苯环还原
Process Research of(R)-Cyclohexyl Lactic Acid and Related Building Blocks: A Comparative Study?
Thomas Storz*and Peter Dittmar
Process Research and De V elopment,Chemical and Analytical De V elopment;No V artis Pharma AG,
CH-4002Basel,Switzerland
Pierre Franc?ois Fauquex and Philippe Marschal
Biotechnology De V elopment,No V artis Pharma AG,CH-4002Basel,Switzerland
Willy Urs Lottenbach and Heinz Steiner
Hydrogenation and High-Pressure Ser V ice,Sol V ias AG,CH-4002Basel,Switzerland
Abstract:
(S)-Cyclohexyl lactic acid is a component of the selective E-selectin inhibitor2((S)-cHexLact-2-O-(3-Gal (1f3)ddGlc-(4f1)r Fuc).We describe the evaluation of various synthetic routes to this building block:(A)diazotation of phenylalanine followed by phenyl ring hydrogenation;(B)phenyl ring hydrogenation of phenyl alanine followed by diazotation;(C) acidic hydrolysis of the cyanohydrin derived from phenylac-etaldehyde,enantiomeric resolution of the resulting,racemic phenyl lactic acid via diasteromeric salt formation and phenyl ring hydrogenation;(D)enantioselective dihydroxylation of a cinnamate ester,followed by hydrogenation of the benzylic hydroxy group and the aromatic nucleus;(E)enantioselective biocatalytic reduction of phenylpyruvic acid,followed by phenyl ring hydrogenation.The development of(2R)-2-O-(4-nitrophe-nyl)sulfonyl-cyclohexyl lactic acid p-bromobenzylester21as a buidling block with improved crystallinity and stability is also described.
Introduction
Excessive leukocyte influx from blood vessels into the surrounding tissues has been linked to acute or chronic reactions as observed in reperfusion injuries,psoriasis,stroke, rheumatoid arthritis or respiratory diseases.1-3Selectin-dependent leukocyte adhesion is the first step in the cascade of events that leads to the extravasation of leukocytes.4In particular,E-Selectin on the surface of the endothelial blood vessel walls recognizes complex glycoprotein ligands on the leukocyte surface via interaction with the common tetrasac-charide epitope sialyl Lewis x(sLe x,1).5Analogues of sialyl Lewis x have therefore been proposed as potential therapeutics for a host of inflammatory disorders(e.g.,ischemia/reper-fusion injury following organ transplantation).6The sLe x analogue2(Figure1)was discovered by Thoma et al.at Novartis Pharmaceuticals Corporation.7Compared to sLe x, 2showed a30-fold improved affinity in a cell-free E-selectin-ligand binding assay.8
As a simplified analogue of SLe x,2features the(S)-cyclohexyl lactic acid moiety as a substitute9for the structurally more complex N-acetylneuraminic acid residue. The former is introduced into the trisaccharide precursor of 2via nucleophilic displacement reaction of a2-O-sulfonyl substituted(R)-cyclohexyl lactic acid building block.Enan-tiomerically pure(R)-cyclohexyl lactic acid10is not com-mercially available.Hence,an efficient synthetic access to this hydroxy acid needed to be elaborated.
Results and Discussion
(A)The Medicinal Chemistry Synthesis.The synthesis (Scheme1)7of the(R)-cyclohexyl lactic acid building block6started from commercially available(R)-3-phenyl lactic acid10b(3).Hydrogenation of the aromatic nucleus, followed by benzyl ester formation with CsCO3/BnBr and O-sulfonylation with triflic anhydride,gave the building block6in three steps and60%total yield after two chromatographies.The triflate6proved to be an unstable oil at room temperature and resisted all attempts to crystal-lization.
?Dedicated to Professor Andrea Vasella on the occasion of his60th birthday.
*To whom correspondence should be addressed.Current address:Amgen Inc.,One Amgen Center Drive,Thousand Oaks,CA91320-1799,U.S.A. E-mail:tstorz@https://www.wendangku.net/doc/9514117935.html,.
(1)Mousa,S.A.Drugs Fut.1996,21,283.
(2)Mousa,S.A.;Cheresh,D.A.Drug Disco V ery Today1997,2,187.
(3)Cines,D.B.;Pollak,E.S.;Buck,C.A.;Loscalzo,J.;Zimmermann,G.A.;
McEver,R.P.;Pober,J.S.;Wick,T.M.;Konkle,B.A.;Schwartz,B.S.;
Barnathan,E.S.;McCrae,K.R.;Hug,B.A.;Schmidt,A.-M.;Stern,D.
M.Blood1998,91,3527.
(4)Spertini,O.;Luscinskas,F.W.;Gimbrone,M.A.;Tedder,T.F.J.Exp.
Med.1992,175,1789.
(5)Kansas,G.S.Blood1996,88,3259.
(6)For a review,see:Simanek,E.E.;McGarvey,G.J.;Jablonowsky,J.A.;
Wong,C.-H.Chem.Re V.1998,98,833.
(7)Thoma,G.;Kinzy,W.;Bruns,C.;Patton,J.T.;Magnani,J.L.;Ba¨nteli,R.
J.Med.Chem.1999,42,4909.
(8)Ba¨nteli,R.;Herold,P.;Bruns,C.;Patton,J.T.;Magnani,J.L.;Thoma,G.
Hel V.Chim.Acta2000,83,2893.
(9)Kolb,H.C.;Ernst,B.Chem.Eur.J.1997,1571.
(10)(a)v.Braun,J.;Nelles,J.Chem.Ber.1933,66,1464(racemate).(b)Bajusz,
S.;Baraba′s,E.;Fauszt,I.;Fehe′r,A.;Horva′th,Gy.;Juha′sz,A.;Szabo′,A.
G.;Sze′ll,E.Bioorg.Med.Chem.1995,3,1079(R-enantiomer).
Organic Process Research&Development2003,7,559?570
10.1021/op030202q CCC:$25.00?2003American Chemical Society Vol.7,No.4,2003/Organic Process Research&Development?559 Published on Web06/27/2003
(B)Process R&D.Surprisingly,there is only one literature report for the production of (R )-cyclohexyl lactic acid (4):aromatic ring hydrogenation of D -(+)-3-phenyl lactic acid (3)over a platinum oxide catalyst.10b Due to the high price and limited availability of 3,and the unfavorable physicochemical properties combined with the instability of the triflate 6,we aimed to find a more economic access to 4and,ultimately,also to replace the triflate 6by a crystalline,more stable activated building block.
In our first strategy,(R )-phenyl alanine (7)was chosen as starting material.Two variants were investigated:
(A )diazotation of phenylalanine under retention of configuration,11followed by hydrogenation of the aromatic
nucleus of the resulting phenyl lactic acid over a more economic catalyst:Although literature reports 11-14had claimed that diazotation of (R )-phenyl alanine to (R )-phenyl lactic acid 3proceeds under complete retention of config-uration (only optical rotation values were cited as proof of enantiomeric purity),we invariably observed a loss of enantiomeric purity as unequivocally determined by HPLC analysis on a chiral column (2-5%,see Experimental Section).The hydrogenation of the aromatic nucleus in 3was investigated under various conditions (Table 1).In general,none,or only insignificant loss (<0.1%)of enan-tiomeric purity was observed (see typical result in Experi-mental Section).
The best overall results of approach A are summarized in Scheme 2.
(B )Hydrogenation of the aromatic nucleus of phenyl-alanine,15followed by diazotation of the resulting cyclohexyl alanine 8under retention of configuration:The hydrogena-tion of phenylalanine showed less variability than the corresponding hydrogenation of phenyl lactic acid (Table 2).
(11)Cohen,S.G.;Weinstein,S.Y.J.Am.Chem.Soc .1964,86,5326.
(12)Yamada,S.-I.;Koga,K.;Juang,T.M.;Achiwa,K.Chem.Lett.1976,927.(13)Terashima,S.;Tseng,C.C.;Koga,K.Chem.Pharm.Bull .1979,27,747.(14)Urban,F.J.;Moore,B.S.J.Heterocycl.Chem .1992,29,431.
(15)Bain,J.D.;Wacker,D.A.;Kuo,E.E.;Chamberlin,A.R.Tetrahedron
1991,47,
2389.
Figure 1.
Table 1.Aromatic ring hydrogenation of phenyl lactic acid:catalyst
screening
entry (concentration,mmol)
batch size (%)
catalyst,H 2pressure solvent (%),temperature (°C)reaction time,h yield (%)/purity (%)112.0(5)5%Rh/C
(10wt %/wt)15bar EtOH (94)50292.9(GLC)
conversion:99.82300.9(5)5%Rh/C
(10wt %/wt)15bar EtOH (94)505
99.6,crude
312.0(5)10%Ru/C
(15wt %/wt)15bar AcOH
50-70-10059h
89.4%(GLC)
conversion:99.9%412.0(14.3)5%Rh/C
(10wt %/wt)15bar AcOH/H 2O (8:6)50-80108
70.6(GLC)
conversion:99.95
12.0(13.5)
10%Ru/C
(10wt %/wt)30bar
1M NaOH 60
16
7.0(GLC)
conversion:13.2
Scheme 1.Medicinal chemistry
synthesis
560
?
Vol.7,No.4,2003/Organic Process Research &Development
However,the subsequent diazotation of 8proceeded only in very poor yields.Hence,approach B ,as summarized in Scheme 3,was quickly abandoned.
(C )Cyanohydrin reaction of phenylacetaldehyde,followed by acidic hydrolysis to (R /S )-phenyl lactic acid,resolution of the racemic acid via diastereomeric salt formation and hydrogenolytic reduction of the phenyl ring as in approach (A ):
Although much progress has recently been achieved with enantioselective cyanohydrin reactions,16R -methylene-alde-hydes,such as arylacetaldehydes,have proved to be notori-
ously difficult substrates and,in general,tend to give lower ee 16f,17,18than their aromatic counterparts.A kinetic resolution of racemic phenylacetaldehyde-cyanohydrin on an analytical scale (no product isolated,no yields given)with a mutant Pseudomonas strain to give enantiomerically enriched (ca.75%ee)(S )-(-)-phenyl lactic acid has been reported.19One study reporting the synthesis of enantiomerically enriched (88%ee)(R )-phenylacetaldehyde-cyanohydrin in 83%yield on a millimolar scale via oxynitrilase-catalyzed transcyana-tion with acetone cyanohydrin has appeared.20However,due to the high substrate dilution,high enzyme concentration (ca.1000units/mmol substrate)and the requirement for a special enzyme purification of the commercial enzyme prior to use,this method appeared not practical for preparative scale synthesis.
On the other hand,we obtained racemic phenyl lactic acid ((-PLA)11without need for the isolation of the intermediate 1021via cyanohydrin reaction of the bisulfite adduct 22of 9
(16)For reviews,see:(a)Groger,H.Ad V .Synth.Catal.2001,343,547.(b)
Van Der Gen,A.;Brussee,J.NATO Sci.Ser.1:Disarm.Technol .2000,33,365.(c)Gregory,R.J.H.Chem.Re V .1999,99,3649.(d)Effenberger,F.Chimia 1999,53,3.(e)Johnson,D.V.;Griengl,H.Chim.Oggi 1997,15,9.(f)North,M.Synlett 1993,807.(g)Kruse,C.G.In Chirality in Industry ;Collins,A.N.,Sheldrake,G.N.,Crosby,J.,Eds.;Wiley:New York,1992;Chapter 14,p 279.
(17)Zandbergen,P.;Van Der Linden,J.;Brussee,J.;Van Der Gen,A.Synth.
Commun .1991,21,1387.(18)Ziegler,T.;Ho ¨rsch,B.;Effenberger,F.Synthesis 1990,575.
(19)Hashimoto,Y.;Kobayashi,E.;Endo,T.;Nishiyama,M.;Horinouchi,S.
Biosci.Biotechnol.Biochem.1996,60,1279.
(20)Ognyanov,V.I.;Datcheva,V.K.;Kyler,K.S.J.Am.Chem.Soc .1991,
113,6992.
Table 2.Aromatic ring hydrogenation of phenyl alanine:catalyst
screening
entry concentration (mmol),
batch size (%)
catalyst,H 2pressure solvent,temperature (°C)reaction time,yield/purity 112.16.75%Rh/C
(10wt %/wt)4bar 1M HCl in H 2O 50 3.25h
96.0%(GLC)
conversion:99.9%212.155%Rh/C
(10wt %/wt)15bar EtOH (945%)50-10043h
94.1%(GLC)
conversion:99.5%312.1510%Ru/C
(10wt %/wt)15bar AcOH 5019h
no conversion (TLC)412.16.710%Ru/C
(10wt %/wt)15bar 1M NaOH 603h
90.1%(GLC)
conversion:99.7%512.114.35%Rh/C
(10wt %/wt)5bar AcOH/H 2O (4:3)50
17h
96.9%(GLC)
conversion:>99%6302.714.35%Rh/C
(10wt %/wt)5bar AcOH/H 2O (4:3)50
7h
100%crude 7
12.113.3
10%Ru/C
2.6wt %/wt)30bar
1M NaOH 60
7h
91.5%(GLC)
conversion:>99.9%
Scheme 2.Diazotization strategies:approach
A
Scheme 3.Diazotization strategies:approach
B
Vol.7,No.4,2003/Organic Process Research &Development
?
561
followed by acid-catalyzed hydrolysis in71%yield after recrystallization of the crude product from toluene(Scheme 4).A variety of readily available optically pure bases were then screened for their potential to form diastereomeric salts23 (Table3).
Resolution with the most promising bases,(+)-dehydro-abietylamine,(S)-phenylglycinol and(S)-phenylalaninol was optimized(data not shown);typical results are shown in Table4.
Especially the resolution via the diastereomeric(S)-salt separation with(+)dehydroabietylamine looked very promis-ing,due to the very low cost of the chiral amine.Resolutions with(S)-phenylglycinol and(S)-phenylalaninol also worked very well,but required recycling of the(expensive)chiral base.
