Bpo c Chapter 16

7/29/2019 Bpo c Chapter 16

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CARBONYL COMPOUNDSALDEHYDES AND KETONES.ON REACTO F THE CARBONYL GROUP

\he carbonyl group, C=O is a structural feature of many different types/of co mp ounds. I t is pre sen t in carbon dioxide and in m ethanal, which represen trespectively the high and low extrem es in the level of oxidation of a carbon ylcarbon:

carbon dioxid e methanal

In between, there ar e carbonyl compounds ranging from aldehydes and ketonesto carboxylic acids and their derivatives (esters, amides, anhydrides, and acyl


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672 16 Carbonyl Compounds I . Aldehydes and Ketones. Addit ion React ions of the Carbonyl Grouphalides). Th e naming of these com pounds is described in Sections 7-4 to 7-7.R R R R\ \ \ \/"="H /"="R /"="H O /"="R Oaldehyd e ketone carboxy l ic acid carboxyl ic ester

R

carboxyl ic X = F, CI, Br, I amideanhydride acyl hal ide

A t the upp er end of the oxidation scale, along with CO ,, are the carbon icacid derivatives such as carbonic esters, amides, halides, and carbonate salts,and isocyanates:

carbonic ester carbonate bicarbonate carbonyl chlo ride(phosgene)

carbonyl carb am ic ester isocyanatediamide (urea)

In this and succeeding cha pters w e describe the chemistry of these com poundswith the intent of emphasizing the similarities that exist between them. Thedifferences turn o ut to be m ore in degree than in kind. Eve n so, it is convenientto discuss aldehyde s an d ketone s separately from carboxylic acids and , follow-ing som e general observations ab out the carbonyl group, this ch apter m ainly isconcerned with aldehydes and ketones.Apart from CO, and metal carbonates, the most abundant carbonylcompounds of natural origin are carboxylic esters and amides. Th es e occuras fa ts an d lipids, which ar e ester s of long-chain alkanoic acids (p p. 789-791),and as proteins, which a re polyamides of natural am ino acids. Th e sa m e struc-


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16-1A The Carbonyl Bond Compared with Carbon-Carbon Dou ble Bondstural features are found in certain synthetic polymers, in particular the poly-este rs (e.g., D acro n) an d the polyamides (e.g., nylon 6):

Dacron (polyester)

nylon 6 (polyamide)l

Co mp ared to carboxylic and carbonic acid derivatives, the less highlyoxidized carbony l com pounds such a s aldehydes and ketones a re not so wide-spread in nature. Tha t is not to say that they ar e unimportant. To the contrary.Aldehydes and ketones are of great importance both in biological chemistryand in synthetic organic chemistry. However, the high reactivity of the car-bony1 group in the se co mpou nds enables them to function more as intermedi-ates in metabolism or in synthesis than a s end products. This fact will becomeevident as we discuss the chemistry of aldehydes and ketones. Especiallyimportant are the addition reactions of carbonyl groups, and this chapter ismostly concerned with this kind of reaction of aldehydes and ketones.

16-1 THE CARBONYL BOND16-1A Com parison with Carbon-Carbon Dou ble BondsT h e carbonyl bond is both a strong bond and a reactive bond. T h e bond energyvaries widely with structure, as we can see from the carbonyl bond energiesin Tab le 16-1. M ethanal has the w eakest bond (166 kcal) and carbon monoxidethe strongest (257.3 kcal). Irrespec tive of these variations, the carbonyl bondnot only is significantly stronger but also is more react ive than a carbon-carbon double bond. A typical difference in stability and-reactivity is seen inhydration:


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674 16 Carbonyl C om poun ds I. Aldeh ydes and Ketones. Add it ion Re actions of the Carbonyl G roupTable 16-1Carbonyl Bond Energies

CompoundsBond energy(kcal m ole- ')

0 0:o=c++Oc 257.3O=C=O 192.0"H2C=0 166.0H2C=C=0 184.8RCH=O (aldehy des) 176R2C =0 (ketones) 179\ /C=C (a1 kenes) 14 6/ \

"Average of AH0 or break ing both of the C=O bonds.

