C. Levy, T. Pehk, and E. Lippmaa, Org. Magn. Res. 14 (1980) 214. 34. M.F. Grenier-Loustalot, J. Bonastre, and P. Grenier, J. Mol. Struct. 65 (1980) 249. 35. U. Burkert and N.L. Allinger, "Molecular Mechanics", American Chemical Society, Washington D.C. (1982) ACS Monogr. No. 177, 47. -175- CHAPTER 12 CONFORMATIONS AND PSEUDOROTATION OF 1,3-DIOXOLANK AND SOME METHYL SUBSTITUTED DERIVATIVES AS STUDIED WITH MOLECULAR MECHANICS CALCULATIONS* Introduction 1 2 3 The rate of formation and the stability ' of borate esters of dihydroxy compounds have been studied extensively. Little is known about the conforma tion of these cyclic compounds; so far only a few X-ray investigations have 4-6 been carried out. Therefore, we decided to perform molecular mechanics calculations on a number of 1,3-dioxolanes, as an extension of our study on 7 the simple vicinal diols. Our decision to use the 1,3-dioxolanes as model compounds for the corresponding borate monoesters is based on the correla- 13 11 tion between the C chemical shift of C„ in the 1,3-dioxolanes and the B chemical shift of the corresponding borate monoesters (Figure 1). Such a 19 correlation is an indication for conformational similarity. The corresponsspon- ,20,21 dence of Raman spectra of 1,3-dioxolanes with those of borate esters supports this view. The compounds studied are 1,3-dioxolane (1), cis- and trans-4,5-dimethyl- -1,3-dioxolane (2 and 3), 2,2-dimethyl-l,3-dioxolane (4), and cis- and £ra/J.s-2,2,4,5-tetramethyl-l,3-dioxolane (5 and 6). The results are compared with 1H NMR data. M. van Duin, M.A. Hoefnagel, J.M.A. Baas, and B. van de Graaf, J. Org. Chem., submitted. -176- 11 5 r- 6[i:)C(2)l(ppml 110 /Me <-o- 105 100 fO. /H 95 90 -130 -140 -15-0 ~5["Bi c0f<°0: [PPH 13 Figure 1. Correlation of the C chemical shift (TMS as internal standard) of C„ in 1,3-dioxolanes vs. the B chemical shift (0.1 M boric acid in D„0 as external reference) of the corresponding borate 3 8 9 monoesters ' ' [the letters refer to the parent diols and the 10 borate bindingsite is given between brackets: glycol (a); 1,2-propanediol (b); meso-2,3-butanediol (c); pinacol (d); glycerol (1,2)9 (e); D-glucitol (l,2/5,6)n (f); (3.4)11 (g); 13 D-mannitol (1,2/5,6) 12 (h); D-ribonic acid (2,3) (i); (4,5)13'14 (j); roeso-tartaric aci•d J9 (k); galactaric acid (2,3/4,5)15 (1); (3-D-fructopyranose (1,2)16'17 (m); (2.3)17 (n); 12,18 18 (4i5)16,17 (o), a_D_glucofuranose (i,2) (p); (5,6) (q) (mean 13C chemical shifts for g, j, m, o, and p)]. -177- Experimental Calculations The calculations were performed using DELPHI, the Delft molecular 22 23 mechanics computer program, and Allinger's MM2 empirical force field. We did not use the refined ^2(82) force field, because the fit between the calculated and experimental data for small cyclic dioxygen compounds was not 24 improved. Dielectric constants (t) of 1.5 and 80 were used. The calculations for 2 and 5 and for 3 and 6 were carried out for the (R,S)- and (S, ^-configurations, respectively. The pseudorotation paths were obtained 25 by torsion angle driving using the Lagrange multiplier method. The minima and transition states were found by unconstrained optimization. Because of symmetry it is not necessary to investigate the complete pseudorotation paths. The conformational changes during the pseudorotation of the five membered rings are described by the changes in the ring torsion angles 0. (i = 1-5; ^ 2fi 27 Figure 2). According to Altona et al. , ' 0. can be approximated with two parameters, the phase angle of pseudorotation f (0-2n) and the maximum torsion angle 0 (a 40°): B max 0. = 0 cos(f + 0.8in + 0.3TT) (1) l max The phase angle tan* = -O.72704/(0j - 02 - 0g + 0g) (2) We obtain envelopes (e) or bent forms at f - 0.2nn (n = 0, 1, and 2-10). Half chairs (he) or twist forms are found at f = (0.1 + 0.2n)n (Figure 2). For 2 and 5, the e with the flap of the envelope towards the 4- and 5-methyl groups corresponds with f = 0; for 3 and 6, the he with the 4- and 5-methyl groups in pseudo-equatorial positions corresponds with °^C7 ^~ V7^ o c101 e10 &( ^ V7 . \--A 77 y^2 1p o3 o«^/^ö hc89 1 5n O v V V ~/° O hC67 56 o V— o ^ V £ V Figure 2. Pseudorotation of 1,3-dioxolane. 1 3 The vicinal H coupling constants J(H.,H_) were calculated from the dihedral angles HC.C-H with the semi-empirical equation of Haasnoot et 28 al., especially derived for rings containing oxygen. Because the 3 29-32 pseudorotation barriers for 1-6 are low, J(H.,H_) has to be averaged: 3 3 J(H4,H5) = J0 J(H4,H5)(s>) x(f) d-f (3) This integration was carried out numerically with steps of O.ln. The fractions x(?) with a certain phase angle of pseudorotation 34 O.78 e ■ is f>c34 000 0 00 8 0 36 '6 0 36 - U 04 5 Figure 3. Pseudorotation of 1,3-dioxolanes 1-6 as calculated with MM2 (energy in kcal/mol, p indicates planar form, and overlined values indicate transition states). -180- 3 obtained by molecular mechanics. The calculated and experimental J(H4,H,-) values are compared in Table 1. The mean steric energies (Ë) were obtained by averaging the steric energies over the pseudorotation paths in the same way as done for J(H.,H_). The heats of formation AH„° were calculated from 23 E and the increments of the MM2 force field. 1ff NMR The H NMR spectra of solutions of 1-3 in CDC1„ were recorded with a Nicolet NT-200 WB spectrometer at 25 °C using TMS as internal standard. The chemical shifts S ( + 0.01 ppm) and coupling constants J (±0.1 Hz) were determined with the LAME spin simulation program (RMS < 0.1). H NMR data 2 not given in Table 1: 1: S(H2): 4.90, 6(H4): 3.88, J(H4>H4'): -10.0, and ^(^."c): 149.0; 2: S(H2): 5.11 and 4.80, S(H4): 4.10, 8(Me): 1.16, 3 4 5 J(Me4,H4): 6.3, J(Me4>H5): -0.2, and J(Me4,Me ): 0.0; 3: 8(H2): 4.94, 6(H.): 3.57, &(Me): 1.28, 3J(Me.,H ): 6.1, J(Me.,H,.): -0.2, and J(Me,,Me_): 0.0. These values are in agreement with literature data as far as available. Compounds 2 and 3 were prepared according to Garner and Lucas. To test * the significance of the calculated steric energies, an equilibration was carried out for a solution of formaldehyde (F: 9.2 M) and mesa- and rac.