(D)Enantioselective dihydroxylation of methyl cinnamate, followed by selective hydrogenolytic removal of the benzylic hydroxy group and hydrogenation of the aromatic nucleus.24 Cinnamate esters are very cheap starting materials(Me, Et,Bn:$8-15/kg),and readily scaleable protocols for their enantioselective dihydroxylation to R, -dihydroxy-phenyl-propionates in good yield and enantiomeric purity are well established.25We aimed at an efficient and selective one pot-reduction process,employing only a noble metal catalyst and hydrogen as the sole reducing agent(Scheme5).
The methyl and benzyl esters of the corresponding(2R,-3S)-3-phenyl-2,3-dihydroxypropionate26were synthesized as starting materials.The methyl ester is easily purified by recrystallization and can be obtained in very high enantio-meric purity,whereas the benzyl ester has to be purified by chromatography and,in our hands,was routinely obtained in inferior optical purity(Scheme6).
The subsequent hydrogenolytic removal of the benzylic hydroxy group proceeded in good yield and without signifi-cant loss in optical purity,but the benzyl ester apparently was prone to acid-catalyzed transesterification,as the intermediate3-phenyl lactic acid was isolated as the methyl ester after the reaction(Scheme7).
Because of this finding and the unfavorable physical properties of the benzyl ester13B in combination with the lower ee in the dihydroxylation reaction of benzyl cinnamate, it was decided to focus on the crystalline methyl ester13A. Initially,we isolated the intermediate phenyl lactic ester14 before starting a fresh hydrogenolysis experiment in a separate vessel with the second catalyst.It was then discovered that equivalent results were also obtained by sequential addition of the two catalysts in one pot in the same solvent(Scheme8).This represents a significant progress over previous methodology for this transformation.24 In the sequence from the dihydroxylation product13A to(R)-cyclohexyl lactic acid4,the enantiomeric purity changes only very slightly.The initial osmium impurity in 13A(200ppm)dropped to a mere4ppm in the final product 4without any special purification measures.Overall,ap-proach D delivered a very practical and readily scaleable process based on a cheap and abundant starting material (methyl cinnamate).
Finally,we also investigated the enantioselective biocata-lytic reduction of phenylpyruvic acid29as an alternative access to(R)-3-phenyl lactic acid3.The enantioselective reduction of2-oxo carboxylic acids to the corresponding(R)-2-hydroxy carboxylic acids by resting cells of Proteus mirabilis or Proteus V ulgaris was reported by H.Simon and collaborators.27The stereospecificity is extremely high(ee >98%)28and the substrate specificity very broad.Proteus possesses a formate dehydrogenase as well as a hydrogenase, in addition to its specific2-oxocarboxylate reductase activity. Therefore,the basic principle of the reaction involves the use of formate or hydrogen gas as reducing agents for the 2-oxocarboxylic acids and,of a catalytic amount of viologen (V2+),for example benzyl viologen or methyl viologen,as electron carrier:
The simplest procedure for the reduction of2-oxo carboxylic acids is the stirring of the Proteus cells together with the substrate,benzyl viologen and formate in phosphate buffer pH7,at37°C under an atmosphere of nitrogen,in a batch-mode process.29When oxidised,one molecule of formate delivers two electrons but only one proton.To provide the additional proton necessary for the substrate reduction and to maintain a constante formate concentration,formic acid is continuously added,using an automatic pH control system.The optimal reaction time to obtain a2-oxo carboxy-
(21)(a)Erlenmeyer,E.;Lipp,A.Ann.Chem.1883,219,187.(b)Ruggli,P.;
Hegedues,B.Hel V.Chim.Acta1942,25,1285.
(22)(a)Biquard,D.Ann.Chim.(Paris)1933,10,97.(b)Meerpoel,L.;Hoornaert,
G.Synthesis1990,905.(c)Chesters,N.C.J.E.;O’Hagan,D.;Robins,R.
J.J.Chem.Soc.,Perkin Trans.11994,1159.
(23)The only diastereomeric salt resolution for(D)-(+)-3-phenyl lactic acid we
are aware of(base:morphine!)was reported by A.McKenzie and H.Wren (J.Chem.Soc.1910,97,1358),who later also described the resolution of racemic PLA via its diastereomeric(-)-menthol esters(J.Chem.Soc.1921, 119,801).
(24)To the best of our knowledge,only two selective reductions of R, -
dihydroxy-dihydro-cinnnamic esters to3-aryl lactic acid esters have been reported:(a)Nakajima,M.;Tomioka,K.and Koga,K.Tetrahedron1993, 49,10807(Et3SiH/TFA);(b)Rho,H.S.;Ko,https://www.wendangku.net/doc/9514117935.html,mun.2001, 31,283(Mg-reduction of the corresponding thionocarbonate derivative).
A Mn-catalyzed oxidation of cinnamates in the presence of triphenyl silane
also leads to3-aryl lactic acid esters:Tanaka,M.;Mukaiyama, C.;
Mitsuhashi,H.;Maruno,M.;Wakamatsu,https://www.wendangku.net/doc/9514117935.html,.Chem.1995,60,4339.
(25)For a review,see:Kolb,H.C.;VanNieuwenhze,M.S.;Sharpless,K.B.
Chem.Re V.1994,94,2483.
(26)Wang,Z.M.;Kolb,H.C.;Sharpless,https://www.wendangku.net/doc/9514117935.html,.Chem.1994,59,5104.(27)Simon,H.;Bader,J.;Gu¨nther,H.;Neumann,S.;Thanos,J.Angew.Chem.,
Int.Ed.Engl.1985,24,539-553.
(28)Gu¨nther,H.;Neumann,S.;Simon,H.J.Biotechnol.1987,5,53-65.
(29)Schummer,A.;Yu,H.;Simon,H.Tetrahedron1991,47,9019-9034.
Scheme4.Approach C:resolution of racemic
PLA
HCOO-+2V++f H++CO2+2V?+
or:H
2
+2V++f2H++2V?+
R-CO-COO-+2V?++2H+f
(R)-R-CHOH-COO-+2V++ 562?Vol.7,No.4,2003/Organic Process Research&Development
lic acid conversion of about 100%is in the range of 24h.After removal of the cells by filtration or by centrifugation,the (R )-2-hydroxy carboxylic acid produced can be recovered by extraction in ethyl acetate and crystallization by addition of methylcyclohexane or cyclohexane.30
After optimization of the reaction conditions and of the extraction procedure,we applied this process successfully to the reduction of phenylpyruvic acid (approach E ):the product (R )-3-phenyl lactic acid was obtained with a conver-sion of >99.8%,a total yield (bioconversion and recovery)of 87%and an enantiomeric purity (R -form)of >99.5%(Scheme 9).
(30)Fauquex,P.;Sedelmeier,G.EP 0371408,1989.
Table 3.Resolution of racemic PLA:base
screening
entry scale (mmol)
base
solvent result yield (%)R /S crude R /S recryst.(yield,%)
115(R )-1-phenyl-ethylamine EtOAc/i PrOH 4:1(oil)n.d.26cinchonine EtOAc/i PrOH (oil)
n.d.36cinchonidine EtOAc/i PrOH crystals 6151:49n.d.
46quinine EtOAc/i PrOH 56quinidine EtOAc/i PrOH (oil)n.d.66(-)-ephedrine
EtOAc (oil)n.d.76(+)-pseudoephredine EtOAc (oil)
n.d.86L -phenylglycinol EtOAc crystals,>10056:4470:30(67)96L -phenylalaninol
EtOAc crystals,>10052:4889:11(73)106L -threo -2-amino-1-phenyl-1,3-propandiol
EtOAc crystals,>10050:50n.d.116D -threo -2-Amino-1-nitrophenyl-1,3-propandiol EtOAc crystals,>10050:50n.d.
126(R )-2-amino-1-butanol EtOAc
(oil)n.d.136N -methyl-D -glucamine i PrOH/MeOH (oil)n.d.146(-)-spartein
EtOAc (oil)
n.d.15
6
(+)-dehydro-abietylamine
EtOAc
crystals,>100
33:67
14:86(87)
Table 4.Resolution of racemic PLA by diastereomeric salt formation:
optimization
entry scale (mmol)base
solvent yield a of diast.salt (%)yield a of recovered acid (%)(R /S )base recovery (%)
price of base ($/kg)A 24L -phenyl-glycinol sec -butanol 93.8(R )93.5(99:1)79995B 24L -phenyl-alaninol
2-butanone
87.6(R )52.2(100:0)99725C
24
(+)-dehydro-abietylamine
4-methyl-2-pentanone
n.d.(S )b
73.0(80:20)after recryst.:49.0(100:0)
100
20
a
Based on (R )-enantiomer.b (S )-Salt precipitates out,(R )-acid isolated from mother liquor.
Scheme 5.Approach D :asymmetric dihydroxylation/selective
reduction
Scheme 6.Approach D :starting
materials
Vol.7,No.4,2003/Organic Process Research &Development
?
563
Table 5compares the four processes:the shortest syntheses investigated were processes A and E ,with the latter being much more reliable in terms of the enantiomeric purity.
However,both A and E featured relatively expensive starting materials.On the other hand,with options C and D ,two more sustainable processes were developed,delivering material of acceptable optical purity from cheap starting materials.Overall,process D was found to be the most attractive option for technical scale manufacture of (R )-cyclohexyl lactic acid.
We then initiated a screening process for crystalline esters of (R )-cyclohexyl lactic acid.Esters were readily accessible by base-catalyzed,selective O -alkylation with the corre-sponding benzyl halide.The cesium carbonate/DMF-alkyl-ation procedure used in the research synthesis could be replaced by a more convenient (no aqueous workup required)alkylation protocol (anhydrous potassium carbonate in acetone,cat.TBAI)without appreciable loss in yield (Scheme 10).Also,no epimerization was observed under these reaction conditions,as proven by determination of enantiomeric purity in the p -bromobenzylester 18by HPLC on a chiral stationary phase (see Experimental Section).The best candidates,on basis of their crystalline properties and ease of preparation,were the 4-bromobenzyl (18)and the 2-naphthylmethyl (20)esters,which were readily acces-sible on a preparative scale (no chromatography required)(Table 6).Several O -sulfonyl derivatives of these two esters s and also of the benzyl ester 5s were synthesized.Their syntheses and properties are summarized in Table 7.The nosylate of the 4-bromobenzyl ester (21)appeared especially attractive.In preliminary experiments with model nucleo-philes (data not shown),sulfonate 21displayed electrophilic reactivity comparable to the triflate derivative 6used in the research synthesis while featuring good crystallinity and improved stability.
Conclusions
In summary,four robust processes amenable for large-scale,chromatography-free preparation of (R )-3-cyclohexyl lactic acid were developed from four different starting materials.Asymmetric dihydroxylation of methyl cinnamate,followed by a one-pot catalytic reduction of the benzylic hydroxy group and the aromatic nucleus,and subsequent saponification of the methyl ester proved to be the most sustainable process with regard to price and stability of
Scheme 7.Approach D :hydrogenation of benzylic hydroxy
group
Scheme 8.Approach D :methyl ester
variant
Scheme 9.Approach E :biocatalytic
reduction
Table https://www.wendangku.net/doc/9514117935.html,parison of different syntheses for (R )-3-cyclohexyl lactic acid
synthesis starting material (price )
number of steps yield (%)optical purity
R /S (A )D -phenylalanine
(～165$/kg )
2
58-75
95:5-98:2
(C )phenylacetaldehyde (～30$/kg )5(3steps
“one-pot”)
17-3299:1-100:0(D )methyl cinnamate (～10$/kg )4(2steps
“one pot”)
68-72g 99.3:0.7(E )
phenylpyruvic acid (≈880$/kg )
280-8599.5:0.5Scheme 10.Ester screening for (R )-cyclohexyl lactic
acid
Table 6.Evaluation of esters of (R )-cyclohexyl lactic acid
ester R
physical state melting point (°C)yield (%)(chromat.)
yield (%)(cryst.)5benzyl
solid 54-568770164-chlorobenzyl oil -50-172,5-dichlorobenzyl oil -93-184-bromobenzyl solid 50-528882194-nitrobenzyl
oil -37-20
2-naphthyl-methyl
solid
54-55
94
73
564
?
Vol.7,No.4,2003/Organic Process Research &Development
starting material,total yield and optical purity of the product (Table 5).As an alternative to the unstable and oily triflate 6,an activated building block with improved stability and crystallinity (p -bromobenzylester nosylate 21)was found.Experimental Section
Starting materials,reagents and solvents were obtained from commercial suppliers and were used without further purification.All the melting points are uncorrected and determined on a Buchi apparatus.1H NMR spectra were recorded at 400MHz,and 13C NMR spectra were recorded at 100or 125MHz on a Bruker DPX 400/500instrument.IR spectra were measured on a Bruker IFS660spectrometer.The enantiopurity of 3,4,5,13and 14was determined on a Hewlett-Packard Series 1100HPLC system using a Chiralcel OD or Chiralpak AD column.
(2R )-2-Hydroxy-3-phenylpropionic Acid (3)(A )(by Diazotation of D -Phenylalanine,Improved Variant of the Procedure of Cohen and Weinstein 11).A 10-L Buchi reactor was charged with a solution of D -phenylalanine (7)(350g,2.12mol,R /S g 99.5:0.5)in 3245mL of 0.5M H 2SO 4.At 5°C,a solution of sodium nitrite (219.3g,3.18mol)was added over a 3-h period.The reaction temperature was kept between 0and 10°C.After the addition was complete,stirring was continued,and the reaction mixture was allowed to reach room temperature overnight.The resulting suspension was cooled to 5°C,and sulfamic acid (5.2g,53.5mmol)was added portionwise under vigorous stirring until iodine -cadmium reagent paper showed no more nitrite.Upon addition of isopropyl acetate (3000mL),a clear biphasic mixture formed.The organic phase was separated and washed with water (1000mL)and 20%aqueous NaCl (750mL).Collected water phases were extracted with isopropyl acetate (2×500mL)and the combined organic phases dried over MgSO4and reduced to about 20%of their volume under reduced pressure,just until crystallization started to set in.Hexane was then added,and the suspension was cooled to 0°C and filtered.The filter cake was washed with 250mL of cold hexane/isopropyl acetate (1:1-mixture)and 300mL of cold hexane and dried under reduced pressure at 40°C (178.8g,50.8%).The filtrate was again evaporated under reduced pressure until crystallization started to set in (approximately one-third of the volume),diluted with hexane (300mL)and allowed to crystallize at 4°C overnight,which gave a second crop (33g,9.4%)of crystals with comparable purity.Total yield of 3:211.8g (60.2%)of a colorless crystalline solid.TLC:R f )0.45(toluene/EtOAc/CH 2Cl 2/HCOOH )24:40:40:4).MS (EI):m /z 166(M +),148(M +-H 2O),121,103,91,77,65.