T he equilibr ium constan t for ethene hydration is considerably greater than formethanal hydration, largely because the carbon-carbon doub le bond is weaker.Even so, methanal adds water rapidly and reversibly at room temperaturewithout need for a catalyst. The corresponding addition of water to etheneoccurs only in the pre senc e of strongly acidic catalysts (Section 10-3E, Tab le15-2).

16-1B Structure and ReactivityT h e reactivity of the carbonyl bo nd is primarily due to the difference in elec-tronegativity between carb on and ox ygen, which leads to a considerable con-tribution of the dipolar resonance form with oxygen negative and carbonpositive:

In terms of an atomic-orbital description, the carbonyl bond can berepresented as sho wn in Fig ure 16-1. T h e carbon is sp2-hybridized so that itscr bond s (one of which is to oxygen) lie in on e plane. Th e remaining p orbitalon carbon is utilized to form a 7~ bond to oxygen. T h e polarity of th e carbon-


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16-1B Structure and Reactivity

Figure 16-1 Atomic-orbital description of the carbonyl group. The CTbonds to carbon are coplanar, at angles near to 120"; the two pairs ofunshared electrons on oxygen are shown as occupying orbitals n .

oxygen double bond implies that the electrons of the 71- bond (and also the crbond) are associated more with oxygen than with carbon. This is supportedby the d ipole moments1 of aldehydes an d ketones, w hich indicate the degreeof the polarization of the C=O bon ds; the dipole mom ents ar e in the neigh-borhood of 2.7 D, which corresponds to 40-50% ionic cha racter for the car-bony1 bond .

Exercise 16-1 Draw valence-bon d structures an d an atom ic-orbital mod el for carbonmo noxide. Why c an the bon d energy of this m olecule be expe cted to b e higher thanfor other carbonyl compounds (see Table 16-I)? Explain why the dipole moment ofCO is very sm all (0.13 deby e)..

lAn electrical dipole results when unlike charges are separated. The magnitude of thedipole, its dipole moment, is given by e x r, where e is the magnitude of the charges andr is the distance the charges are separated. Molecular dipole moments are measured in

0 0debye units (D). A pair of ions, C and 0 , as point charges at the C= O distance of1.22 A, would have a dipole moment of 5.9 D. Thus, if the dipole moment of a carbonylcompound is 2.7 D , we can estimate the "% ionic character" of the bond to be (2.715.9)x 100= 46%. The analysis is oversimplified in that the charges on the atom are notpoint charges and we have assumed that all of the ionic character of the molecule isassociated with the C= O bond. One should be cautious in interpreting dipole momentsin terms of the ionic character of bonds. Carbon dioxide has no dipole moment, butcertainly has polar C= O bonds. The problem is that the dipoles associated with theC=O bonds of CO, are equal and opposite in direction to each other and, as a result,

60 260 6 0cancel. Thus, 0-C-0 has no net dipole moment, even though it has highly po-lar bonds.


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676 16 Carbonyl Compou nds I. Aldehydes and K etones. Add it ion Rea ctions of the Carbonyl Group

Exercise 16-2 W hich of the fol lowing com poun ds wou ld you expe ct to have zero ornearly zero dipole moments? Give your reasoning and don't forget possible con-formational equ il ibria. (Mod els wil l be helpful.)

T he polarity of the carbon yl bond facilitates addition of wa ter and oth erpolar reagen ts relative to addition of th e sam e reagents to alke ne double bonds.This we have seen previously in the addition of organometallic compounds60 60 60 60R-MgX and R-Li to carbonyl com pound s (Section 14-12A). Alk ene doublebonds are normally untouched by these reagents:

Likewise, alcohols add readily to carbonyl compounds, as described in Sec-tion 15-4E. However, we must keep in mind the possibility that, whereasadditions to carbonyl groups may be rapid, the equilibrium constants may besmall because of the strength of the carbonyl bond.