-2,3-butanediol (M and R: 1.0 M each) in DgO/DgSO (50/50:v/v) at 25 °C: H+ M + F £► 2 + 2 LO „+ R + F ^U. 3 + 2 H„0 The experimental value of A(AG) (0.9 kcal/mol) is compared with the 38 calculated enthalpy differences, obtained from molecular mechanics: A(üG)exp = _RT 1"{([2][R])/([3][M])} (4) *(AH)calc -~ \ + ËR " h ~ *M <5) -181- Discussion General 39 Pseudorotation has been used by Kilpatrick et al. to describe the 40 41 dynamic deformation or conformational flexibility of the puckered cyclopentane ring. Introduction of heteroatoms or substitution increase the 40 41 pseudorotation energy barrier (AE) ' and result in pseudolibration 42-44 (AE > RT) or even in a rigid conformation (AE >> RT). Also deviations from the ideal pseudorotation path, as defined by Equation (1), occur (mainly ring flattening; cf. Table SI: ZI0.I < 100°). _. , . 45-47 1„ „^ 33-36,42,44,48-52 TD 53-55 , . Dipole measurements, H NMR, IR, and micro- 56 57 wave spectroscopy, and X-ray diffraction have demonstrated that 1,3-dioxolanes indeed are puckered. However, these techniques do not provide explicit information with respect to the actual conformations of the minima and transition states on the pseudorotation path. 1,3-Dioxolane (1) The pseudorotation path of 1 is rather simple (Figure 3), due to the C symmetry in the equivalent minima e, and eR (0. = 0°; C„ in the flap of the envelope) and C„ symmetry in the equivalent transition states hc„. and hc„q (0. = ±39°). The symmetry elements of e, , eR, hc„., and he™ are also symmetry elements of the pseudorotation. Going from the minima to the transition states, the increase in torsion and valency angle strain (0.60 and 0.30 kcal/mol) is only partly compensated by the decrease in the energy from the electrostatic and non-bonded interactions (0.38 and 0.21 kcal/mol). The resulting calculated steric energy difference (AE = 0.37 kcal/mol) is larger than the experimental value of about 0.15 kcal/mol. Because AE < RT at 25 °C, free pseudorotation occurs. The calculated AH„ is close fin to the experimental value (-71.8 vs. -71.1 kcal/mol ). Quantum chemical calculations have not yet provided reliable results: very flat conforma- 61 40 41 tions and much larger energy barriers (AE > 0.8 kcal/mol ' ) have been predicted. -182- 4,5-Dimethyl substituted 1,3-dioxolanes (2 and 3) Upon cis-4,5-dimethyl substitution of 1, the C symmetry of e./eR is preserved, whereas the C„ symmetry of hc„-/hcRq is lost. As a result of the latter, e1 and eR are non-equivalent in the case of 2. The conformation of minimum energy is eR, in which the flap of the envelope points away from the cj's-4,5-dimethyl groups. The two equivalent transition states hc,„ and he,-, enclose the relative minimum e, (1.48 kcal/mol). These conformations are very similar and hc,?, e,, and he,.., form a single transition state around f - 0. Because ÖE = 1.5 kcal/mol, pseudolibration occurs for 2. Upon trans-4,5-dimethyl substitution of 1 the C symmetry of e,/efi is lost, whereas the C„ symmetry of hc„./hc„q is conserved. In the case of 3, e,/e_ are not minima due to steric hindrance between the flap of the 1 b envelope and one of the methyl groups. This unfavourable interaction is diminished by increasing 0. and two equivalent minima e„ and e„ are found (0. = 37°). In these minima the methyl substituents are in pseudo-equatorial positions, in contrast with the pseudo-axial positions in the relative minimum hcRq. The two minima e„ and e. are separated by a negligible barrier hc„. and the relative minimum hcRq is enclosed between two equivalent transition states hc_„ and hcq,n. In a simplified description, the pseudorotation of 3 involves a single minimum around f = 0.5n and a single transition state around f = 1.5n with AE = 1.7 kcal/mol (pseudolibration). 13 For both 2 and 3, it has been demonstrated using C NMR that the barriers are low and that the methyl substituents are probably in an uncompressed environment. ' The calculated AHf of 3 is smaller than that of 2 (-91.3 vs. -90.2 kcal/mol). Upon increase of E from 1.5 to 80, the overall picture for 1-3, as discussed above, is retained (Figure 3). The optima at t - 80 are close to those at t =1.5. The electrostatic interactions almost vanish at t =80, which results in small increases in the pseudorotation barriers, in agreement with literature data. 2,2-Dimethyl substituted 1,3-dioxolanes (4-6) Upon 2,2-dimethyl substitution of 1-3, the symmetry of the parent compounds is preserved. The pseudorotation paths are affected drastically. In e,/efi of 4 unfavourable interactions between one of the geminal methyl -183- groups and transannular hydrogen atoms occur. As a result, contrary to 1, the global minima of 4 are hc„4/hc„q (0. = ±39°). The relative minima e./e_ are enclosed by equivalent transition states e„/ein and e,/e_. The combinations of e,_, e,, and e„ and of e-, eR, and e_ can be seen as two transition states around For 5 the difference in conformational energy between e. and eR is enlarged relatively to that for 2, due to increased steric hindrance in e, caused by the 2,2-dimethyl substitution. The general picture of 2 is preser ved, but the global minima e./e0 are close to those of 4. The pseudorotation of 5 is characterized by a rather flat region between p = 1.5n, and a transition state around f = 0 (AE = 2.6 kcal/mol). Finally, for 6 the pseudorotation is similar to that for 3, though it is somewhat simplified due to merging of the optima e„, hc„., and e. of 3 into a single minimum ha,.. The height of the broad barrier at f = 1.2n-1.8n is enlarged (AE = 3.3 kcal/mol), due to steric hindrance between the geminal methyl groups and the 4- and 5-methyl groups in the pseudo-axial position. In this case the conformational energy of the planar form (AE = 3.7 kcal/mol) is close to this barrier. Therefore, considerable ring flattening can occur during the pseudorotation of 6. Both for 5 and 6, 1,3-transannular non-bonded interactions have been demonstrated using C NMH. The difference between the calculated AH„ values of 5 and 6 (-112.7 vs. -111.3 kcal/mol) is close to the difference between the corresponding values of 2 and 3. If NMF experiments 3 Differences between experimental and calculated values of J(H.,HC.) (Table 1) are smaller than 0.8 Hz. This is strong evidence that the energy profiles, obtained by molecular mechanics calculations, are realistic. Especially in the case of 4,5-disubstituted 1,3-dioxolanes, the calculation 3 of J(H ,Hg) is rather sensitive for differences in E(f). From the equilibration at 25 °C a value for A(AG) of 0.9 kcal/mol is obtained, which is in agreement with experimental data for other substituted 1,3-dioxolanes and borate monoesters. We calculated A(AH) =0.6 -184- Table 1. Experimental and calculated vicinal H coupling constants 3 a [ J(H4,H5)] of 1,3-dioxolanes 1-6. 