Enantiomeric purity was determined by HPLC on a chiral column (Chiralpak AD,25mm ×4.6mm,eluent:n -hexane/i -PrOH/TFA 96:4:0.2,flow:0.5mL/min,λ)210nm,40°C;[R ]-and [S ]-enantiomers from Fluka as analytical standards):R /S )97.4:2.6.A smaller batch (25-g scale)gave 78%total yield,enantiomeric purity R /S )95.5:4.6.
(C)(By Resolution of Racemic PLA via Diastereomeric Salt Separation).A suspension of phenylacetaldehyde (50.0g,416.1mmol)in 228mL of commercial (38%)aqueous sodium bisulfite solution (832.3mmol)was stirred in an icebath at 0°C for 30min before a solution of potassium cyanide (108.39g,1.665mol)in 200mL of water was slowly added over 45min.The reaction mixture was stirred at 5-10°C for additional 60min.Water (100mL)was added,and the mixture was extracted with TBME (2×250mL).Organic phases were dried over sodium sulfate and,after addition of 1drop of concentrated H 2SO 4,were evaporated under reduced pressure.To the resulting 10,a yellow oil,was added concentrated aqueous HCl (300mL),and the mixture was heated under reflux (95°C)for 60min.The mixture was allowed to cool to room temperature overnight,and the clear,yellow solution was extracted with TBME (8×300mL)and ethyl acetate (300mL).Organic phases were dried over sodium sulfate and evaporated under reduced pressure.The crude 11(65.54g,95%),a brown oil,was dissolved in toluene (180mL)and heated to reflux.Upon cooling,a colorless precipitate formed,which was filtered and dried in a vacuum oven (50°C).Yield 48.44g (70.1%based on phenylacetaldehyde)racemic phenyl lactic acid (PLA)11as colorless crystals.
(C1):Resolution of Racemic PLA with L -(+)-Phenyl-glycinol.11(4.0g,24.1mmol)and L -(+)-phenylglycinol (3.63g,26.5mmol)were dissolved in 2-butanol (80mL)at
Table 7.Evaluation of different
sulfonates
ester R 1
R 2
melting point yield (%)(chromat.)
yield (%)(cryst.)
214-brom-benzyl 4-nitrophenyl-71-72°C -60224-brom-benzyl methyl-oil
81-234-brom-benzyl 4-bromophenyl-68-69°C 4852242-naphthyl-methyl methyl-oil 79-252-naphthyl-methyl 4-nitrophenyl-oil 58-26benzyl 4-nitrophenyl-oil 80-27benzyl 4-bromophenyl-oil 63-28
benzyl
4-methylphenyl
oil
60
-
Vol.7,No.4,2003/Organic Process Research &Development
?
565
80°C.The clear solution was heated to115°C and slowly cooled to room temperature.At70°C,TBME(80mL)was added.At50°C,a few seed crystals of recrystallized(R)-salt12A from a previous batch were added.The resulting, thick suspension was stirred in an ice bath for several hours and filtered.The filter cake was washed with ice cold TBME (20mL)and dried in a vacuum oven(35°C).The crude salt12A was dissolved in methylene chloride(40mL)at room temperature.Aqueous1M sodium hydroxide(40mL) was added,and after stirring vigorously for5min,the aqueous phase was separated and extracted with methylene chloride(40mL)before adjusting the pH to1by addition of concentrated aqueous HCl(5mL).The aqueous phase was then extracted with ethyl acetate(4×50mL).The combined extracts were evaporated to yield crystalline, colorless3(1.87g,93.5%).Enantiomeric purity(vide supra):R/S)99.0:1.0.
(C2):Resolution of Racemic PLA with L-Phenylalani-nol.11(4.56g,27.45mmol)and L-phenylalaninol(4.61g, 30.5mmol)were suspended in2-butanone(180mL)and heated to70°C.After filtration,the clear filtrate was slowly cooled to room temperature.At30°C,a few seed crystals of recrystallized(R)-salt12B from a previous batch were added.The resulting,thick suspension was stirred for another 1.5h at rt and1.5h in an ice bath and filtered.The filter cake was washed with ice-cold TBME(30mL)and dried in
a vacuum oven(35°C).The resulting salt12B(3.82g,
87.6%)was then suspended in methylene chloride(20mL) and1M sodium hydroxide(20mL).After stirring vigorously for5min,the aqueous phase was separated and extracted with methylene chloride(20mL).Both methylene chloride phases were washed with aqueous1M sodium hydroxide (10mL).Water phases were combined,and the pH was adjusted to pH1by addition of concentrated aqueous HCl (4mL).The resulting suspension was stirred in an ice bath for30min and filtered.The filter cake was dissolved in TBME and evaporated to yield crystalline,colorless3(1.19 g,52.2%).Enantiomeric purity(vide supra):R/S)100:0.
(C3):Resolution of Racemic PLA with(+)-Dehydroa-bietylamine.To a solution of11(4.0g,24.1mmol)in isobutyl methyl ketone(50mL)was added a solution of(+)-dehydroabietylamine(Merck,z.S.)(8.22g,26.5mmol)in the same solvent(100mL).After stirring the initially clear solution at room temperature for approximately10-15min, a precipitate formed.The suspension was heated to95°C, whereupon a clear yellow solution formed that was slowly cooled to room temperature.At85-90°C,a few seed crystals of recrystallized(S)-salt12C from a previous batch were added.At70°C,a thick suspension of(S)-salt12C formed which was stirred for1.5h and filtered.The filter cake was washed with isobutyl methyl ketone(50mL).The filtrate was evaporated to dryness under reduced pressure, the oily residue taken up in methylene chloride(30mL), and the clear solution extracted with1M sodium hydroxide (3×20mL).The combined water phases were extracted with methylene chloride(20mL),and the pH of the water phase was adjusted to pH1-2by addition of concentrated aqueous HCl(5mL).The resulting suspension was extracted with ethyl acetate(4×30mL).EtOAc phases were combined and evaporated under reduced pressure to yield crude3(1.46g,73%).Enantiomeric purity(vide supra):R/S )80.4:19.6.A portion of the crude material(1.28g)was recrystallized from deionized water(7mL)to give colorless, crystalline3(0.86g,49.0%).Enantiomeric purity(vide supra):R/S)100:0.
(E)(By Enantioselective Biocatalytic Reduction of Phenyl Pyruvic Acid).Proteus mirabilis DSM30115was grown on5-L scale at37°C,under anaerobic conditions (nitrogen flow via sparger)and with pH6.5regulation (corrected with a30%NaOH solution in case of decrease below pH6.5),in a medium of the following composition: 20g/L soy peptone,5g/L yeast extract,5g/L K2HPO4,pH 7.2,inoculated with a preculture of10%volume.During the fermentation a70%(w/v)glucose monohydrate solution was fed at a constant flow rate of7.2mL/h.After23h of fermentation,the culture was cooled to15°C,and the cells were harvested by centrifugation(Cryofuge8000,Heraeus, 35min at5000rpm,at4°C).The wet cells obtained(about 17g of wet packed cells/L of culture)were frozen and stored during2years at-20°C.
The reduction of phenyl pyruvic acid was conducted on 100-mL scale in a stirred glas reactor with jacket(Metrohm) at37°C,under anaerobic conditions(nitrogen flow subsur-face).A mixture was prepared with the following compo-nents added(and dissolved)in the same sequence as indicated below:43g of purified water,0.256g of KH2PO4,0.384g of K2HPO4,1.36g of potasium formate,7g of phenyl pyruvic acid(Fluka No.78190,purum,～99%),24g of poly-(ethylene glycol)4000,～5.73g of a50%(w/w)KOH solution(to adjust pH7.0),11.27g of purified water,40 mg of benzyl viologen previously dissolved in1.5mL of purified water, 1.5g of wet packed cells previously suspended in4mL of purified water,a drop of antifoam polypropylene glycol2025,the whole giving a total weight of100g(corresponding to a volume of about90mL).During the reaction,the pH was controlled and continuously adjusted to pH7.0by addition of a50%(v/v)formic acid solution with an automatic buret(Dosimat Metrohm665with a20-mL buret,Impulsomat Metrohm614,pH meter Metrohm 632).Samples were taken at different times for determination of the percentage of conversion by HPLC analysis:20μL of a400-fold diluted sample(with0.1M KH2PO4pH3.0) was applied to a5μNucleosil C18column(length:16cm, diameter:4.6mm,mobile phase:950mL of0.05M KH2-PO4pH3.0+500mL of acetonitrile,flow rate:1mL/min, detection at216nm).The end of the reaction was reached after20h,with a measured phenyl pyruvic acid conversion of>99.8%and a formic acid consumption of3.16mL.
The(R)-3-phenyl lactic acid was recovered as indicated below.The reaction mixture(about91mL)was adjusted to pH2.0with3.69g of H2SO496%,and90mL of ethyl acetate was added at room temperature under stirring.The mixture was transferred to a separatory funnel for partial phase separation during30min and then filtered through a1-cm thick Hyflo layer(on a Bu¨chner filter of diameter6.5cm). The filter was rinsed with6mL of ethyl acetate,and the
566?Vol.7,No.4,2003/Organic Process Research&Development
filtrate was tranfered to a separatory funnel for complete phase separation(during30-60min).The aqueous phase was recovered and subjected to a second extraction step at pH2.0(adjusted with H2SO496%)with90mL of ethyl acetate,and after phase separation,the organic phase was recovered and added to the organic phase of the first extraction step.The organic pool(168mL)was subjected to two consecutive wash steps with0.2volume of a saturated Na2SO4solution(52g of Na2SO4per100g of purified water) at pH2.0(adjusted with H2SO496%).The recovered,washed organic pool was then concentrated to about30mL in a rotavapor.Fresh ethyl acetate(30mL)was added to the concentrate,and the solution was reduced again to30mL. The crystallization of the product was performed by addition of100mL methylcyclohexane to the concentrate,and complete removal of ethyl acetate by evaporation in the rotavapor.The product suspension in methylcyclohexane was then cooled to10°C and filtered on a paper filter.After two rinse steps with10mL of ice cold methylcyclohexane, the final product was recovered and dried at65°C,to give white(colorless),crystalline(R)-3-phenyl lactic acid(3)(6.17 g,87%).Enantiomeric purity(vide supra):R/S>99.5:0.5.
General Procedure for the Hydrogenation Screening Experiments(Tables1and2).The starting material was placed in stainless steel pressure vessel and dissolved in the solvent indicated,and the moistened catalyst was added.The reaction vessel was closed,flushed twice with nitrogen gas and twice with hydrogen gas.The reactor was pressurized to the hydrogen pressure indicated and stirred at the given temperature for the indicated period of time.The consump-tion of hydrogen ceased within this period of time.The reactor was cooled to room temperature,the hydrogen pressure released,and the reactor flushed twice with nitrogen gas.The crude reaction mixture was filtered and evaporated to dryness,and the crude product mixture was analyzed by GLC(percent area)after derivatization with AcCl/i PrOH/ TFAA.
(2R)-2-Hydroxy-3-cyclohexylpropionic acid(4).10(A) From Phenyl Lactic Acid.A Buchi reactor was charged with a solution of(2R)-2-hydroxy-3-phenyl lactic acid(3)(50.0 g,0.3mol,R/S>99.5:0.5,from enantioselective bioreduction with Proteus mirabilis;see procedure E)in94%ethanol (1000mL)and5%Rh-C hydrogenation catalyst(5.0g). The mixture was hydrogenated at50°C under15bar H2 pressure under vigorous stirring for3h.The suspension was filtered,the clear filtrate was evaporated,and the resulting crystalline solid was dried in a vacuum-drying oven at50°C.Yield50.2g(96.9%).Enantiomeric purity(vide supra): R/S)99.5:0.5.Mp92-94°C.1H NMR(400MHz,DMSO)δ0.75-1.0(m,2H),1.1-1.3(m,3H),1.35-1.52(m,3 H),1.55-1.82(m,5H),3.0-3.8(br s,1H,H-O-C(2)),3.98 (m,1H,H-C(2)).13C NMR(100MHz,DMSO)δ26.5,26.8, 27.0(C(3′),C(4′),C(5′)cHexyl),32.7/34.4(C(2′),C(6′) cHexyl),34.1(C(1′)cHexyl),42.4(C(3),68.4(C(2),177.3 (C(1)).MS(EI)m/z173(MH+),154(M+-H2O),136,127, 109,83,67,55.
(B)From Methyl Dihydroxyphenylpropionate13A(V ide infra).To a solution of13A(R/S)99.7:0.3)(35.0g,178.4mmol)in methanol(310mL)was added98mL of2M methanolic HCl and5%Pd-C hydrogenation catalyst(10.5 g).Under vigorous stirring in a Buchi glass hydrogenation reactor,the suspension was hydrogenated at67°C under4 bar H2pressure for5h.The temperature was lowered to50°C,and5%Rh-C hydrogenation catalyst(3.5g)was added. Hydrogenation was continued at50°C for another17h before the suspension was filtered,the clear filtrate was evaporated,and the resulting oil(15)33was dried in a vacuum-drying oven at35°C/1mbar for1h.The oil was taken up in methanol(633mL)and water(211mL).Lithium hydroxide monohydrate(10.7g,255.0mmol)was added at 30°C,and the turbid solution was stirred at25°C overnight. Amberlyst IR-120(H+-form,dry,60.9g≈268.1mEq H+) was added,the ion-exchange resin was filtered off andwashed with excess methanol and water,and the clear filtrate was evaporated under reduced pressure to yield a crystalline material which was dried in a vacuum drying oven(40°C, 1mbar).Yield:28.95g(94.2%over three steps)4as off-white,crystalline solid.Enantiomeric purity(vide supra):R/S )99.3:0.7.Os-content:4ppm(by elemental analysis).