Exercise 16-3 The foregoing discussion exp licit ly refers to addit ion of polar reagentsto carbony l groups. Therefore an ionic mechanism is implied . Con sider whether thesame reac t ivity dif ferences wo uld be expec ted for ethene and methanal in the radical-chain addit ion of hydrogen bromide to methanal and ethene init iated by peroxides.What about the relat ive equ il ibrium constants? Show your reasoning. (Review Section10-7.)H2C=0 + HBr- rCH2-OHH2C=CH2 + HBr- rCH2-CH,


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16-1C Further Considerations of Reactivity 67716-1C Further Considerations of ReactivityT h e impo rtant reactions of carbony l groups c haracteristically involve additionat one step or another. For the reactions of organometallic reagents and al-cohols with carbonyl compounds (Chapters 14 and 15), you may recall thatsteric hindrance plays a n imp ortant role in determining the ratio between addi-tion and othe r, competing reactions. Similar effects are ob served in a widevariety of other reactions. We expect the reactivity of carbonyl groups inaddition processes to be influenced by the size of the substituents thereon,because when addition occurs the substituent groups are pushed back closerto one another. In fact, reactivity and equilibrium constant decrease withincreasing bulkiness of substituents, as in the following series (also see Table15-3):

Strain effects also contribute to reactivity of cyclic carbonyl com pound s.The normal bond angles around a carbonyl group are about 120":

Consequently if the carbonyl group is on a small carbocyclic ring, there willbe substantial angle strain and this will amount to about 120"- 0" = 60" ofstrain for cyclopropanone,

and 120" - 90" = 30" of strain for cyclobutanone (both values being for theL C-C-C at the carbonyl group). Add ition of a nucleophile such as CH ,O H(cf. Section 15-4E) to thes e carbonyl b onds c reates a tetrahedral center withless strain in the ring bonds to C 1:


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678 16 Carbonyl Co mp oun ds I . Aldehydes and Ketones. Add i t ion Re act ions of the Carbonyl GroupThus the hemiketal from cyclopropanone will have 109.5"- 0"= 49.5", an dthat from cyclobutanone 109.5"- 0"= 19.5" of strain at C 1. Th is c hang e inthe angle strain means that a sizable enhancement of both the reactivity andequilibrium co nstan t for add ition is expected. In practice, the strain effect isso large that cyclopropanone reacts rapidly with methanol to give a stablehemiketal from which the ketone cannot be recovered. Cyclobutanone is lessreactive than cyclopropanone but more reactive than cyclohexanone orcyclopentanone.Electrical effects also a re im portan t in influencing the ea se of addition tocarbonyl groups. Electron-attracting groups facilitate the addition of nucleo-philic reagents to carbon by increasing its positive character:6 0 x

\ 36@ 60 (X. Y. and 0 epresent atoms that areelectronegative relat ive to carbon in ahydrocarbon, Sect ion 10-4B)

T h us com pound s such a s the following add nucleophilic reagents readily:

t r ichloroethanal (chloral) oxopropanedioic ac id(oxomalonic acid)

Exercise 16-4 Which compound in each of the fol lowing pairs would you expectto be more react ive toward addit ion of a common nucleophil ic agent such as hy-droxide ion to the carbo nyl bon d? Indicate your reasoning.a. 2-propanone and 1 I I-tr ichloro-2-propanoneb. 2,2-dimethylpropanal and 2-propanonec. methyl 2-oxopropanoate and methyl 3-oxobutanoated. 2-propanone and 2,3-butanedionee. 2-oxopropaneni tr ile an d 2-propanonef. ketene (CH,=C=O) and cyclobutanoneg. bicyc lo [2 .1 . I1-5-hexanone and cy clobutanon e

16-2 PHYSICAL PROPERTIESThe polarity of the carbonyl group is manifest in the physical properties ofcarbonyl comp ounds. Boiling points for the lower mem bers of a series of alde-hydes and ketones ar e 50-80" higher than for hydrocarbons of the same mo-lecular weight; this m ay be seen by com paring the d ata of Ta ble 16-2 (physical


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16-2 Physical Properties 679Table 16-2Physical Properties of Aldehydes and Ketones

d;, Solubil i tyMp , "C BP, "C g ml-' in watepompound Formula

methanalethanalpropanal2-propenal2-butenalbutanal2-methyl propanalbenzenecarbaldehyde(benzaldehyde)2-propanone2-butanone3- buten-2-one

+++++sl.+v. sl.

cyclobutanone

cyclopentanone

cyclohexanone

4-methyl-3-penten-2-onephenylethanone(acetophenone)2,3-butanedione2,bpentaned ione

"A plus sign means the compound is soluble; however, i t may not be soluble in al l proportion s-sl meansslightly soluble.

properties of aldehydes and ketones) with those in Table 4-1 (physical proper-ties of alkanes).