3! 1,3-dioxolane J(H4!,H 5) experimenta 1 calculated 1 6.3/6.8* 5.7/7.1 2 6.2 5.6 3 7.4 8.1 4 6.3/6.3*' c 5.7/7.0 5 5.9^ 5.6 6 8.4rf 8.6 in Hz. Using C satellites. ' Reference 33. Reference 48. 69 kcal/mol for e = 1.5 and for B = 80/aprotic media."" At t - 80/protic media 70 a correction should be made for specific solvation and A(üH) decreases to 0.3 kcal/mol. The calculated entropies are very similar of M and R, but that of 3 is about 2 e.u. larger than that of 2. Taking this into account brings A(AG) , close to the experimental value. Supplementary material available from author: characteristic torsion angles, phase angle of pseudorotation, point group, and steric energy of all relevant optima as calculated with the MM2 force field (2 pages). References and notes 1. R. Pizer and R. Selzer, Inorg. Chem. 23 (1984) 3023 and references cited therein. 2. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 40 (1984) 2901 and references cited therein; this thesis, chapter 2. -185- 3. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 41 (1985) 3411 and references cited therein; this thesis, chapter 3. 4. J.D. Dunitz, D.W. Hawley, D. Miklós, D.N.J. White, Yu. Berlin, R. Marusic, and V. Prelog, Helv. Chim. Acta 54 (1971) 1709. 5. H. Nakamura, Y. Iitaka, T.Kitahara, T. Okazaki, and Y. Okami, J. Antibiotics 30 (1977) 714. 6. H. van Koningsveld, M. van Duin, and J.C. Jansen, the pentasodium(I) borate diester of rac.-tartrate, in progress. 7. M. van Duin, J.M.A. Baas, and B. van de Graaf, J. Org. Chem. 51 (1986) 1298; this thesis, chapter 11. 8. M. Makkee, A.P.G. Kieboom, and H. van Bekkum, Reel. Trav. Chim. Pays- -Bas 104 (1985) 230. 9. Unpublished results. 10. E.L. Eliel, V.S. Rao, and K.M. Pietrusiewicz, Org. Magn. Res. 12 (1979) 461. 11. J. Kuszmann, P. Sohar, G. Horvath, E. Tomori, and M. Idei, Carbohydr. Res. 79 (1980) 243. 12. A.J.P. Gorin, Can. J. Chem. 51 (1973) 3277. 13. G. Aslani-Shotorbani, J.G. Buchanan, A.R. Edgar, D. Henderson, and P. Shahidi, Tetrahedron Lett. 21 (1980) 1792. 14. J.G. Buchanan, M.E. Chacón-Fuertes, A.E. Edgar, S.J. Moorhouse, D.I. Rawson, and R.H. Nightman, Tetrahedron Lett. 21 (1980) 1793. 15. I.J. Burden and J.F. Stoddart, J. Chem. Soc., Perkin I (1975) 682. 16. E.J. Prisbe, J. Smojkal, J.P.H. Verheyden, and J.G. Moffatt, J. Org. Chem. 41 (1976) 1836. 17. G. de Wit, thesis, Delft (1979). 18. A. Liptaken and P. Nanasi, Carbohydr. Res. 86 (1980) 133. 19. For the 2,2-dimethyl-l,3-dioxolanes the correlation is not as good as for the 1,3-dioxolanes. This is probably due to the fact that the former systems are often further derivatized. 20. S.A. Barker, E.J. Bourne, R.M. Pinkard, and D.H. Whiffen, J. Chem. Soc. (1959) 802. 21. S.A. Barker, E.J. Bourne, R.M. Pinkard, and D.H. Whiffen, J. Chem. Soc. (1959) 807. 22. B. van de Graaf, J.M.A. Baas, and A. van Veen, Reel. Trav. Chim. Pays- -Bas 99 (1980) 175. 23. N.L. Allinger and Y.H. Yuh, QCPE 13 (1981) 395. -186- 24. L. Ntfrskov-Lauritsen and N.L. Allinger, J. Comput. Chem. 5 (1984) 326. 25. B. van de Graaf and J.M.A. Baas, J. Comput. Chem. 5 (1984) 314. 26. C. Altona, H.J. Geise, and C. Romers, Tetrahedron 24 (1968) 13. 27. C. Altona and M. Sundaralingam, J. Am. Chem. Soc. 94 (1972) 8205. 28. C.A.G. Haasnoot, F.A.A.M, de Leeuw, and C. Altona, Tetrahedron 36 (1980) 2783. 29. V. Tabacik, Tetrahedron Lett. 9 (1968) 555. 30. V. Tabacik, Tetrahedron Lett. 9 (1968) 561. 31. W.E. Willy, G. Binsch, and E.I,. Elliel, J. Am. Chem. Soc. 92 (1970) 5394. 32. W.K. Olson and J.L. Sussman, J. Am. Chem. Soc. 104 (1982) 270. 33. R.U. Lemieux, J.D. Stevens, and R.R. Fraser, Can. J. Chem. 40 (1962) 1955. 34. R.J. Abraham, J. Chem. Soc. (1965) 256. 35. M. Anteunis, F. Anteunis-de Ketelaere, and F. Borremans, Buil. Soc. Chim. Belg. 80 (1971) 701. 36. F. Kametani and Y. Sumi, Chem. Pharm. Buil. 20 (1972) 1479. 37. H.K. Garner and H.J. Lucas, J. Am. Chem. Soc. 69 (1947) 2483. 23 38. Actually A(AH) , = H„ + HR - H„ - H^ with H = E + I increments. The incremental corrections for 2 and 3 and for M and R, respectively, are equal and thus A(AH) , = A(AE) = E„ + I - E„ - Ë... calc 2 Rn 3 M 39. J.E. Kilpatrick, E.S. Pitzer, and R. Spitzer, J. Am. Chem. Soc. 69 (1947) 2483. 40. D. Cremer and J.A. Pople, J. Am. Chem. Soc. 97 (1975) 1358. 41. D. Cremer, Isr. J. Chem. 23 (1983) 72. 42. C. Romers, C Altona, H.R. Buys, and E. Havinga, Top. Stereochem. 4 (1969) 39. 43. E.L. Eliel, Ace. Chem. Res. 3 (1970) 1. 44. J.F. Stoddart, "Stereochemistry of Carbohydrates", Wiley Interscience, New York (1971) 194. 45. C.W.N. Cumper and A.I. Vogel, J. Chem. Soc. (1959) 3521. 46. B.A. Arbousow, Bull. Soc. Chim. France' (1960) 1311. 47. B.A. Arbuzov and L.K. Yuldasheva, Izv. Akad. Nauk. SSSR, Otd. Khim. Nauk. (1962) 1728; Chem. Abstr. 58 (1963) 12392. 48.. F.A.L. Anet, J. Am. Chem. Soc. 84 (1962) 747. 49. J. Chuche, G. Dana, and M. Monot, Bull. Soc. Chim. France (1967) 3300. 50. C. Altona and A.P.M. van de Veek, Tetrahedron 24 (1968) 4377. -187- 51. T.J. Botterham, "NMR Spectra of Simple Heterocycles", John Wiley Interscience, New York (1973) 382. 52. CA. de Lange, J. Magn. Hes. 21 (1976) 37. 53. J.R. Durig and D.W. Wertz, J. Chem .Phys. 49 (1968) 675. 54. J.A. Greenhouse and H.L. Strauss, J. Chem. Phys. 50 (1969) 124. 55. R. Davidson and P.A. Warsop, J. Chem. Soc, Faraday Trans. II (1972) 1875. 56. P.A. Baron and D.0. Harris, J. Mol. Spectrosc. 49 (1974) 70. 57. S. Furberg and 0. Hassel, Acta Chem. Scand. 4 (1950) 1584. 42 50 57 58. Data on 1,3-dioxolanes with alkoxy substituents at C_ ' ' should be 59 interpreted with care, because dipole-dipole interactions influence the ring conformation. 59. J. Dale, Tetrahedron 30 (1974) 1683. 60. J.D. Cox and G. Pilcher, "Thermochemistry of Organic and Organometallic Compounds", Academic Press, New York (1970) 222. 61. P. Felker, D.M. Hayes, and L.A. Hull, Theoret. Chim. Acta 55 (1980) 293. 62. V.T. Aleksanyan and B.G. Antipov, in J.Lascombe and P.V. Huong (eds.), "Raman Spectrosc., Proc. • Int. Conf. 8th", Wiley Interscience, Chichester (1982) 605; Chem. Abstr. 99 (1983) 175112. 63. J.H. Stern and F.H. Dorer, J. Phys. Chem. 66 (1962) 97. 