(2R,3S)-2,3-Dihydroxy-3-phenylpropionic Acid Methyl Ester(13A).According to the procedure of Sharpless et al.,26 from41.85g of methyl cinnamate were obtained37.72g (74.5%)13A,R/S)98.8:1.2after first recrystallization from toluene;respectively35.40g(69.9%),R/S)99.7:0.3after second recrystallization from toluene.Os-content:102ppm (by elemental analysis).
(2R,3S)-2,3-Dihydroxy-3-phenylpropionic Acid Benzyl Ester(13B).31Following the same procedure,26from15.9g of benzyl cinnamate was obtained17.9g of13B,99%yield, R/S)90.7:9.3after chromatograpy from toluene/ethyl acetate5:1.MS(EI)m/z272(M+),197,166,148,107,91, 79,65.
(2R)-2-Hydroxy-3-phenylpropionic Acid Methyl Ester (14A).32(A)From Hydrogenolysis/Transesterification of the Benzyl Ester Diol.To a solution of13B(R/S)90.7:9.3) (8.7g,32.0mmol)in methanol(100mL)was added8.8 mL of1.1M methanolic HCl and5%Pd-C hydrogenation catalyst(870mg).Under vigorous stirring,the suspension was hydrogenated at25°C under2bar H2pressure for16 h.The suspension was filtered,the clear filtrate was evaporated,and the resulting crystalline solid was dried in a vacuum-drying oven at50°C.Yield 4.805g(83.3%). Enantiomeric purity(vide supra):R/S)93.3:6.7.
(B)From Hydrogenolysis of the Methyl Ester Diol.To a solution of13A(R/S)98.6:1.4)(5.7g,29.1mmol)in methanol(50mL)was added16mL of1.1M methanolic HCl and5%Pd-C hydrogenation catalyst(770mg).Under vigorous stirring,the suspension was hydrogenated at25°C under1.7-4bar H2pressure for30h.The suspension was filtered,the clear filtrate was evaporated,and the resulting crystalline solid was dried in a vacuum-drying oven at50 (31)Mukaiyama,T.;Sugimura,H.;Ohno,T.;Kobayashi,S.Chem.Lett.1989,
1401.
(32)(a)Schoofs,A.;Weidmann,R.;Collet,A.;Horeau,A.Bull.Soc.Chim.Fr.
1976,2031.(b)Mor,G.;Ehret,A.;Cohen,S.G.Arch.Biochem.Biophys.
1976,174,158.
(33)Damon,D.B.;Hoover,D.J.J.Am.Chem.Soc.1990,112,6439.
Vol.7,No.4,2003/Organic Process Research&Development?567
°C.Yield5.22g(99.0%).Enantiomeric purity(vide supra): R/S)98.2:1.8.
General Synthesis Procedure for the Esters5,and16-20.Anhydrous potassium carbonate(1.15equiv)was added to a solution of4(10-50mmol)in dry acetone(80-400 mL).The white suspension was stirred at room temperature for3h,whereupon tetrabutylammonium iodide(1.0equiv) and the corresponding benzyl halide(1.15equiv)were added, and the suspension was stirred for a further12-18h at40°C, until TLC had indicated complete consumption of the hydroxy acid.After cooling to room temperature,the suspension was filtered over a sand/Celite pad,and the filter cake was washed with acetone.Evaporation under reduced pressure gave the crude product as a colorless-to-yellowish oil,which was further purified or crystallized by the solvent system indicated below with the individual compounds. Following this procedure we obtained:
(2R)-2-Hydroxy-3-cyclohexyl-propionic acid benzyl ester(5):787%yield(chromat.from n-hexane/EtOAc9:1), colorless oil,crystallizes slowly in the refrigerator,mp54-56°C,1H NMR+13C NMR identical to lit.7MS(EI)m/z 262(M+),181,166,153,127,109,91,83,67,55.IR(KBr, cm-1)3314s/br,2923s,2849m,1751ss,1742s,1538m, 1511s,1463w,1444w,1212m,1192s,1143s,1087s,1078s, 738m,695m.
(2R)-2-Hydroxy-3-cyclohexylpropionic acid p-chlo-robenzyl ester(16):50%yield,(chromat.n-hexane/EtOAc 9:1),colorless oil,1H NMR(400MHz,DMSO)δ0.79-1.73(m,13H,H2-C(3)+cHexyl),4.12(dt,J)6.4Hz, 6.7Hz,1H,H-C(2)),5.12(AA′,2H,ClPh-C H2),5.40(d, 1H,J)6.1Hz,H O-C(2)),7.39-7.47(AA′BB′,4H,ClPh). 13C NMR(100MHz,DMSO)δ26.5,26.7,26.9,32.7,34.0, 34.1,34.2,42.3,65.5,68.7,129.3,129.8,130.8,133.6,135.6, 136.1,175.3.MS(EI)m/z298,296(M+),171,153,127,125, 109,89,83,81,67,55.IR(Film,cm-1)3479s/br,2924ss, 2851s,1736ss,1494s,1449m,1274s,1198s,1142s,1094s, 1017m,965w,845w,809m.Elemental analysis calcd for C16H21ClO3(296.79):C64.75%,H7.13%,Cl11.95%; found:C64.84%,H6.90%,Cl11.88%.
(2R)-2-Hydroxy-3-cyclohexylpropionic acid2,5-dichlor-benzyl ester(17):93%yield,(chromat.n-hexane/EtOAc 9:1),colorless oil,1H NMR(400MHz,DMSO)δ0.74-1.71(m,13H,H2-C(3)+cHexyl),4.10(br dt,1H,H-C(2)), 5.31(AA′,2H,Cl2Ph-C H2),5.43(d,1H,J)6.0Hz,H O-C(2)),7.42-7.58(m,3H,Cl2Ph).13C NMR(100MHz, DMSO)δ26.5,26.7,26.9,32.9,34.0,34.1,34.15,42.5, 61.7,68.7,129.6,131.7,132.5,136.9,175.2.MS(CI)m/z 331(MH+),285,171,159,125,79.IR(Film,cm-1)3477m/ br,2924ss,2851s,1738ss,1583m,1565m,1438s,1248m, 1200s,1142m,1096s,989w,965w,779m,769m.Elemental analysis calcd for C16H20Cl2O3(331.24):C58.02%,H 6.09%,Cl21.41%;found:C57.92%,H6.09%,Cl21.30%.
(2R)-2-Hydroxy-3-cyclohexylpropionic acid p-bro-mobenzyl ester(18):88%yield(chromat.n-hexane/EtOAc 4:1),respectively82%(recryst.from n-hexane),yellowish crystals,mp50-52°C,1H NMR(400MHz,DMSO)δ0.77-1.75(m,13H,H2-C(3)+cHexyl),4.12(dt,J)6.0 Hz,6.5Hz,1H,H-C(2)),5.11(AA′,2H,BrPh-C H2),5.38(d,1H,J)6.0Hz,H O-C(2)),7.32-7.53(AA′BB′,4H, ClPh).13C NMR(100MHz,DMSO)δ26.5,26.7,26.9,32.8, 34.0,34.2,42.3,65.5,68.7,110.0,122.1,131.1,132.2,136.5, 175.3.MS(CI):m/z367[M+C2H5-gas adduct],343,342, 341,340(M+),339,295,293,277,211,198,171,169,127, 125,109,83.IR(KBr,cm-1)3408s/br,2923s,2848s,1752ss, 1728s,1489m,1223m,1209m,1186m,1170m,1142m, 1091m,1070s,1012m,805s.Elemental analysis calcd for C16H21BrO3(341.24):C56.32%,H6.20%,Br23.42%; found:C56.31%,H6.07%,Br23.30%.
The potential for epimerization during this reaction was checked in two separate batches:Exp.A: 3.3mmol of4 (R/S)98.2:1.8)gave88%of18,R/S)99.5/0.5;Exp.B: 50mmol of4(R/S)99.3:0.7)gave82%of18,R/S)99.8: 0.2).
(2R)-2-Hydroxy-3-cyclohexylpropionic acid p-nitroben-zyl ester(19):37%yield,yellow oil,(chromat.n-hexane/ EtOAc4:1),1H NMR(400MHz,DMSO)δ0.80-1.77(m, 13H,H2-C(3)+cHexyl),4.20(dt,J)6.0Hz,6.7Hz,1 H,H-C(2)),5.28(A2,2H,NO2Ph-C H2),5.46(d,1H,J) 6.0Hz,H O-C(2)),7.65,8.27(AA′BB′,4H,ClPh).13C NMR (100MHz,DMSO)δ25.8,26.0,26.2,32.0,33.3,33.5,41.5, 64.4,68.0,123.7,128.7,144.1,147.3,174.5.MS(EI):m/z 308,307(M+),289,262,211,193,171,153,137,127,109, 107,97,83,81,67,55.IR(Film,cm-1)3485s/br,2924ss, 2851s,1741ss,1608m,1524ss,1449m,1348ss,1275s,1194s, 1142s,1098s,1013m,853w,738w.Elemental analysis calcd for C16H21NO5(307.35):C62.53%,H6.89%,N4.56%; found:C62.79%,H7.02%,N4.49%.
(2R)-2-Hydroxy-3-cyclohexylpropionic acid2-naphth-ylmethyl ester(20):94%yield,mp54-55°C,(chromat. from n-hexane/EtOAc9:1),colorless oil,crystallizes slowly while standing at rt,mp54-55°C,1H NMR(400MHz, DMSO)δ0.77-1.74(m,13H,H2-C(3)+cHexyl),4.18 (dt,J)6.2Hz,6.8Hz,1H,H-C(2)),5.30(AA′,2H, Naphth-C H2),5.42(d,1H,J)6.2Hz,H O-C(2)),7.50-7.57(m,3H,Naphth-H),7.90-7.95(m,4H,Naphth-H). 13C NMR(100MHz,DMSO)δ26.5,26.7,26.9,32.8,34.0, 34.2,42.4,66.5,68.8,126.8,127.2,127.3,127.7,128.5, 128.6,129.0,133.5,133.6,134.6,175.4.MS(CI):m/z312 (M+),281,141,109,83.IR(KBr,cm-1)3506s,3483s, 2923s,2849m,1708ss,1742s,1465w,1291m,1258m, 1233w,1132m,980m,823s,750m.Elemental analysis calcd for C20H24O3(312.41):C76.89%,H7.74%;found:C 76.77%,H7.75%.
General Synthesis Procedure for the Sulfonates16-28.Toluene-4-sulfonyl chloride,4-bromobenzenesulfonyl chloride or4-nitrobenzenesulfonyl chloride(1.3equiv)was added to a solution of the corresponding hydroxyester(5, 18or20)(1-5mmol)in dry toluene(5-25mL)at room temperature.N-Methylmorpholine(1.4equiv)was added,and the suspension was stirred for a further2-4h at room temperature and10-18h at50°C,until TLC had indicated complete consumption of the hydroxy ester.After cooling to room temperature,the suspension was washed with20% NaHCO3(2×10mL)and water(2×15mL).Combined water phases were extracted with toluene(1×15mL). Drying of the toluene phases over sodium sulfate and
568?Vol.7,No.4,2003/Organic Process Research&Development
evaporation under reduced pressure gave the crude product ususally as a yellow oil,which was further purified or crystallized by the solvent system indicated below with the individual compounds.
(2R)-2-(4-Nitrophenyl)sulfonyloxy-3-cyclohexyl-propi-onic acid p-brombenzyl ester(21):60%yield,(crude product recryst.from EtOH),yellowish crystals,mp71-72°C,1H NMR(400MHz,DMSO)δ0.67-1.76(m,13H, H2-C(3)+cHexyl),4.12(dt,J)6.0Hz,6.5Hz,1H, H-C(2)),5.09-5.15(m,3H,H-C(2)+BrPh-C H2),7.28-7.56(AA′BB′,4H,BrPh),8.20-8.43(AA′BB′,4H,NO2-Ph).13C NMR(100MHz,DMSO)δ26.1,26.4,26.5,26.6, 32.1,32.4,33.6,33.7,33.9,67.0,77.8,122.5,124.2,125.7, 127.8,130.4,131.2,132.3,135.4,141.5,151.6,169.1.MS-(EI):m/z527[MH+],356,322[M+-NO2PhSO3H],230, 186,171,169[BrPhCH2+],138,94,83.IR(KBr,cm-1) 3120m,2926s,1752s,1734s,1535ss,1372s,1351s,1190ss, 1171m,1166m,982s,961s,858m,843s,748m,617s. Elemental analysis calcd for C22H24BrNO7S(526.41):C 50.20%,H4.60%,Br15.18%,N2.66%,S6.09%;found: C50.17%,H4.59%,Br15.05%,N2.58%,S6.10%.
(2R)-2-Methansulfonyloxy-3-cyclohexyl-propionic acid p-brombenzyl ester(22):81%yield,(crude product chro-mat.from n-Hexane/EtOAc9:1),colorless oil,1H NMR(400 MHz,DMSO)δ0.85-1.79(m,13H,H2-C(3)+cHexyl),
3.25(s,3H,C H3SO2),5.14-5.24(m,3H,H-C(2)+BrPh-
C H2),7.36-7.61(AA′BB′,4H,BrPh).13C NMR(125MHz, DMSO)δ25.9,26.0,26.2,32.1,33.2,33.3,38.3,66.4,76.0, 122.1,130.9,131.9,135.2,169.5.MS(CI):m/z421[MH+], 420,419,418,417,339,337,323,321,249,171,138,94. IR(KBr,cm-1)3030w,2926ss,2852s,1756ss,1490m, 1449m,1361ss,1277m,1174ss,1141m,1071m,1010s,967s, 922m,858m,801s.