The water solubility of the lower-molecular-weight aldehydes and ke-tones is pronounced (see Table 16-2). This is to be expected for most carbonylcompounds of low molecular weight and is the consequence of hydrogen-bonding between the water and the electronegative oxygen of the carbonylgroup:\so .soC=o. solvation of carbonyl compounds/ *'\, through hydrogen bonding


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680 16 Carbonyl C om pou nds I. Aldehydes and Ketones. Add it ion R eactions of the Carbon yl GroupTable 16-3Characterist ic Infrared Absorpt ion Frequencies of Carbonyl Compoundsa

Frequency FrequencyFunctional gro up (C=O stretch), cm-' Functional gro up (CEO stretch), cm-'amides

0iiR-C- NH2ketones

0IR-C-R'

a ldehydes0IR-C-H

carboxylic esters0IR-C-OR'

carboxylic acid s 17100I1R-C-OH

acyl hal ides0IR-C-X

carboxyl ic anhydrides

"The quoted frequen cies are for typical o pen-chain saturated hydrocarbon cha ins (R). Conjuga-tion and cyclic structures wil l influence the absorption frequency.

16-3 SPECTROSCOPIC PROPERTIES16-3A l nf rared SpectraA carbonyl group in a compound can be positively identified by the stronginfrared absorption band in the region 1650-1850 cm-l, which correspondsto the stretching vibration of the carbon-oxygen double bond. T h e positionof the band within this frequency range depends on the molecular environ-men t of the carbo nyl group. A s a result , we frequently can tell from the bandposition whether the structure is an aldehyde, ketone, carboxylic acid, ester,amide, or anhyd ride. Th e dat a of Table 16-3 show typical infrared absorption


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16-3 Spectroscopic Propert ies 689frequencies for specific types of carbonyl compounds. Thus aldehydes andketones absorb at slightly lower frequencies (longer wavelengths) than car-boxylic esters and anhydrides-. We usually find that absorption shifts to lowerfrequencies (-20 cm-l) when the carbonyl group is conjugated with othermultiple bon ds, a s in arom atic ketones, C,H,COCH,.Aldehydes can be distinguished from ketones by a band at 2720 cm-lwhich is characteristic of the C-H stretching vibration of an aldehydefunction: r

-C c2720 cm-I (medium to weak intensi ty)\)-IThis band is unusually low in frequency for a C-H stretching vibration;although the band is rather weak, it occurs in a region of the spectrum whereother absorptions generally are absent so it can be identified with no specialdifficulty.

Exercise 16-5 Use the infrared spectra given in Figure 16-2 (pp. 682-683) and thedata of Tables 9-2 an d 16-3 to ded uce the type of carbonyl com pound giv ing r ise toeach spectrum.

16-38 Electronic Absorpt ion SpectraAldehy des and ke tones abs orb ultraviolet light in the region 275-295 nm, andthe result is excitation of an unshared electron on oxygen to a higher energylevel. Th is is the n -+ n* transition discussed in Se ction 9-9. A more intensen -+ n* transition occurs about 180-190 nm, which corresponds to excita-tion of a n electro n from a n--bonding orbital to a n-antibonding orbital. Neith erof these absorptions is especially useful for specific identification unless thecarbon yl group is conjugated, in w hich case th e n -+ n * and n -+ -* bandsocc ur at longer wavelengths (by 30-40 nm). F o r example, if you suspect thata compound is an allcenone from its infrared spectrum, you easily could tellfrom the A of the n --+ -* and n-- * absorptions of the compoundwhether it is a conjugated alkenone. The absorption frequency would be ex-pected around 320 nm and 220 nm (see Figure 9-20).