64. Y. Senda, J. Ishiyama, and S. Imaizumi, Bull. Chem. Soc. Jpn. 50 (1977) 2813. 65. P.H. Hermans, Z. Physik. Chem. 113 (1924) 337. 66. J.A. Mills, Chem. Ind. (1954) 633. 67. J.A. Mills, Advan. Carbohydrate Chem. 10 (1955) 1. 68. J.M. Conner and V.C. Bulgrin, J. Inorg. Nucl. Chem. 29 (1967) 1953. 69. E values for M and R (t = 1.5 and t = 80/aprotic media) are taken from reference 7. 70. For t = 80/protic media the E values were corrected for the stabili zation of the gauche OCCO forms (0.8 kcal/mol), as a result of the 7 formation of cyclic diol-water structures. The E values thus obtained are 4.7 and 4.3 kcal/mol, respectively. -189- CHAPTEB 13 THE CONFORMATIONS, PSEUDOROTATION, AND STABILITY OF THE BORATE MONOKSTERS OF THE SIMPLE DIOLS AS STUDIED WITH MOLECULAR MECHANICS CALCULATIONS* Introduction Borate esters of diols have found numerous chemical, technical, and biological applications. The stability of these compounds in aqueous medium 2 has been studied extensively. Conformational studies are limited to three X-ray investigations: the five membered borate ester rings in the solid 3 4 state structures of boromycine, aplasmomycine, and the borate diester of 5 rac. -tartrate have half chair, envelope, and planar conformations, respectively (Figure 1). In the previous chapter we have shown that 1,3- dioxolanes can be used as model compounds for borate monoesters. The effects of methyl substitution at C. _ on the minima and transition states 4,5 during the pseudorotation of the 1,3-dioxolanes have been studied with molecular mechanics calculations. Pseudorotation barriers have been found to be small (AE < 3 kcal/mol). \7B /A C half chair envelope planar 3 Figure 1. Conformations of the borate ester rings in boromycine, 4 5 aplasmomycine, and the borate diester of rac.-tartrate. M. van Duin, J.M.A. Baas, and B. van de Graaf, to be published, -190- \ .o OH __o OH NÏ I/O ÖH -0 OH 2 R, = Me;R2 = R3 = R4 = H 3 R, = R3 = H;R2 = Ril =Me 4 R, =R4 = Me;R2 = R3 = H Figure 2. Borate monoesters 1-5. In this chapter an empirical force field study on the borate monoesters of the vicinal diols 1,2-ethanediol (1), 1,2-propanediol (2), and mesa- and rac.-2,3-butanediol (3 and 4) and of 1,3-propanediol (5) is presented (Figure 2). Differences in calculated steric energy between the borate monoesters and the parent diols are compared with experimental enthalpy data. Calculations The calculations were performed using DELPHI, the Delft computer program 8 9 for molecular mechanics and Allinger's MM2 force field, using a dielectric constant (e) of 80. The force field was supplemented with the following parameters for tetrahedral boron atoms: the strainless B-0 bondlength 1» is 1.476 A ' and the strainless O-B-0 valency angle 0Q is 109.47°. For the other stretch, bend, and torsion parameters the corresponding values for 9 aliphatic carbon atoms were used. The electrostatic interactions were 12 calculated using mean partial charges, instead of the MM2 procedure using bond dipoles. In a conformational study on borate monoesters, the various conformations of the B(0H)„ moiety and the pseudorotation of the borate ester ring must be considered. The conformation of the B(OH)„ moiety is characterized by the two torsion angles O.B-OH and O-B-O'H'. Preferred values for each are about 60, 180, and -60°, which are denoted as g , a, and g , respectively. The ndocyclic torsion angles ®i_9c and the phase angle of pseudorotation f describe the geometry of the borate ester ring. They are'defined as for the -191- 1,3-dioxolanes. The pseudorotation paths were obtained by torsion angle 14 driving, using the Lagrange multiplier method. The conformations of the minima and transition states were found by unconstrained optimization. It is not necessary to investigate the complete pseudorotations, because of symmetry. The calculations for 2, 3, and 4 were carried out for the (S)-, (R, S)-, and (S, ^-configurations, respectively. The characteristic torsion angles, phase angle of pseudorotation, point group, and steric energy of the optima of 1-4 are given in Table SI and those of 5 in Table S2 (supplementary material). The torsion angles and phase angle of pseudorotation of the known solid state structures are given in Table S3. The pseudorotations of 1-4 are represented schematically in Figure 3 for the preferred B(OH)„ conformations. The mean steric energy E is averaged numerically over the pseudorotation path with steps of O.ln using the Boltzmann equation at 25 °C (Table 1). The formation of a borate monoester (B L) from borate (B ) and a diol (L) is given by: B + L lï B It 2 LO The calculated reaction enthalpies for 2-5, relative to that for 1 7 [A(AH) . ], are compared with experimental A(AH) values (Table 1): fl(AH) . = Ën-. - I, - ËT + È. , (1) calc B L 1 L glycol v ' A(AH)exp = AH. - Wl (i = 2-5) (2) Discussion Conformation of the B(OH) „ moiety For each B(OH)„ conformation, the pseudorotation of the five membered ring of the borate monoesters 1-4 is characterized by two minima and two transition states. In combination with the 9 possible B(OH)„ conformers, this results in a rather complex energy surface. The complete energy surface contains 18 minima and 18 transition states with respect to the -192- 092 hce9 1 2 a/a and g*/g" ota 3 4 a/a a/a Figure 3. Pseudorotation for the borate monoesters 1-4 as calculated with MM2 (energy in kcal/mol and overlined values indicate transition states). pseudorotation and 36 transition states with respect to the rotations around 0,B2OH and O.B-O'H'. It was determined only for 1 (cf. SI). For compounds 1-5 the range in steric energies of the various B(OH)„ conformers is small: < 0.2 kcal/mol (except for hc„q of 4: < 0.4 kcal/mol). The energy barriers for the rotation of the torsion angles O.B-OH and 0.B„0'H' are also low: CE - 0.4-0.5 kcal/mol. Free rotation occurs at 25 °C, because AE < RT. So, the influence of changes in the B(OH) moiety of the -193- borate monoester on the energy surface can be neglected. In addition, it should be realized that for borate monoesters in aqueous solution intermolecular hydrogen bonds between the borate monoester and the water molecules determine the actual B(OH)„ conformation. Pseudorotation of the borate ester ring The pseudorotation of the five membered borate ester ring of 1-4 is rather similar (Figure 