(2R)-2-(4-Bromphenyl)sulfonyloxy-3-cyclohexyl-propi-onic acid p-brombenzyl ester(23):52%yield(crude product recryst.from EtOH),respectively48%yield(crude product chromatographed from n-hexane/EtOAc9:1),yel-lowish crystals,mp68-69°C,1H NMR(400MHz,DMSO)δ0.67-1.71(m,13H,H2-C(3)+cHexyl),4.94(dd,J) 3.8Hz,9.6Hz,1H,H-C(2)),5.12(s,3H,BrPh-C H2),7.29-7.61(AA′BB′,4H,BrBn),7.88(s,4H,BrPhSO2).13C NMR (125MHz,DMSO)δ25.7,26.0,26.1,31.6,33.2,66.5,76.6, 122.0,128.2,129.3,130.1,130.8,131.0,131.9,132.0,133.3, 134.8,135.0,168.9.MS(ESI):dec,m/z236,234[BrPhSO3H]. IR(Film,cm-1)2924s,1760ss,1745sh/s,1576s,1490m, 1392s,1377s,1278m,1190s,1071s,1012s,919s,861m, 823s,797m,611s.
(2R)-2-Methansulfonyloxy-3-cyclohexyl-propionic acid 2-naphthylmethyl ester(24):79%yield,(crude product chromat.from n-hexane/EtOAc9:1),slightly yellowish oil, 1H NMR(400MHz,DMSO)δ0.88-1.75(m,13H,H2-C(3)+cHexyl),3.25(s,3H,C H3SO2),5.20(m,1H, H-C(2)),5.40(Naphth-C H2),7.51-7.56(m,3H,Naphth), 7.92-7.95(m,4H,Naphth).13C NMR(125MHz,DMSO)δ25.8,26.0,26.2,32.2,33.2,33.3,38.3,67.3,76.2,126.4, 126.9,127.7,128.1,128.3,128.6,133.1,133.3,169.6.MS-(CI):m/z390[MH+],141[Naphth-CH2+].IR(Film,cm-1) 3035w,2925ss,2852s,1753ss,1455m,1361ss,1277m,1175ss,1142m,1043m,1001s,965s,922m,858m,818m, 797m.
(2R)-2-(4-Nitrophenyl)sulfonyloxy-3-cyclohexyl-propi-onic acid2-naphthylmethyl ester(25):58%yield,(crude product chromat.from n-hexane/EtOAc9:1),yellowish oil, 1H NMR(400MHz,DMSO)δ0.70-1.52(m,11H, cHexyl),1.64(m,1H,H-C(3)),1.75(m,1H,H′-C(3)),5.15 (dd,1H,J)4.1,9.3Hz,H-C(2)),5.30(Naphth-C H2),
7.42-7.56(m,3H,Naphth),7.87-7.93(m,4H,Naphth),
8.21-8.38(AA′BB′,NO2PhSO2).13C NMR(125MHz, DMSO)δ25.8,26.0,26.1,26.2,32.0,33.2,33.5,60.2,67.5, 68.2,77.5,81.1,123.8,125.2,126.5,126.9,127.0,127.4, 128.1,128.2,128.3,128.6,128.8,130.0,132.9,133.0,133.1, 133.2,141.1,147.7,151.1,154.8,168.7,170.6.MS(CI):m/z 526[M++C2H5gas adduct],497[M+],156,141[Naphth-CH2+].IR(Film,cm-1)3100w,2925s,2852m,1757s, 1534ss,1381m,1350s,1278m,1188ss,991m,920w,853m, 819w,745m.
(2R)-2-(4-Nitrophenyl)sulfonyloxy-3-cyclohexyl-propi-onic acid benzyl ester(26):80%yield,(crude product chromat.from n-hexane/EtOAc9:1),yellowish oil,1H NMR (400MHz,DMSO)δ0.72-1.76(m,13H,H2-C(3)+ cHexyl),5.11-5.14(m,3H,H-C(2)+Ph-C H2),7.30-7.43 (m,5H,Ph),8.21-8.42(AA′BB′,NO2PhSO2).13C NMR (100MHz,DMSO)δ26.1,26.4,26.5,32.1,33.2,33.6,33.7, 39.4,67.8,77.9,125.7,129.1,129.2,129.3,130.4,135.9, 141.5,147.7,151.6,169.1.MS(EI):m/z447[M+],356[M+ -PhCH
2
?],330,312,244,186[NO2PhSO2+.],153,138, 122,109,92,67,55.IR(Film,cm-1)3100w,2925s,2852m, 1758s,1534ss,1404m,1381s,1351s,1314m,1278m,1188ss, 1100m,920m,853m,819w,745s,617m.
(2R)-2-(4-Bromphenyl)sulfonyloxy-3-cyclohexyl-propi-onic acid benzyl ester(27):63%yield,(crude product chromat.from n-hexane/EtOAc9:1),yellowish oil,1H NMR (500MHz,DMSO)δ0.80-1.68(m,13H,H2-C(3)+ cHexyl),4.91(dd,1H,J)2.3,9.7Hz,H-C(2)),5.11(s,2 H,Ph-C H2),7.30-7.41(AA′BB′,4H,BrPhSO2),7.85-7.87(m,5H,Ph).13C NMR(125MHz,DMSO)δ25.7, 26.0,26.1,31.6,33.2,39.0,67.3,76.6,128.6,128.8,128.9, 129.3,130.2,133.3,134.8,135.6,168.9.MS(CI):m/z481 [M+],390[M+-PhCH2?],244,220,181,153,138,91.IR (Film,cm-1)3100w,2924s,2850m,1759s,1534ss,1450m, 1392s,1378s,1278m,1190ss,1069m,1012m,1001m,919m, 861m,777w,749m,613m.Elemental analysis calcd for C22H25BrO5S(10%toluene)(442.48):C55.65%,H5.31%, S6.52%;found:C55.74%,H5.30%,S6.57%.
(2R)-2-(4-Tolyl)sulfonyloxy-3-cyclohexyl-propionic acid benzyl ester(28):60%yield,(crude product chromat.from n-hexane/EtOAc9:1),colorless oil,1H NMR(500MHz, DMSO)δ0.60-1.69(m,13H,H2-C(3)+cHexyl),2.42 (s,3H,C H3-PhSO2),4.83(dd,1H,J)3.6,9.1Hz,H-C(2)), 5.12(s,2H,Ph-C H2),7.32-7.43(m,5H,Ph),7.46-7.82 (AA′BB′,4H,Me Ph SO2).13C NMR(100MHz,DMSO)δ26.1,26.4,26.5,32.0,33.5,33.6,39.6,67.6,76.4,128.6, 129.0,129.2,129.3,131.0,133.0,136.1,146.3,169.5.MS-(CI):m/z417[MH+],327,325,299,281,245,227,181, 138,107,91.IR(Film,cm-1)3050w,2925s,2852m,1761s, 1740sh,1595m,1498m,1450m,1374s,1278s,1190ss, Vol.7,No.4,2003/Organic Process Research&Development?569
1178ss,1002s,918m,861m,815m,698m,666s,554m. Elemental analysis calcd for C23H28O5S(416.54):C66.32%, H6.78%,S7.70%;found:C66.38%,H6.75%,S7.79%. Acknowledgment
We gratefully acknowledge the support of Dr.Christoph Spoendlin for the determination of enantiomeric purities by HPLC.Mr.Dominique Grimler and Mr.Michael Haller are thanked for their technical assistance with some scale-up experiments,and Dr.C.-P.Mak for his encouragement. Received for review February27,2003.
OP030202Q
570?Vol.7,No.4,2003/Organic Process Research&Development
苯衍生物取代基定位效应
定义含有取代基的苯衍生物，在进行芳香族亲电取代反应时，原有的取代基，对新进入的取代基主要进入位置，存有一定指向性的效应。这种效应称为取代基定位效应。 单取代的苯衍生物的定位效应①如苯环上的取代基为-NH2（-NHR、-NR2，R 为烷基）、-OH、-OCH3(-OC2H5等)、-NHCOCH3、-C6H5、-CH3(-C2H5等)等(按定位效应由强到弱次序排列)时，其亲电取代的反应性较苯高。在取代反应中，此类取代基导致得到大部分为邻位和对位取代的异构体。此类取代基称为有活化作用的邻、对位取代基。 取代基的定位效应是个反应速率问题。上邻、对位反应快而上间位慢,就显示邻、对位定位效应;上间位反应快而上邻、对位慢，就显示间位定位效应。 稳定的活性中间体的能量低，与之相应的过渡状态的能量也就低，活化能低，反应速率就快；过渡状态能量高，活化能高，反应速率就慢。因此，不同的反应速率实质上反映了活性中间体的稳定性，而活性中间体的稳定性，可以用共振论的方法加以分析。例如用甲苯进行亲电取代反应时，亲电试剂E+可以进攻邻、对位和间位。当亲电试剂进攻邻、对位时，有比较稳定的极限式(a，b)参与共振,CH3与带正电荷的碳相连，CH3有给电子效应,可以中和部分正电荷，使正碳离子稳定，杂化产生的活性中间体也比较稳定。亲电试剂进攻间位时，没有比较稳定的极限式,没有CH3与带正电荷的碳相连的极限式参与杂化。因此，甲基是邻、对位定位基。 ② 如苯环上的取代基为 -F、-Cl、-Br、-I、-CH2Cl、-CH匉CHNO2等时，则具有这些取代基的苯的亲电取代反应性较苯低，即这些基使苯环钝化。邻位和对位钝化程度较间位小，有利于形成邻位和对位的取代异构体。此类取代基称为有钝化作用的邻、对位取代基。 这类取代基的情况比较特殊。如在氯苯中，氯原子是强的吸引电子的取代基，在进行亲电取代反应时，它使苯环正碳离子的电荷更加集中，正碳离子不稳定，对苯环起钝化作用。 如果亲电试剂进攻邻、对位，有比较稳定的极限式(c、e)，这是由于氯原子的非共享电子对向苯环转移，使(c、e)的每个原子均具有稳定的八隅体结构，由稳定极限式参与共振杂化所产生的活化中间体也较稳定。如亲电试剂进攻间位，极限式(d)有六电子的碳,不如极限式(c、e)稳定。因此，氯原子是邻、对位定位基。 ③ 如苯环上的取代基为-NO2、-+NH3、-+NR3、-CF3、-+PR3、-+SR2、-SO3H、-SO2R、-COOH、-COOR、-CONH2、-CHO、-COR、-CN等时,则具有这些取代基的苯的亲电取代反应性不如苯，即这些基团使苯环钝化。邻位和对位钝化程度较间位大，在取代反应中，新取代基大多进入间位，形成间位异构体。这类取代基称为有钝化作用的间位取代基。 这些取代基都有吸电子作用。例如当三氟甲基取代苯上的氢后，由于三氟甲
苯环上取代基的定位效应
取代基定位效应 开放分类：化学、效应、芳香烃 目录 ? 定义 ? 单取代的苯衍生物的定位效应 ? 苯环上有两个取代基的定位效应 ? 取代基定位效应解析 取代基定位效应 英文名称：Substituent??positioning??effects定义 ? ?? ?含有取代基的苯衍生物，在进行芳香族亲电取代反应时，原有的取代基，对新进入的取代基主要进入位置，存有一定指向性的效应。这种效应称为取代基定位效应。 单取代的苯衍生物的定位效应 ? ? ①如苯环上的取代基为-NH2（-NHR、-NR2，R为烷基）、-OH、
-OCH3(-OC2H5等)、-NHCOCH3、-C6H5、-CH3(-C2H5等)等(按定位效应由强到弱次序排列)时，其亲电取代的反应性较苯高。在取代反应中，此类取代基导致得到大部分为邻位和对位取代的异构体。此类取代基称为有活化作用的邻、对位取代基。 取代基的定位效应是个反应速率问题。上邻、对位反应快而上间位慢,就显示邻、对位定位效应;上间位反应快而上邻、对位慢，就显示间位定位效应。 ? ?? ? 稳定的活性中间体的能量低，与之相应的过渡状态的能量也就低，活化能低，反应速率就快；过渡状态能量高，活化能高，反应速率就慢。因此，不同的反应速率实质上反映了活性中间体的稳定性，而活性中间体的稳定性，可以用共振论的方法加以分析。例如用甲苯进行亲电取代反应时，亲电试剂E+可以进攻邻、对位和间位。当亲电试剂进攻邻、对位时，有比较稳定的极限式(a，b)参与共振,CH3与带正电荷的碳相连，CH3有给电子效应,可以中和部分正电荷，使正碳离子稳定，杂化产生的活性中间体也比较稳定。亲电试剂进攻间位时，没有比较稳定的极限式,没有CH3与带正电荷的碳相连的极限式参与杂化。因此，甲基是邻、对位定位基。 ②如苯环上的取代基为 -F、-Cl、-Br、-I、-CH2Cl、-CH匉CHNO2等时，则具有这些取代基的苯的亲电取代反应性较苯低，即这些基使苯环钝化。邻位和对位钝化程度较间位小，有利于形成邻位和对位的
教学目标了解联苯及联多苯的结构及性质.