3 and Table SI). The minima are he,, and hc8g (8. ss + 38°). For 1-3 the transition states are e, and e_ (8. a 0°) and for 4 the transition states are he ,-,, and hc_„. The pseudorotation barrier CE is lul of 2.1-3.2 kcal/mol and originates mainly from an increase in torsion strain. As a result of C and C„ symmetry in 1, hc„. and hc„_ are equivalent minima and e, and e„ are equivalent transition states. No symmetry is i b present in 2-4. A comparison of the non-equivalent minima hc„. and hcR„ for 2-4 shows that methyl groups in pseudo-equatorial positions are preferred over those in pseudo-axial positions: for 2 and 4 the steric energy of hc„. is smaller than that of hc„q. For 3 the energies of hc„. and hcfi_ are nearly equal, because both conformers have one pseudo-equatorial and one pseudo- -axial methyl substituent. With respect to the transition states, the envelopes with the flap directed away from the methyl group(s) are preferred: e, for 2 and e_ for 3. For 4 the steric energies of hc„„ and lb of he,-, are about equal. Summarizing, methyl substitution does not change the pseudorotation of 1 drastically, which is in contrast with the effect of methyl substitution in 1,3-dioxolane. During pseudorotation of the borate monoesters significant ring flattening occurs as indicated by the change of Z|8.I from 115-130° for hc„. and hc„_ to 85-105° for e. and e_. In the case of the 1,3-dioxolanes II 0.1 remains rather constant, except in the cases with severe steric hindrance. These differences between borate monoesters and 1,3-dioxolanes can be explained with the difference in natural bondlengths. Viz. the 10 9, bondlength for B-0 is larger than that for C-0 (1 = 1.476 vs. 1.407 A ) and, as a result, the steric hindrance between the 0X0 moieties [X = B(0H)„ or CH2/CMe„] and the methyl substituents at C. . will be relatively small for the borate monoesters. The calculated minima for the five membered borate ester rings (f = 0.5n and II8.I = 115-130°) are in agreement with the solid state conformations of -194- o A boromycine and aplasmomycine (Table S3: In Table 1 calculated (t = 80/protic media) and experimental enthalpies of borate raonoester formation relative to 1 [fl(AH)] are compared. Under these conditions the stabilization of the gauche forms of vicinal diols via 20 the formation of a cyclic diol-water adduct has to be taken in account. The values for A(AH) , follow the experimental order: ]>2=3>5>4. Table 1. Calculated and experimental enthalpies of borate monoester formation relative to 1. borate monoester E . c E A(AH) e min EL calc exp 1 17.81 18.23 2.2 0.0 0.0 2 18.02 18.61 2.9 -0.3 -0.3 3 19.91 20.36 4.7 -0.3 -0.7 4 18.49 18.85 4.3 -1.4 -2.3 5 19.00 19.00f 4.2 -1.2 -1.9 For e = 80/protic media. In kcal/mol. ' St.eric energy for the conformer of lowest energy. Reference 20; the values for e = 80/protic media are corrected for the formation of a cyclic diol-water adduct (except for e f - 1,3-propanediol). ' Reference 7; + 20%. E = E . . * * ' mm -195- Supplementary material available from author: characteristic torsion angles, phase angle of pseudorotation, point group, and steric energy of all relevant optima of 1-5 as calculated with the MM2 force field, including data on the known solid state structures of borate esters (5 pages). References and notes 1. This thesis, chapter 1. 2. M. van Duin, J.A. Peters, A.P.G. Kieboom, and H. van Bekkum, Tetrahedron 41 (1985) 3411 and references cited therein; this thesis, chapter 3. 3. J.D. Dunitz, D.M. Hawley, D. Miklós, D.N.J. White, Yu. Berlin, R. Marusic, and V. Prelog, Heïv. Chim. Acta 54 (1971) 1709. 4. H. Nakamura, Y. Iitaka, T. Kitahara, T. Okazaki, and Y. Okami, J. Antibiot. 30 (1977) 714. 5. H. van Koningsveld, M. van Duin, and J.C. Jansen, refinement of the structure is in progress. 6. M. van Duin, M.A. Hoefnagel, J.M.A.Baas, and B. van de Graaf, J. Org. Chem. , submitted; this thesis,, chapter 12. 7. J.M. Conner and V.C. Bulgrin, J. Inorg. Nucl. Chem. 29 (1967) 1953. 8. B. van de Graaf, J.M.A. Baas, and A. van Veen, Reel. Trav. Chim. Pays- -Bas 99 (1980) 175. 9. N.L. Allinger and Y.H. Yuh, QCPE 13 (1981) 395. 10. Mean B-0 bondlength from crystal structures contained in the Cambridge Data File. 11. For the calculated optima of 1-5 the B-0 bondlength in the borate ester rings is 1.49 A and in the B(0H)„ moieties 1.48 A. 13 12. The partial charges were obtained from CNDO and INDO calculations. They are independent of the conformation of a borate monoester. In addition, the partial charges in the 0_B(OH)„ moiety of 1-5 are equal. Mean values from CNDO and INDO: COB: -0.40, B: 0.48, BOH: -0.44, and H: 0.09. Electrostatic interactions between atoms in the same valency angle were excluded. Because the molecular mechanics calculations were performed at t =80 the electrostatic interactions are small (-0.40, -0.32, -0.32, -0.33, and -0.79 kcal/mol for 1-5). The pseudorotation is not affected by changes in t or in the charge distribution (Ü6. < 0.5°). -196- 13. J.A. Pople and D.L. Beveridge, "Approximate Molecular Orbital Theory", McGraw-Hill, New York (1970). 14. B. van de Graaf and J.M.A. Baas, J. Comput. Chem. 5 (1984) 314. 15. Cf. note 25 from reference 6. 16. M. Nogradi, "Stereochemistry", Pergamon Press, Oxford (1981) 164. 17. H.B. Kagan, "Organische Stereochemie", Georg Thieme Verlag, Stuttgart (1977) 42. 18. J. Dale, "Stereochemistry and Conformational Analysis", Universitets forlaget, Oslo (1978) 147. 19. E.L. Eliel, N.L. Allinger, S.J. Angyal, and G.A. Morrison, "Conforma tional Analysis", Interscience Publishers, New York (1965) 36. 20. M. van Duin, J.M.A. Baas, and B. van de Graaf, J. Org. Chem. 51 (1986) 1298; this thesis, chapter 11. -197- SUM4ARY This thesis deals with the identification, structure, stability, and cation coordinating ability of borate esters. In chapter 1 a short introduction on esters of boric acid and borate is given. Applications of these esters in analytical chemistry, organic synthe sis, technical processes, chemical products, and biology are reviewed. In addition, the scope of this thesis is discussed. Chapter 2 deals with the pH dependent stability of esters of boric acid and borate with glycol, glycolic acid, oxalic acid, and glyceric acid as dihydroxy compounds. B NMR provides a suitable analytical tool for the quantitative determination and structure elucidation of the various esters in aqueous medium. The pH dependent stability of esters of boric acid and borate is formulated in a general rule of thumb: esters of boric acid and borate with dihydroxy compounds in aqueous medium show the highest stability at that pH, where the sum of the charges of the free esterifying species is equal to the charge of the ester. In chapter 3 B NMR data are presented for borate esters of a series of polyols and polyhydroxycarboxylates in aqueous alkaline solution. For each compound the prevailing borate mono- and diesters are identified. B chemical shifts and line widths together with the corresponding association constants are determined. Empirical rules are put forward for predicting the B chemical shift, the relative stability, and the structure of borate esters in aqueous medium. 13 1 In chapter 4 a combined C and H NMR study on borate esters of a series 13 of polyhydroxycarboxylates is presented. C substituent effects upon borate ester formation, as obtained from a set of model compounds, established that borate esters of the £/?reo-3,4-diol functions of D-gluconate, D-glucarate, L-idarate, and probably also of D-gulonate are preferred. The conformational changes of the polyhydroxycarboxylates upon borate ester formation are 1 1 13 determined using vicinal H coupling constants. Both in H and C NMR spectra peak doubling due to diastereomerism in borate diesters is observed. In chapter 5 a combination of H, B, and C NMR is used to determine the identity, structure, and stability of compounds present in the aqueous D-glucarate-borate-calcium(II) system. Borate ester formation was found to -198- occur preferably at the £Areo-3,4-position of D-glucarate. Two diastereo- meric borate diesters of D-glucarate are the major calcium(II) coordinating species. Each borate diester contains two calclum(II) coordinating sites, consisting of two carboxylate oxygens, two borate ester ring oxygens, and - depending on the a-CHOH-configurations - up to two oc-hydroxyl oxygens. The overall calcium(II) coordinating strength of both borate diester diastereomers of D-glucarate is about equal, whereas this is not the case for the D-arabinonate diastereomers. Chapter 6 deals with the increased calcium(II) coordinating ability of polyhydroxycarboxylates (I.) in aqueous alkaline solution upon addition of borate (B ), as studied with B NMR, calcium(II) sequestering capacity determinations, and calcium(II) ion selective electrode measurements. The synergic effect is caused by the formation of mono- and dicalcium(II) complexes of the borate diesters of the polyhydroxycarboxylates (B L„). The Ca association constants PD-T and 0„ _-T for the equilibria: D iin v.a D L0 Z n Z B" + 2 L — B~L„ "-£? Ca B~L_ -*— z —— n z determine the synergic effect quantitatively. In chapter 7 a study on cation coordination in aqueous cation-borate- - D-glucarate systems using B NMR is discussed. The monovalent cations Na(I), K(T), and Ag(I) do not show preferential coordination by the borate esters of D-glucarate. The divalent cations Mg(II), Ca(II), Co(II), Ni(II), Sr(II), Cd(II), and Ba(II) are coordinated by the borate diesters. The cations that ionize the ot-hydroxyl functions of D-glucarate, Cu(II), Zn(II), Pr(III), Dy(III), and Pb(TI), and/or compete with borate for the diol functions, Al(III) and Fe(III), are more strongly coordinated by free D-glucarate than by its borate diester. The different behaviour of the cations is discussed in terms of differences in charge/radius density and polarizing ability. In tKe Ca(II)-oxyacid anion- D-glucarate system, Ca(II) ion selective electrode measurements and Ca(II) sequestering capacity determinations are performed. Apart from borate, synergic Ca(II) coordina tion is observed at high pH for the oxyacid anion esters of D-glucarate with stibite, stannate, aluminate, and germanate. In chapter 8 structural changes of coordination compounds of polyhydroxy- carboxylijs acids as a function of the pH are discussed. A general coordina- tion-ionization scheme, based on literature data, covering such effects for some fourty cations is provided. The following sequence is observed going from low to high pH: (i) bidentate coordination of the cation by the -199- oc-hydroxycarboxylic acid moiety, (ii) ionization of the carboxylic acid function, (iii) ionization of the oe-hydroxyl group, and (iv) coordination by an ionized diol function. For complexes of metal ions the pH effects are correlated with the acidity of the hydrated cation and explained with an extended electrostatic model. For oxyacid anion esters, with non-metal cation centers, there is a correlation with the acidity of the oxyacid. Chapter 9 describes a combined H, B, and C NMR study of 1,3-dione- -boric acid systems in water and DMSO. Formation of borate diesters is preferred over that of borate monoèsters. The 1,3-dione moiety of the borate diester closely resembles that of the free enol tautomer. The stability of the borate diester in DMSO is not influenced by substituents at the 1,3-dione moiety. Increase of pH and addition of water result in dissociation of the borate diesters. Chapter 10 deals with an analysis of H NMR spectra of carbohydrate- -derived polyhydroxycarboxylates. Conclusions with regard to the configuration and the conformation are drawn from chemical shifts and vicinal coupling constants. In chapter 11 the results of molecular mechanics calculations using the MM2 force field on 1,2-ethanediol, 1,2-propanediol, and the 2,3-butanediols are reported; results on 1,3-propanediol and 1,2-dimethoxyethane are included for comparison. The preference of the 1,2-diols for gauche OCCO forms is evoked by the torsion energy function in the force field and is strengthened by electrostatic interactions between the hydroxyl groups at low dielectric constant. The effects of solvation are discussed. Calcula tions show that the gauche OCCO forms of the diols are stabilized in protic media by specific solvation. A cyclic structure, composed of the diol and a hydroxyl group of the solvent molecule, is proposed. Energy increments for gauche Me/Me, Me/OH, and OH/OH interactions are calculated; those involving hydroxyl groups are dependent on the dielectric constant. In chapter 12 the conformations and pseudorotation of 1,3-dioxolane (1), cis- and trans-4,5-dimethyl-l,3-dioxolane (2 and 3), and the corresponding 2,2-dimethyl derivatives (4-6) are studied with molecular mechanics calculations, using the MM2 force field. Free pseudorotation occurs in 1 and 4 (AE = 0.4 kcal/mol), pseudolibration in 2, 3, 5, and 6 (AE = 1.5, 1.7, 2.6, and 3.3 kcal/mol, respectively). The heats of formation of 3 and 6 are lower than those of 2 and 5 (-91.3 and -112.7 vs. -90.2 and -111.3 kcal/mol), since in 3 and 6 the 4- and 5-methyl groups can occupy pseudo- -equatorial positions. Vicinal H coupling constants are calculated from the appropriate torsion angles and averaged over the pseudorotation circuit. -200- They are in good agreement with experimental values. The 1,3-dioxolanes are used as model compounds for borate monoesters of vicinal diols. In chapter 13 results of MM2 empirical force field calculations for the borate monoesters of glycol (1), of 1,2-propanediol (2), of meso- and rac.