教学目标：了解联苯及联多苯的结构及性质 教学重点：联苯的性质 教学安排：G —>G9；10min 1，G4 基本概念：联苯：分子中两个或两个以上的苯环直接以单键相连接的多环芳烃称为联苯或联多苯，例如： 一、联苯的性质 联苯为无色晶体，熔点70℃，沸点254℃，不溶于水而溶于有机溶剂。联苯的化学性质与苯相似，在两个苯环上均可以发生磺化、硝化等取代反应。联苯环上碳原子的位置采用下式所示的编号来表示： 联苯可以看作是苯的一个氢原子被苯基所取代，而苯基是邻对位定位基，所以当联苯发生取代反应时，取代基主要进入苯基的对位，同时也有少量的邻位产物生成。例如联苯硝化时，主要是生成4，4'-二硝基联苯。 二、联苯的制法 工业上联苯是由苯蒸气通过温度在700℃以上红热的铁管，热解得到。 实验室中可由碘苯与铜粉共热而制得。 联苯对热很稳定，用作热载体。26.5% 的联苯和73.5% 的二苯醚组成的低共熔点混合物
是工业上普遍使用的热载体。它的熔点12℃，沸点260℃，在1MPa 下加热到400℃仍不分解。 三、关键词 联苯，联多苯 教学目标：掌握稠环芳烃的结构、性质及其应用 教学重点：萘的结构及性质 教学安排：G ，G4—>G10；60min 1，G3 基本概念：稠环芳烃：多个苯环共用两个或多个碳原子稠和而成的芳烃称为稠环芳烃。一、萘 1．萘的结构 萘的分子式为C10H8。化学方法已经证明，萘是由两个苯环共用两个碳原子稠合而成。物理方法已证明，萘与苯相似，也具有平面结构，即两个苯环在同一平面上。但又与苯不同，碳碳键键长不完全相等。
萘的NMR谱图 萘的UV谱图 1，4，5，8位相当，称为α 位；2，3，6，7 位相当，称为β 位。萘具有芳香性。萘的离域能约为254.98kJ·mol-1，因此比较稳定，但芳香性比苯差。
谁 发 现 了 苯 的 结 构
谁发现了苯的结构？ 北京师范大学化学系吴国庆 谁发现了苯的结构？你要是向任何一名化学教师提这样一个问题，一定会得到千篇一律的答案----19世纪著名的德国化学家凯库勒（F·A·Kekule 1829--1896）！他在1865年发表了一篇明 确给出苯的六员环的结构图，这篇文章登载在法国化学会会志该年第3卷第二期第98页上。 可是…… 1995年，奥地利发行了一张邮票，中间是一帧画像，画像上方写着：纪念约瑟夫·劳施密特（Josef Loschmidt）逝世100周年， 这说明画中人是劳施密特；邮票的左下角画着一个用试管夹夹持的装有深色溶液的试管，这表明劳施密特是位化学家；令人感兴趣的是邮票的右下角画着许多连环套似的大大小小的圆圈，临摹如下： 这些连环套是什么？ 原来，这是劳施密特画的肉桂酸的结构式。肉桂酸，樟属肉桂的树皮里的一种芳香物质----肉桂的衍生物，肉桂是人们很早就懂得用于烹调的香料。用现代的结构式来翻译劳施密特的结构式，肉桂酸就是：
这正是人们现在知道的肉桂酸的结构式！这个结构式里有一个大圈，这就是苯环。如果你知道这个结构式是在凯库勒发现苯的结构 之前给出的，你就不得不为之惊叹！原来，在伟大的凯库勒发现苯 环结构之前，他，约瑟夫·劳施密特，一名不知名的奥地利中学教 师早在1861年就已经得知苯环的结构了。后来人们在劳施密特写 的“化学研究第一卷”里看到，劳施密特用这样的结构式画了许许 多多有机物的正确的结构式，其中有许多结构式是含苯环的，肉桂 酸只是其中之一。 劳施密特不仅对有机化学的发展作出了杰出的贡献，还应当提到的是，正是他第一个测定了阿伏加德罗常数。因此，没有哪一位欧 洲的中学生不把阿伏加德罗常数叫做劳施密特常数的，而且，这个 物理量的符号在欧洲多是用劳施密特（Loschmidt）的第一个字母 L表示的。 值得一提的是，告诉我们是劳施密特而不是凯库勒发现苯的结构的是里查德·安舒茨（Richard Anschochtz），令人敬佩的是，他 是凯库勒的学生！除了苯的结构问题，他还告诉人们，碳的四价， 也不是如同公认的那样是在1865年由凯库勒首先提出的，而是由 一名英年早逝的苏格兰化学家库伯（Archibald Scott Couper）在 1858年就已经先提出来了。 还应重复一句：劳施密特跟伟大的凯库勒的地位相差很大----他只不过是一名奥地利中学教师！历史资料里并没有说，伟大的凯 库勒是否预先读过劳施密特的文章，但有一点是可以肯定的，劳施 密特画的苯环结构图绝对是在凯库勒做梦之前。 亲爱的读者们，你从化学史上这则小故事得到了一点什么有益的启发呢？
苯环上亲电取代反应的定位规律
苯环上亲电取代反应的定位规律 基本概念：定位基：在进行亲电取代反应时，苯环上原有取代基，不仅影响着苯环的取代反应活性，同时决定着第二个取代基进入苯环的位置，即决定取代反应的位置。原有取代基称做定位基。 一、两类定位基 在一元取代苯的亲电取代反应中，新进入的取代基可以取代定位基的邻、间、对位上的氢原子，生成三种异构体。如果定位基没有影响，生成的产物是三种异构体的混合物，其中邻位取代物40%（2/5）、间位取代物40%（2/5）和对位取代物20%（1/5）。实际上只有一种或二种主要产物。例如各种一元取代苯进行硝化反应，得到下表所示的结果： 排在苯前面的取代硝化产物主要是邻位和对位取代物，除卤苯外，其它取代苯硝化速率都比苯快；排在苯后面取代硝化产物主要是间位取代物，硝化速率比苯慢得多。归纳大量实验结果，根据苯环上的取代基（定位基）在亲电取代反应中的定位作用，一般分为两类：第一类定位基又称邻对位定位基：—O-，—N(CH3)2，—NH2，—OH，—OCH3，—NHCOCH3，—OCOCH3，—F，—Cl，—Br，—I，—R，—C6H5等。 第二类定位基又称间位定位基：—N+(CH3)3，—NO2，—CN，—SO3H，—CHO，—COCH3，—COOH，—COOCH3，—CONH2，—N+H3等。 两类定位基的结构特征：第一类定位基与苯环直接相连的原子上只有单键，且多数有孤对电子或是负离子；第二类定位基与苯环直接相连的原子上有重键，且重键的另一端是电负性
大的元素或带正电荷。两类定位基中每个取代基的定位能力不同，其强度次序近似如上列顺 序。 苯环上亲电取代反应的定位规律 二、定位规律的电子理论解释 在一取代苯中，由于取代基的电子效应沿着苯环共轭链传递，在环上出现了电子云密度较 大和较小的交替分布现象，因而环上各位置进行亲电取代反应的难易程度不同，出现两种定 位作用。也可以从一取代苯进行亲电取代反 应生成的中间体σ络合物的相对稳定性的角度进行考察，当亲电试剂E +进攻一取代 时，生成三苯 σ络合物： Z 不同，生成的三种σ 络合物碳正离子的稳定性不同，出现了两种定位作用。 1．第一类定位基对苯环的影响及其定位效应 以甲基、氨基和卤素原子为例说明。 甲基在甲苯中，甲基的碳为sp3杂化，苯环碳为sp2杂化，sp2杂化碳的电负性比sp3杂 化碳的大，因此，甲基表现出供电子的诱导效应（A）。另外，甲基C—H σ 键的轨道与苯 环的π 轨道形成σ—π 超共轭体系（B）。供电诱导效应和超共轭效应的结果，苯环上电 子密度增加，尤其邻、对位增加得更多。因此，甲苯进行亲电取代反应比苯容易，而且主要 发生在邻、对位上。 亲电试剂E+进攻甲基的邻、间、对位置，形成三种σ 络合物中间体，三种σ 络合物 碳正离子的稳定性可用共振杂化体表示： 进攻邻位：
苯的发现和苯分子结构学说
科目化学 年级 文件 hxs0005.doc 标题苯的发现和苯分子结构学说 关键词苯/凯库勒/化学史 内容 苯是在1825年由英国科学家法拉第(Michael Faraday,1791- 1867)首先发现的。19世纪初，英国和其他欧洲国家一样，城市的照明已普遍使用煤气。从生产煤气的原料中制备出煤气之后，剩下一种油状的液体却长期无人问津。法拉第是第一位对这种油状液体感兴趣的科学家。他用蒸馏的方法将这种油状液体进行分离，得到另一种液体，实际上就是苯。当时法拉第将这种液体称为"氢的重碳化合物"。1834年，德国科学家米希尔里希(E.E.Mitscherlich,1794-863)通过蒸馏苯甲酸和石灰的混合物，得到了与法拉第所制液体相同的一种液体,并命名为苯。待有机化学中的正确的分子概念和原子价概念建立之后，法国化学家日拉尔(C.F.Gerhardt,1815-856)等人又确定了苯的相对分子质量为78，分子式为C6H6。苯分子中碳的相对含量如此之高，使化学家们感到惊讶。如何确定它的结构式呢？化学家们为难了：苯的碳、氢比值如此之大，表明是高度不饱和的化合物。但它又不具有典型的不饱和化合物应具有的易发生加成反应的性质。德国化学家是一位极富想象力的学者，他曾提出了碳四价和碳原子之间可以连接成链这一重要学说。对苯的结构，他在分析了大量的实验事实之后认为：这是一个很稳定的"核"，6个碳原子之间的结合非常牢固，而且排列十分紧凑，它可以与其他碳原子相连形成芳香族化合物。于是，凯库勒集中精力研究这6个碳原子的"核"。在提出了多种开链式结构但又因其与实验结果不符而一一否定之后，1865年他终于悟出闭合链的形式是解决苯分子结构的关键，他先以(Ⅰ)表示苯结构。1866年他又提出了(Ⅱ)式，后简化为(Ⅲ)式，也就是我们现在所说的凯库勒式。 有人曾用6只小猴子形象地表示苯分子的结构.关于凯库勒悟出苯分子的环状结构的经过，一直是化学史上的一个趣闻。据他自己说这来自于一个梦。那是他在比利时的根特大学任教时，一天夜晚，他在书房中打起了瞌睡，眼前又出现了旋转的碳原子。碳原子的长链像蛇一样盘绕卷曲，忽见一蛇抓住了自己的尾巴，并旋转不停。他像触电般地猛醒过来，整理苯环结构的假说,又忙了一夜。对此，凯库勒说："我们应该会做梦！……那么我们就可以发现真理，……但不要在清醒的理智检验之前,就宣布我们的梦。" 应该指出的是,凯库勒能够从梦中得到启发,成功地提出重要的结构学说,并不是偶然的。这是由于他善于独立思考,平时总是冥思苦想有关的原子、分子、结构等问题,才会梦其所思；更重要的是,他懂得化合价的真正意义,善于捕捉直觉形象；加之以事实为依据,以严肃的科学态度进行多方面的分析和探讨,这一切都为他取得成功奠定了基础。
苯环上的取代定位规则
苯环上的取代定位规则 大量实验事实表明，当一些基团处于苯环上时，苯环的亲电取代反应会变得容易进行，同时指使再进入的基团将连接在它的邻位或对位。例如，当苯环上已存在一个甲基时（即甲苯），它的卤化、硝化和磺化等反应，反应温度均远低于苯，且新基团的导入均进入苯环上甲基的邻或对位： Cl Gil, CH） NO, 甲基的这种作用称为定位效应。在这里甲基是一个邻、对位指向基，具有活 化苯环的作用，称为活化基。类似的活化基团还有许多，它们也被称为第一类取代基，并按活化能力由大到小的顺序排列如下： O -NH2，-NHR -N艮，-OH>-NHCO,R-OR,亠°匸? >-R，-Ph>-X 处于这一顺序最末的卤素是个特例。它一方面是邻、对位指向基，另一方面 又是使苯环致钝的基团，这是由于卤素的电负性远大于碳，因此其吸电子效应已超过了本身的供电子能力，这就使环上的电子云密度比卤素进入前有所降低，因而使亲电试剂的进攻显得不力。此称为钝化作用。 还有许多比卤素致钝力更强，而且使再进基团进入间位的取代基，它们被称为间位指示基或第二类取代基，按其致钝能力由大到小的顺序排列如下：-NR3，-NQ, -CF a，-CCl3>-CN, -SQH, -CH= O, -COR -COOH -COOR 常见的取代基的定位作用见表
-NR2(-H)-CN -NHR-CHCI-SQH -NH2-CHCI -OH-F-CHO -OCH3-Cl-COCH -NHCOR-Br-COOH -CH3-I-COOR -C2H5-CONH -CH(CH3)2 -C(CH3)2 -Ar (-H) 由于取代基的指向和活化或钝化作用，在合成一个指定化合物时，采取哪种路线就必须事先作全面考虑。如：欲合成下列化合物时，显然b-路线是合理的。 如果以苯为原料，欲合成对-硝基苯甲酸（此物质在后面章节将学到）时，则 应该先对苯进行甲基化后再进行硝化，最后将甲基氧化：
苯环上取代反应的定位规则