~ -2,3-butanedi'ol (3 and 4), and of 1,3-propanediol (5) at t = 80 are presented. The effects of variations in the B(0H)„ moiety can be neglected. The pseudorotation of 1-4 is rather similar and the global minima correspond with solid state conformations. The calculated reaction enthalpies for borate monoester formation follow the experimental order: 1>2=3>5>4. -201- SAMENVATTING Dit proefschrift behandelt de identificatie, structuur, stabiliteit, en kation coördinerende eigenschappen van boraatesters. In hoofdstuk 1 wordt een korte inleiding gegeven over esters van boorzuur en boraat. Toepassingen van deze esters in de analytische chemie, de organische synthese, technische processen, chemische produkten, en de biologie zijn samengevat. Vervolgens wordt de strekking van dit proefschrift besproken. Hoofdstuk 2 behandelt de invloed van de pH op de stabiliteit van esters van boorzuur en boraat met glycol, glycolzuur, oxaalzuur, en glycerolzuur als dihydroxyverbindingen. B NMR blijkt een geschikte analytische techniek te zijn voor de kwantitatieve bepaling en de structuuropheldering van de verschillende esters in waterig milieu. De invloed van de pH op de stabili teit van esters van boorzuur en boraat is geformuleerd in een algemene vuistregel: esters van boorzuur en boraat met dihydroxyverbindingen in waterig milieu vertonen de grootste stabiliteit bij die pH waar de som van de ladingen van de te veresteren deeltjes gelijk is aan de lading van de ester. In hoofdstuk 3 worden B NMR gegevens gepresenteerd voor een serie boraatesters van polyolen en polyhydroxycarbonzuren in waterige, alkalische oplossing. Voor elke verbinding zijn de belangrijkste boraatmono- en diësters geïdentificeerd. B chemische verschuivingen en lijnbreedtes van de boraatesters zijn bepaald samen met de bijbehorende associatieconstanten. associatieconstanten. Empirische regels worden gegeven voor de voorspelling van de B chemische verschuiving, de relatieve stabiliteit, en de structuur van boraatesters in waterig milieu. 13 1 In hoofdstuk 4 wordt een gecombineerde C en H NMR studie over boraat- 13 esters van een serie polyhydroxycarboxylaten gepresenteerd. C substituent- effecten ten gevolge van boraatester vorming zijn verkregen met behulp van een set modelverbindingen en maken duidelijk dat boraatesters van de threo- -3,4-diol functies van D-gluconaat, D-glucaraat, L-idaraat, en waarschijn lijk ook van D-gulonaat de voorkeur verdienen. De conformationele verander- -202- ingen van de polyhydroxycarboxylaten ten gevolge van de vorming van boraat- esters zijn bepaald met behulp van vicinale H koppelconstanten. Zowel in H 13 als C NMR spectra is piekverdubbeling waargenomen tengevolge van diaste- reomerie in boraatdiësters. In hoofdstuk 5 wordt met een combinatie van H, B, en 'C NMR de identiteit, structuur, en stabiliteit van de verbindingen in het waterige D-glucaarzuur-boraat-calcium(II) systeem bepaald. Vorming van boraatesters vindt voornamelijk plaats op de tAreo-3,4~positie van D-glucaraat. De twee diastereomere boraatdiësters van D-glucaraat zijn de belangrijkste calcium(II)coördinerende deeltjes. Elke boraatddëster bezit twee calcium(II)coördinerende sites, die elk bestaan uit twee carboxylaat zuurstofatomen, twee zuurstofatomen van de boraatester ringen, en - afhanke lijk van de a-CHOH-configuraties - ten hoogste twee a-hydroxylgroepen. De calcium(II)coördinerende kracht van de twee diastereomere boraatdiësters van D-glucaraat is ongeveer gelijk. Dit is voor de D-arabinonaat diastereomeren niet het geval. Hoofdstuk 6 behandelt de toegenomen calcium(II)coó'rdinerende eigen schappen van polyhydroxycarboxylaten (L) in waterige, alkalische oplossing na toevoeging van boraat (B ). Gebruik is gemaakt van B NMR en metingen van de calcium(II)complexering. Het synergetisch effect wordt veroorzaakt door de vorming van mono- en dicalcium(II)complexen van de boraatdiësters van de polyhydroxycarboxylaten (B L„). De associatiecohstan-ten p_-T en Ca 6_ _- voor de evenwichten: Ca B L„ n B~ + 2 L ^i B~~L n-£a Ca B~L„ £0 -*— n £ bepalen kwantitatief het synergetisch effect. In hoofdstuk 7 wordt een B NMR studie over de coördinatie van kationen in waterige kation-boraat- D-glucaraat systemen besproken. De eenwaardige kationen Na(I), K(I), en Ag(I) vertonen geen voorkeur bij de coördinatie van de boraatesters van D-glucaraat. De tweewaardige kationen Mg(II), Ca(II), Co(II), Ni(II), Sr(II), Cd(II), en Ba(II) worden gecoördineerd door de boraatdiësters. De kationen welke de a-hydroxylfuncties van D-glucaraat ioniseren, Cu(II), Zn(II), Pr(III), Dy(III), enPb(II), en/of met boraat concurreren om de diol functies, Al(III) en Fe(III), worden sterker door het vrije D-glucaraat gebonden dan door de boraatdiësters. Het verschillend -203- gedrag van de kationen wordt besproken in termen van verschillen in lading/straal dichtheid en polarisatie. Daarnaast zijn voor de Ca(II)- -oxyzuuranion- D-glucaarzuur systemen Ca(II)ion selectieve electrode metingen verricht en Ca(II) sequestrerings capaciteiten bepaald. Behalve voor boraat is synergetische coördinatie van Ca(II) bij hoge pH waargenomen voor de oxyzuuranionesters van D-glucaarzuur met stibiet, stannaat, al uminaat, en germanaat. In hoofdstuk 8 worden structurele veranderingen van coordinatieverbin- dingen met polyhydroxycarbonzuren besproken als functie van de pH. Een algemeen coördinatie-ionisatie schema, gebaseerd op literatuurgegevens, is gegeven voor ongeveer 40 kationen. De volgende volgorde is waargenomen, gaande van lage naar hoge pH: (i) tweetandige coördinatie van het kation door het a-hydroxycarbonzuur gedeelte, (ii) ionisatie van de carbonzuur- functie, (iii) ionisatie van de o-hydroxylgroep, en (iv) coördinatie door een geïoniseerde diolfunctie. Voor complexen van metaalionen zijn deze pH effecten gecorreleerd met de zuursterkte van het gehydrateerde kation en verklaard met een uitgebreid elektrostatisch model. Voor oxyzuuranionesters met niet-metaal kation centra bestaat er een correlatie met de zuursterkte van het oxyzuur. Hoofdstuk 9 beschrijft een gecombineerde H, B, en C NMR studie over 1,3-dion-boorzuur systemen in water en DMSO. Vorming van boraatdiësters heeft de voorkeur boven dat van boraatmonoësters. Het 1,3-dion gedeelte van de boraatdiëster lijkt sterk op dat van het vrije enol tautomeer. De stabiliteit van de boraatdiëster in DMSO wordt niet beïnvloed door substituenten aan het 1,3-dion gedeelte. Toename van de pH en toevoeging van water leidt tot ontleding van de boraatdiësters. Hoofdstuk 10 behandelt een analyse van H NMR spectra van koolhydraat- afgeleide polyhydroxycarboxylaten. Met behulp van de chemische verschui vingen en vicinale koppelconstanten worden conclusies getrokken met betrekking tot de configuratie en de conformatie. In hoofdstuk 11 worden de resultaten vermeld van moleculaire mechanica berekeningen met het MM2 krachtveld voor 1,2-ethaandiol, 1,2-propaandiol, en de 2,3-butaandiolen; resultaten voor 1,3-propaandiol en 1,2-dimethoxyethaan zijn ter vergelijking meegenomen. De voorkeur van 1,2-diolen voor gauche OCCO vormen wordt teweeg gebracht door de torsieënergiefunctie in het krachtveld en wordt bij lage diëlektrische constante versterkt door elektrostatische interacties tussen de hydroxylgroepen. Solvatatie effecten -204- worden besproken. Berekeningen laten zien dat in protische media de gauche 0CC0 vormen van de diolen worden gestabiliseerd door specifieke solvatatie. Ken cyclische structuur wordt voorgesteld, bestaande uit de diol en een hydroxylgroep van het oplosmiddelmolecuul. Energieïncrementen voor gauche Me/Me, Me/OH, én OH/OH interacties zijn berekend; de incrementen die betrekking hebben op hydroxylgroepen zijn afhankelijk van de diëlektricische constante. In hoofdstuk 12 worden de conformaties en pseudorotatie van 1,3-dioxolaan (1), cis- en £ra;?.s-4,5-dimethyl-l,3-dioxolaan (2 en 3), en de overeenkom stige 2,2-dimethylderivaten (4-6) bestudeerd met behulp van moleculaire mechanica berekeningen met het MM2 krachtveld. Vrije pseudorotatie komt voor in 1 en 4 (AE = 0.4 kcal/mol), pseudolibratie in 2, 3, 5, en 6 (CE = 1.5, 1.7, 2.6, en 3.3 kcal/mol, respectievelijk). De vormingswarmten van 3 en 6 zijn lager dan die van 2 en 5 (-91.3 en -112.7 in vergelijking met -90.2 en -111.3 kcal/mol),omdat in 3 en 6 de 4- en 5-methylgroepen pseudo-equatori- ale posities kunnen innemen. Vicinale H koppelconstanten zijn berekend met behulp van de betreffende torsiehoeken en gemiddeld over het pseudorotatie- circuit. Zij komen goed overeen met experimentele waarden. De 1,3-dioxolanen zijn gebruikt als modelverbindingen voor boraatmonoësters van vicinale diolen. In hoofdstuk 13 worden de resultaten besproken van MM2 empirische krachtveldberekeningen voor de boraatmonoësters van 1,2-ethaandiol (1), van 1,2-propaandiol (2), van meso- en rac.-2,3-butaandiol (3 en 4), en van 1,3-propaandiol (5) bij t = 80. De effecten van veranderingen in het B(0H)„ gedeelte zijn te verwaarlozen. De pseudorotatie van 1-4 is nagenoeg gelijk en de absolute minima komen overeen met vaste stof conformaties. De berekende reactieënthalpiën voor boraatmonoëstervorming volgen de experimentele volgorde: 1>2=3>5>4. -205- DANKWOORD Hier wil ik iedereen bedanken die heeft bijgedragen bij de totstandkoming van dit proefschrift. De afgelopen vier jaar ben ik altijd met plezier bezig geweest met mijn promotieonderzoek. Dat komt enerzijds door de samenwerking met een groep enthousiaste wetenschappers van wie ik veel geleerd heb, anderzijds door de gezellige sfeer in de Vakgroep Organische Chemie. Ik ben mijn promotoren prof. Herman van Bekkum en prof. Tom Kieboom zeer erkentelijk voor de kritische begeleiding en de vrijheid die ik tijdens het onderzoek heb genoten. Dr. Joop Peters en ir. Anton Sinnema dank ik voor het grote aantal NMR spectra die zij voor mij hebben opgenomen en voor de hulp bij de intei— pretatie. Dr. Joop Peters dank ik tevens voor de vele discussies en de goochellessen met chemische verschuivingen. Van dr. Maarten Nieuwenhuizen heb ik afgekeken hoe een experiment op een practische wijze opgezet moet worden. Ook had hij de (on)dankbare taak als mijn praatpaal te fungeren. Deze taak is later op een voortreffelijke wijze overgenomen door ir. Erik Bleichrodt. Ik dank Jan van Egmond voor zijn voorbereidend literatuur spitwerk voor hoofdstuk 8. Dr. Jan Baas en dr. Bas van de Graaf ben ik erkentelijk voor de vele discussies over moleculaire mechanica en conformatieanalyse. Theo Hoefnagel wil ik bedanken voor de nodige series moleculaire mechanica berekeningen en zijn synthetische hulp. Dit laatste geldt ook voor Jacqueline van der Werff. Dr. Henk van Koningsveld en Koos Jansen wil ik bedanken voor de röntgen- diffractie ondersteuning. Mieke van der Kooy dank. ik voor het vele en snelle typewerk, Wijn Jongeleen voor zijn geduld met mijn eigenwijsheid wanneer het om tekeningen ging, en Fred Hammers en Piet Dullaart voor het vlotte fotowerk. Tenslotte mag ik drs. Jacques Scheele niet vergeten, een fijne collega. \ -207- CUHRICULDM VITAK Martin van Duin werd geboren op 3 augustus 1959 in Den Haag. In 1977 behaalde hij het diploma gymnasium p op het Gymnasium Haganum. Vervolgens studeerde hij in 1982 cum laude af als ingenieur bij de Afdeling der Scheikundige Technologie van de TH Delft. In augustus 1982 trad hij als adjunct wetenschappelijk ambtenaar in dienst van SON-ZWO en begon, in aansluiting op zijn afstudeerwerk, aan een promotieonderzoek onder leiding van prof. dr. ir. H. van Bekkum, prof. dr. ir. A.P.G. Kieboom, en dr. ir. J.A. Peters bij de Vakgroep Organische Chemie. Sinds October 1986 is hij als researchmedewerker werkzaam bij DSM Research B.V. te Geleen. 13 "ö w CM O) C•M* CM CM CO CM co CO CM co t> CO 05 oo" CO r—t o i—t i—i m CM r-H CM CM co co CM CM