苯环上原有的取代基对新导入取代基有影响，这种影响包括反应活性和进入位置两个方面。通常，苯环上原有的第一取代基称为定位基，从大量实验事实的分析总结中发现，定位基的定位作用遵循一定的规律，这一规律称为苯环上亲电取代反应定位规律（又称定位规则）。下面分别讨论定位基的类型；定位规则的理论解释；二元取代苯的定位规律；定位规律的应用。 （一）定位基的类型 1．邻、对位定位基。这类定位基的结构特征是定位基中与苯环直接相连的原子不含不饱和键（芳烃基例外），不带正电荷，且多数具有未共用电子对。常见的邻、对位定位基及其反应活性（相对苯而言）如下： 强致活基团：―NH2(―NHR,―NR2),―OH 中致活基团：―OCH3(―OR),―NHCOCH3(－NHCOR) 弱致活基团：―ph(―Ar),―CH3(－R) 弱致钝基团：―F,―Cl,―Br,―I 这类定位基多数使亲电取代反应较苯容易进行，但卤素例外。 2．间位定位基。这类定位基的结构特征是定位基中与苯环直接相连的原子一般都含有不饱和键（－CX3例外）或带正电荷。常见的间位定位基及其定位效应从强到弱顺序如下：―N+H3，―N+R3，―NO2，―CF3，―CCl3，―CN，―SO3H，―COH，―COR，―COOH，―COOR，―CONH2等。 这类定位基属致钝基团，通常使苯环上亲电取代反应较苯难进行，且排在越前面的定位基，定位效应越强，反应也越难进行。 （二）定位规则的理论解释 苯环上的取代反应是亲电取代反应。因此，从反应活性的角度分析，凡有助于提高苯环上电子云密度的基团，就能使苯环活化，反应活性提高；反之，凡是使环上电子云密度降低的基团，就能使苯环钝化，反应活性降低。从反应位置的角度分析，当苯环上没有取代基时，环上六个碳原子的电子云密度是均等的；但当苯环上有取代基时，由于取代基的电子效应沿着苯环共轭体系传递。在环上出现了出现了电子云密度的疏密交替分布现象。第二个取代基总是进入苯环上电子云密度相对较大的部位，从而使这些碳原子上的取代物占了多数。现以―CH3，―OH，―Cl，―NO2为代表加以说明。 1．甲基（―CH3）。甲基具有正的诱导效应（＋I），是供电子基；此外，甲基的 C－H键的σ电子可与苯环的п电子发生σ,п－超共轭效应。其结果均可使苯环上的电子云密度增大，特别是甲基的邻、对位增加的更多。 因此，甲苯比苯易发生亲电取代反应，而且主要发生在邻、对位上。 2．酚羟基（－OH）。从诱导效应看，氧的电负性大于碳，存在负的诱导效应（-I），但氧上的未共用电子对可与苯环上的п电子产生给电子的p,п－共轭效应（＋C）。在反应时，动态的共轭效应占主导地位，总的结果是使苯环上电子云密度提高，而不是降低，而且邻、对位增加的较多。 所以，苯酚的亲电取代反应比苯容易进行，且第二个取代基主要进入酚羟基的邻、对位。 3．氯原子（―Cl）。氯原子的电负性较大，是吸电子基，存在负的诱导效应（-I）。但同时，氯原子的未共用电子对，同样可以与苯环上的п电子产生给电子的p,п－共轭效应（＋C）。但与酚羟基不同的是氯原子的＋C不足以抵消-I，总的结果是使苯环上电子云密度降低，且间位降低较多，邻、对位降低的较少，量子化学的计算也表明同样的结果。 （+）表示电子云密度比苯小
苯(知识点总结+典例解析)
苯 【学习目标】 1、了解苯的物理性质和分子组成； 2、掌握苯的结构式并认识苯的结构特征； 3、掌握苯的化学性质。 【要点梳理】 要点一、苯的分子结构 2、苯的空间构型：苯分子具有平面正六边形结构，六个碳原子、六个氢原子在同一平面上，键角120°。 3、苯的结构特征 要点诠释： （1）六元环上碳碳之间的键长相同，键能也相同。 （2）苯环上碳碳间的键不是一般的碳碳单键，也不是一般的碳碳双键，而是一种介于单键和双键之间的独 特的键，六个碳碳键是等同的，所以用来表示苯的结构简式更恰当。 要点二、苯的性质 1、苯的物理性质 苯是一种无色、有特殊气味的液体，有毒、难溶于水，密度比水小，熔沸点较低，是常用的有机溶剂。 2、苯的化学性质 由于苯的结构的特殊性，使其兼具有饱和烃和不饱和烃的性质。 （1）氧化反应 C6H6+7.5O26CO2+3H2O 要点诠释： a、苯在空气中燃烧，产生明亮的火焰，并带有浓烈的黑烟。 b、燃烧带浓烟是由于苯分子里含碳量很高，在空气中燃烧不充分的缘故。 c、苯易燃烧，但很难被高锰酸钾等氧化剂氧化，故在一般的条件下苯不能使酸性高锰酸钾溶液褪色。 （2）取代反应 苯分子的环状结构使得环上的氢原子容易被其他原子或原子团所代替，因此使其具有了和烷烃相似的化学性质—取代反应。 ①苯与溴的反应 在FeBr3催化剂的作用下，苯环上的氢原子被溴原子所取代，生成溴苯。 要点诠释： a、该实验用的溴为液溴，苯与溴水不反应，仅发生萃取分层。
b、该反应不需加热，常温下即可反应，且放出大量的热，使反应器内充满红棕色的气体（溴蒸气），导气管口有白雾。 c、溴苯为无色液体，密度比水大，不溶于水，实验时溴苯因溶解了没反应的溴而呈褐色。 d、溴苯的提纯：用NaOH溶液洗涤（Br2+2NaOH=NaBr+NaBrO+H2O），然后再分液。 e、在催化剂存在时，苯也可以与其他卤素发生取代反应，又称卤代反应。 各类烃与液溴、溴水、溴的四氯化碳溶液、酸性KMnO溶液反应的比较 ②苯与硝酸的反应 在浓硫酸作用下，苯在50～60℃还可以与浓硝酸发生取代反应生成硝基苯。 要点诠释： a、硝酸分子中的-NO2原子团叫做硝基，苯分子中的氢原子被-NO2所取代的反应，叫做硝化反应，硝化反应的实质属于取代反应。 b、浓硫酸在苯的硝化反应中的主要作用是催化剂和脱水剂。 c、该反应的温度必须控制在50～60℃，故采用水浴加热（易于控制温度，且受热均匀），且需借用温度计控制水浴温度。 d、实验时加入试剂的顺序是先加浓硝酸，再加浓硫酸，并用玻璃棒不断搅拌，最后加苯。 e、硝基苯是无色、有苦杏仁味、密度比水大、难溶于水的油状液体，有毒，常因溶有NO2而显黄色，可采用多次水洗或NaOH溶液洗涤的方法提纯。 （3）加成反应 苯虽然不具有像烯烃一样典型的碳碳双键，但在特定条件下，仍能发生加成反应。例如，在镍作催化剂的条件下苯可以与氢气发生加成反应。 乙烷、乙烯和苯的比较
取代基定位效应解析
取代基定位效应解析 一、定位基分类与定位效应解析： 苯环上已有的取代基叫做定位取代基。 1、邻对位定位取代基 ①概念：当苯环上已带有这类定位取代基时，再引入的其它基团主要进入它的邻位或对位，而且第二个取代基的进入一般比没有这个取代基（即苯）时容易，或者说这个取代基使苯环活化。 ②特征：这类取代基中直接连于苯环上的原子多数具有未共用电子对，并不含有双键或三键。 ③定位取代效应按下列次序而渐减： -N（CH3）2，-NH2，-OH，-OCH3，-NHCOCH3，-R，（Cl，Br，I） 二甲氨基氨基羟基甲氧基乙酰氨基烷基卤素 2、间位定位取代基 ①定义：当苯环上己有在这类定位取代基时，再引入的其它基团主要进入它的间位，而且第二个取代基的进入比苯要难，或者说这个取代基使苯环钝化。 ②特征：取代基中直接与苯环相连的原子，有的带有正电荷，有的含有双键或三键。 ③定位效应按下列次序而渐减： -N+（CH3）3，-NO2，-CN，-SO3H，-CHO，-COOH 三甲铵基硝基氰基磺酸基醛基羧基 3、取代定位规律并不是绝对的。实际上在生成邻位及对位产物的同时，也有少量间位产物生成。在生成间位产物的同时，也有少量的邻位和对位产物生成。 4、苯环的取代定位规律的解释 当苯环上连有定位取代基时，苯环上电子云密度的分布就发生变化。这种影响可沿着苯环的共轭链传递。因此共轭链上就出现电子云密度较大和电子云密度较小的交替现象，从而使它表现出定位效应。 ①邻对位定位取代基的定位效应： 邻对位定位取代基除卤素外，其它的多是斥电子的基团，能使定位取代基的邻对位的碳原子的电子云密度增高，所以亲电试剂容易进攻这两个位置的碳原子。 卤素和苯环相连时，与苯酚羟基相似，也有方向相反的吸电子诱导和共轭两种效应。但在此情况下，诱导效应占优势，使苯环上电子云密度降低，苯环钝化，故亲电取代反应比苯难。但共轭使间位电子云密度降低的程度比邻对位更明显，所以取代反应主要在邻对位进行。
高中化学选修五重难点专题突破(第一章认识有机化合物)第一节
第一节有机化合物的分类 [学习目标定位] 1.能够根据不同的分类标准对简单的有机物进行分类。2.能记住常见的官能团。3.会说出简单有机物所属的类别及分子的结构特点。 一按碳的骨架对有机物进行分类 1．根据所学物质分类知识，回答下列问题。 有下列10种物质 ①CH3CH2CH3②CH2===CH2③ ④⑤CH3CH2CH2OH ⑥CH3CHO ⑦CuSO4·5H2O ⑧Fe ⑨CH3COOH ⑩CH3COONa (1)属于无机化合物的是⑦。 (2)属于有机化合物的是①②③④⑤⑥⑨⑩。 (3)属于烃的是①②③；属于烃的衍生物的是④⑤⑥⑨⑩。 (4)属于烷烃的是①，属于酸的是⑨。 2．如果对有机物按如下方式进行分类，请填空： (1)有机化合物按其组成元素不同，可分为烃和烃的衍生物。烃的组成元素有碳和氢，常见的烃的含氧衍生物的组成元素有碳、氢、氧。
(2)有机物按其碳的骨架不同，可分为链状化合物和环状化合物。分子结构中含有碳环的有机物称为环状化合物。 (3)环状化合物按其碳环不同，可分为脂环化合物和芳香化合物。分子结构中含有苯环的有机物叫做芳香化合物。 3．有下列四种有机物，分析比较它们的分子结构特点。 回答下列问题： (1)它们分子结构上的共同点是都含有苯环，有机物类别是芳香烃。 (2)与②相比较，③和④在分子结构上的共同点是都含有1个苯环，与①相比较，③和④在分子结构上的共同点是苯环上都连有烷烃基。 (3)苯的同系物是分子中含有一个苯环，苯环上的侧链全为烷烃基的芳香烃。 4．在下列六种有机物中，属于烃的是①③④⑤，烃的衍生物的是②⑥，链状烃的是④⑤，脂环化合物的是①⑥，芳香化合物的是②③，芳香烃的是③。 ①② ③④ ⑤⑥ [归纳总结]
苯环的成键特点与立体结构
苯环的成键特点与立体结构 凡是具有一个苯环或多个苯环的化合物都是芳香族化合物。要认识和研究芳香族化合物，就当从认识苯环的成键特点着手，进而了解其立体结构。 一、苯环的成键特点 1．苯环中C原子的sp2杂化情况 苯环中的任一个C原子，基态时的价层电子构型为2s22p2，杂化轨道理论认为，成键时C原子中的一个2s电子可以被激发到一个空的2p轨道上去，使基态的C原子转变为激发态的C原子（2s12p3 ）。同时，C原子的2s轨道与各填有一个电子的两个2p轨道发生sp2杂化，形成三个能量等同的sp2杂化轨道： ` 2．苯环中C原子之间、C原子与H原子之间的成键情况 苯环上的每个C原子都以sp2杂化方式分别与2个C原子形成C—Cσ键、与1个H原子形成C—Hσ键。由于C原子是sp2杂化，所以键角是120°，并且6个C原子和6个H 原子都在同一平面内(参见示意图1)。另外，苯环上6个碳原子各有1个未参加杂化的2p 轨道，它们垂直于环的平面(参见示意图2)，并从侧面相互重叠而形成一个闭合的π键，并且均匀地对称分布在环平面的上方和下方。通常把苯环的这种键型称为大π键(参见示意图3)。
二、苯环的立体结构 由于三个sp2杂化轨道都处在同一平面内，所以苯分子中的所有C原子和H原子必然都在同一平面内，每个碳碳键的键长相等，其数值介于C—C单键和C=C双键之间，键长都是0.140nm（C-H键的键长都是0.108nm），不存在单双键之分，六个C原子形成一个正六边 形，所有键角均为120o，这些都得到了现代物理方法 三、相关知识运用与拓展训练 [例1]有人提出，苯除了平面正六边形的分子结构外，还可能有两种具有三维空间的立体结 构的分子（Ⅰ）和（Ⅱ），如图所示。 请你根据现有的实验事实分析这两种结构是否合理? 若在结构（Ⅱ）分子中引入2个-X基团，可形成____种同分异构体。 [解析]
苯环上的定位基
一、定位基定位效应 苯环上已有的取代基叫做定位取代基。 1、邻对位定位取代基 ①概念：当苯环上已带有这类定位取代基时，再引入的其它基团主要进入它的邻位或对位，而且第二个取代基的进入一般比没有这个取代基(即苯)时容易，或者说这个取代基使苯环活化。 ②特征：这类取代基中直接连于苯环上的原子多数具有未共用电子对，并不含有双键或三键。 ③定位取代效应按下列次序而渐减： -N(CH3)2 , -NH2 , -OH , -OCH3 , -NHCOCH3 , -R , (Cl,Br,I) 二甲氨基氨基羟基甲氧基乙酰氨基烷基卤素 2、间位定位取代基 ①定义：当苯环上己有在这类定位取代基时，再引入的其它基团主要进入它的间位，而且第二个取代基的进入比苯要难，或者说这个取代基使苯环钝化。 ②特征：取代基中直接与苯环相连的原子，有的带有正电荷，有的含有双键或三键。 ③定位效应按下列次序而渐减： -N+(CH3)3 , -NO2 , -CN , -SO3H , -CHO , -COOH 三甲铵基硝基氰基磺酸基醛基羧基 3、取代定位规律并不是绝对的。实际上在生成邻位及对位产物的同时，也有少量间位产物生成。在生成间位产物的同时，也有少量的邻位和对位产物生成。 4、苯环的取代定位规律的解释 当苯环上连有定位取代基时，苯环上电子云密度的分布就发生变化。这种影响可沿着苯环的共轭链传递。因此共轭链上就出现电子云密度较大和电子云密度较小的交替现象，从而使它表现出定位效应。 ①邻对位定位取代基的定位效应： 邻对位定位取代基除卤素外，其它的多是斥电子的基团，能使定位取代基的邻对位的碳原子的电子云密度增高，所以亲电试剂容易进攻这两个位置的碳原子。 卤素和苯环相连时，与苯酚羟基相似，也有方向相反的吸电子诱导和共轭两种效应。但在此情况下，诱导效应占优势，使苯环上电子云密度降低，苯环钝化，故亲电取代反应比苯难。但共轭使间位电子云密度降低的程度比邻对位更明显，所以取代反应主要在邻对位进行。 ②间位定位基的定位效应： 这类定位取代基是吸电子的基团，使苯环上的电子云移向这些基团，因此苯环上的电子云密度降低。这样，对苯环起了钝化作用，所以较苯难于进行亲电取代反应。 ③共振理论对定位效应的解释 邻对位中间体均有一种稳定的共振式（邻对位定位基的影响）。 在间位定位基的影响下，在三个可能的碳正离子中间体中，邻对位共振式中正电荷是在连有吸电子基的碳上，它使碳正离子中间体更不稳定。所以间位碳正离子中间体是最有利的。 二、二取代苯的定位规律 如果苯环上已经有了两个取代基，当引入第三个取代基时，影响第三个取代基进入的位置的因素较多。定性地说，两个取代基对反应活性的影响有加和性。 1.苯环上已有两个邻对位定位取代基或两个间位定位取代基，当这两个定位取代基的定位方向有矛盾时，第三个取代基进入的位置，主要由定位作用较强的一个来决定。 2．苯环上己有一个邻对位定位取代基和一个间位定位取代基，且二者的定位方向相反，这时主要由邻对位定位取代基来决定第三个取代基进入的位置。 3．两个定位取代基在苯环的1位和3位时，由于空间位阻的关系，第三个取代基在2位发生取代反应的比例较小。 参考资料：有机化学高等教育出版社
有机化学第7、8章习题答案讲解
第7章芳烃及非苯芳烃 思考题答案 思考题7-1苯具有什么结构特征? 它与早期的有机化学理论有什么矛盾? 答案：苯分子具有高度的不饱和性，其碳氢比相当于同分子量的炔烃，根据早期的有机化学理论，它应具有容易发生加成反应、氧化反应等特性。 但事实上，苯是一种高度不饱和却具异常稳定性的化合物。因此，要能够很好地解释这一矛盾是当时有机化学家所面临的重大挑战。[知识点：苯 的结构特征] 思考题7-2早期的有机化学家对苯的芳香性认识与现代有机化学家对苯的芳香性认识有什么不同? 答案：早期的有机化学把那些高度不饱和的苯环类结构并具有芳香气味的化合物称为芳香化合物，这些化合物所具有的特性具称为芳香性。随着对事物认识的不断深入，人们已经意识到，除了苯环以外还有一些其他类型的分子结构也具有如苯一样的特别性质。现在仍然迫用芳香性概念，但其内涵已超出了原来的定义范围。现在对芳香性的定义为：化学结构上环状封闭的共轭大π键，不易被氧化，也不易发生加成反应，但是容易起亲电反应的性质。[知识点：苯的芳香性] 思考题7-3 关于苯分子的近代结构理论有哪些?其中,由Pauling提出的共振结构理论是如何解释苯分子结构? 答案：现代价键理论：苯分子中的六个碳原子都以sp2杂化轨道和相邻的碳和氢原子形成σ键，此sp2杂化轨道为平面其对称轴夹角为120°，此外每个碳原子还有一个和平面垂直的p轨道，六个p轨道相互平行重叠形成了一个闭合共轭体系。 分子轨道理论：基态时，苯分子的六个π电子都处在成建轨道上，具有闭壳层电子结构。离域的π电子使得所有的C-C键都相同，具有大π键的特殊性质因此相比孤立π键要稳定得多。 Pauling提出的共振结构理论：苯的每个1，3，5-环己三烯都是一种共振结构体，苯的真实结构是由这些共振结构式叠加而成的共振杂化体。【知识点：苯近代结构理论】 思考题7-4什么是休克尔规则? 如何利用休克尔规则判别有机分子的芳香性? 答案：休克尔规则：单环化合物具有同平面的连续离域体系，且其π电子数为4n+2,n为大于等于0的整数，就具有芳香性； 如果π电子数为芳香性，符合4n，为反芳香性，非平面的环状共轭烯烃 则为非芳香性。【知识点：休克尔规则】
《苯分子结构》教学设计
《苯分子结构》教学设计 一、教学内容及地位分析 本次课的教学内容为：高中化学必修2（人教版）第三章有机化合物，第二节来自石油和煤的两种基本化工原料，介绍的第二种有机物——苯。包括苯的结构、物理性质、化学性质和取代、加成反应，这节课主要介绍苯的分子结构及其物理、化学性质。下节课将介绍取代和加成反应。 苯是重要的化工原料，它是饱和烷烃、不饱和烯烃和炔烃等烃类物质性质的应用，也是新的一类烃——芳香烃的代表，它起到了一个承上启下的桥梁作用，使得烃的知识得到完善和升华，所以掌握苯分子的结构及其性质和反应是至关重要的。 二、课时数：一课时。 三、教学目标 1．知识与技能目标 ●记住苯分子的结构，能解释其结构形成的原因； ●了解芳香烃的概念；能动手制作一个苯分子的模型。 2．过程与方法目标 ●通过身边实际例子的展示，激发学习兴趣； ●通过实验探究及现象分析，尝试利用实验发现问题、探究问题和解决问 题的方法； ●通过倾听科学故事，了解科学探究的过程。 3.情感态度与价值观目标 ●由生活实例展开，激发好奇心和学习兴趣； ●通过实验探究，尝试勤于思考，勇于探索、实践的科学精神； ●以化学史为镜，感受科学家严谨治学、执着追求、勤奋钻研和开拓创新 的精神。
四、教学重点、难点 教学重点：苯的分子结构。 教学难点：苯的分子结构与其化学性质的关系。 五、学情与学法分析 本节课的教学对象是普通高二学生，他们已经具备了一定的化学基础知识，在对前面学习的饱和烷烃、不饱和烯烃和炔烃，有了一定的认识和了解之后，已经形成了一套系统地学习有机物的知识体系，为这节课的学习做好了铺垫，通过这节课苯分子结构的学习，又为接下来学习取代、加成反应和芳香烃打下了基础。但苯分子的结构毕竟和前面学习的烃类物质不同，有一个非常明显的反差，所以为了让学生从另一个角度来认识苯，本节课设计了以实验探究为主的教学，引导学生积极思考，并动手验证，得出结论，从而加深认识，降低学习难度。 六、设计理念 本节课通过药品展示和学生实验，使学生对苯的物理性质有直观的印象。在已有知识的基础之上让学生初步推测苯的可能结构，这样既复习了旧知识，又对新知识进行了探索。在初步推测出苯的可能结构之后，学生通过实验进一步验证结构是否正确，这样既提高了动手能力，有学到了新知识，从而突破难点。在探索出苯的分子结构之后，再由学生总结归纳出苯分子的结构特点，从而使学生对苯分子结构的真正理解和苯化学性质的学习打下了坚实的基础，并培养了科学的探索精神。 七、教学准备 教师准备：苯、蒸馏水、试管、冰、溴水、酸性高锰酸钾溶液、教具、教学媒体设备、教案。 学生准备：纸、笔；复习烃类的性质、预习苯的结构及结构解释的问题。 八、教学流程图
苯_苯环
【中文名称】苯（běn） 【英文名称】benzene;benzol(e)【相对分子量或原子量】78.11 【密度】0.879 【熔点（℃）】5.5 【沸点（℃）】80.1【性状】 无色易挥发和易燃液体，有芳香气味，有毒。 【溶解情况】 不溶于水，溶于乙醇、乙醚等许多有机溶剂。 【用途】 是染料、塑料、合成橡胶、合成树脂、合成纤维、合成药物和农药等的重要原料，也是涂料、橡胶、胶水等的溶剂，也可以作为燃料。 【制备或来源】 工业上由焦煤气（煤气）和煤焦油的轻油部分提取和分馏而得。也可由环己烷脱氢或甲苯歧化或与二甲苯加氢脱甲基和蒸气脱甲基制取。 【其他】 闪点10～12℃。蒸气与空气形成爆炸混合物，爆炸极限1.5%～8.0%（体积） 最简单的芳烃。分子式C6H6。为有机化学工业的基本原料之一。无色、易燃、有特殊气味的液体。熔点5.5℃，沸点80.1℃，相对密度0.8765（20／4℃）。在水中的溶解度很小，能与乙醇、乙醚、二硫化碳等有机溶剂混溶。能与水生成恒沸混合物，沸点为69.25℃，含苯91.2％。因此，在有水生成的反应中常加苯蒸馏，以将水带出。苯在燃烧时产生浓烟。 苯能够起取代反应、加成反应和氧化反应。苯用硝酸和硫酸的混合物硝化，生成硝基苯，硝基苯还原生成重要的染料中间体苯胺；苯用硫酸磺化，生成苯磺酸，可用来合成苯酚；苯在三氯化铁存在下与氯作用，生成氯苯，它是重要的中间体；苯在无水三氯化铝等催化剂存在下与乙烯、丙烯或长链烯烃作用生成乙苯、异丙苯或烷基苯，乙苯是合成苯乙烯的原料，异丙苯是合成苯酚和丙酮的原料，烷基苯是合成去污剂的原料。苯催化加氢生成环己烷，它是合成耐纶的原料；苯在光照下加三分子氯，可得杀虫剂666，由于对人畜有毒，已禁止生产使用。苯难于氧化，但在450℃和氧化钒存在下可氧化成顺丁烯二酸酐，后者是合成不饱和聚酯树脂的原料。苯是橡胶、脂肪和许多树脂的良好溶剂，但由于毒性大，已逐渐被其他溶剂所取代。苯可加在汽油中以提高其抗爆性能。苯在工业上由炼制石油所产生的石脑油馏分经催化重整制得，或从炼焦所得焦炉气中回收。苯蒸气有毒，急性中毒在严重情况下能引起抽筋，甚至失去知觉；慢性中毒能损害造血功能。 1865年，F.A.凯库勒提出了苯的环状结构式，目前仍在采用。根据量子化学的描述，苯分子中的6个π电子作为一个整体，分布在环平面的上方和下方，因此，近年来也用图1b式表示苯的结构。 苯是一种无色、具有特殊芳香气味的液体，能与醇、醚、丙酮和四氯化碳互溶，微溶于水。苯具有易挥发、易燃的特点，其蒸气有爆炸性。经常接触苯，皮肤可因脱脂而变干燥，脱屑，有的出现过敏性湿疹。长期吸入苯能导致再生障碍性贫血。 苯分子具有平面的正六边形结构。各个键角都是120°，六角环上碳碳之间的键长都是1.40×10 -10 米。它既不同于一般的单键(C—C键键长是 1.54×10 -10 米)，也不同于一般的双键(C=C键键长是1.33×10 -10 米)。从苯跟高锰酸钾溶液和溴水都不起反应这一事实和测定的碳碳间键长的实验数据来看，充分说明苯环上碳碳间的键应是一种介于单键和双键之间的独特的键。 为了表示苯分子结构的这一特点，常用下式来表示苯的结构简式。直到现在，凯库勒式的表示方法仍被沿用，但在理解上绝不应认为苯是单、双键交替组成的环状结构。 苯分子里6个碳原子的电子都以sp 2 杂化轨道相互重叠，形成6个碳碳的σ键，又各以1个sp 2 杂化轨道分别跟氢原子的1s轨道进行重叠，形成6个碳氢的σ键。
苯环的定位规则概要
苯环的定位规则 学习目标 掌握亲电取代反应的定位规则 了解定位规则的应用 一、苯环的定位规则 一元取代苯再进行取代反应时，新引进的基团在理论上讲应该进入原有基团的邻位、间位和对位，应该有3种不同的异构体。但实际情况并不是这样。例如硝化反应： CH 3 HNO 3 （浓） ? +NO 2 CH 3 + 浓H 2SO 4 20℃～30℃ CH 3 NO 2 + CH 3 NO 2 62% 33% 5% NO 2 HNO 3(发烟) +NO 2 NO 2 + 浓H 2SO 4 NO 2 2 NO 2 NO 2 + 6% 1% 93% 可以看出，甲苯的硝化主要生成邻对位产物，而且反应比较容易进行；硝基苯硝化主要生成间位产物，而且反应比较难以进行。由此可见，第二个取代基进入的位置是受苯环上原有基团的影响，这种现象称为定位效应。苯环上原有基团称为定位基。人们根据大量实验事实，总结归纳出下面的定位规律。 1、第二个取代基在苯环上取代的位置由苯环上原有基团的性质决定，与第二个取代基的性质无关。 2、定位基分为两类： 邻对位定位基，这一类基团大部分使苯环活化，致使苯环取代反应容易进行， HNO 3 （浓） ?+ 浓H SO 55℃～60℃ NO 2 + H 2O 硝基苯
故又称致活基团；能支配第二个取代基在苯环上主要取代在它的邻位和对位。常见的邻对位定位基按定位效应强弱次序排列如下： 一NR 2、一NHR 、一NH 2、一OH 、一OR 、一NHCOR 、一R 、一X 间位定位基，这一类基团大部分使苯环钝化，致使苯环取代反应较难进行，故又称致钝基团；能支配第二个取代基在苯环上主要取代在它的间位。常见的间位定位基按定位效应强弱次序排列如下： 3、在苯环上有两个取代基，欲引入第三个取代基时，第三个取代基所进入的位置，取决于苯环上原有两个基团的综合效应。 当苯环上原有两个定位基的定位作用一致时，第三个取代基进入的位置由原有两个取代基共同决定。例如： 3 H 2 3 2 当苯环上原有两个定位基的定位作用不一致时，有两种情况：一是两个定位基为同一类时，则第三个取代基进入的位置由定位效应强的取代基决定。例如： 二是苯环上有两个不同类定位基时，第三个取代基进入的位置则由原取代基中是邻对位定位基所决定。例如： 二、定位效应的解释 苯环是一个电子云分布均匀的闭合体系，当苯环上有一个取代基时，取代基能使苯环上的电子云分布发生改变。定位基对苯环的影响是通过电子效应(包括诱导效应和共轭效应)及立体效应来实现的。现以几个典型的定位基为例做具体的 一NR 3、一NO 2、一CN 、一SO 3H 、一CHO 、一 COR 、一COOH(R) + 2 3 3 2