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16 Carbonyl Co mp oun ds I. Aldehydes and Ketones. Ad di t ion R eact ions of the Carbony l Group

frequency, cm- '

Figure 16-2 Infrared spectra for Exercise 16-5


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16-3 Spectroscopic Propert ies

3000 2000 1600 1200 800f requency , cm - I


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684 16 Carbonyl Com pounds I . Aldehydes and Ketones. Add it ion Re act ions of the Carbonyl G roup16-3C Mass SpectraAldehydes and ketones generally give moderately intense signals due to theirmolecular ions, M +. Thus the determination of the molecular weight of a ke-tone by mass spectrosc opy usually is not difficult . Furthe rmo re, there are som echaracteristic fragmentation patterns that aid in structural identification.These a re :a c l e a v a g e

t rans fe r o f y h y d r o g e n with ,G cleavage (McT,afferty rearran gem ent)

Exercise 16-6 A hydrocarbon isolated from a plant extract was treated with ozone,and the ozonide decomposed with z inc to g ive two ketones, A and B, which werereadily separated by gas chromatography. Ketone A gave a m ass spectrum ident icalwith that of Figure 9-52c w hile ketone B gave m ass spectral peaks at m le = 100 (M+ ) ,85, 58, and 43. With this information, suggest possible structures for these ions andthe parent hydro carbon . Give your reasoning.

16-3D NMR SpectraThe character of the carbonyl bond gives r ise to very low-field nmr absorp-tions for the proton of an aldehyde group (-CH =O ). A s Table 9-4 (pp. 308-309) shows, these absorptions a re som e 4 ppm to lower fields than alkenyl hy-

/drogens (-- C H= ). So m e of this difference in shift ca n be ascribed to the\ s@ sopolarity of the carbonyl group C = O , which reduces electron density aroun dthe aldehyde hydrogen (see Section 9-10E). T he effect appears to carry overin much smaller degree to hyd rogens in the a positions, and protons of the typ e

I /CH 3-A=O ar e abou t 0.3 ppm to lower f ields than those of C H 3- C =C .\


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16-4 Some Typical Carbonyl-Addit ion React ions 685

Exercise 16-7 Show how structures can be deduced for the four substances withthe infrared and nmr sp ectra shown in Figure 16-3 (pp . 686-687).Exercise 16-8 Assuming that you had ready acc ess to ultraviolet, infrared, nmr, andmass spectrometers, which spectral technique would you select to differentiate asunambiguously as possible between the following pairs of compounds? Give yourreasoning in enough detail to show that you understand how well each technique iscap ab le of distinguishing between the mem bers of each pair. (D = hydrogen ofmass 2)a. 2-butanone an d 2-butanone-1 D,b. 3-cyclohexenone and 2-cyclohexenonec. 4-penten-2-one and 4,4-dichloro-1 -pentened. propanal and 2-butanonee. 3-hexanone-6-D, an d 3-hexanone-1 -D,

SOME TYPICAL CARBONYL-ADDITION REACTIONSW e turn now to discuss a few specific addition reactions of the carbonylgroups of aldehydes and ketones. W e shall not a ttem pt to provide an extensivecatalog of reactions, but will try to emphasize the principles involved withespecially important reactions that are useful in synthesis.Grignard reagents, organolithium comp ounds, and the like generallyadd to aldehydes and ketones rapidly and irreversibly, but the same is not trueof many other reagents; their addition reactions may require acidic or basiccatalysts; the ad du cts may be formed reversibly a nd with relatively unfavorableequilibrium constants. Also, the initial adducts may be unstable and reactfurther by elimination. (We recommend that you work Exercise 16-9 to seeexam ples of these points, or review Section 15-4E.) T o organize this very largenum ber of addition reactions, w e have arranged the reactions according to then~lcle oph ile hat adds to th e carbonyl carbon. Th e types of nucleophiles con-sidered here form C-C, C - 0 , C-N , C-halogen, C-S, and C-H bonds. Asum m ary is given in Tab le 16-4 (pp. 688-689).

Exercise 16-9 Write equations to show the steps inv olved in the following carbon yl-add it ion reactions: (a) b ase-cata lyzed add it ion of ethanol to ethanal to form the cor-resp ond ing hem iace tal, 1-ethoxyethanol; (b) formation of 1-ethoxyethano l from ethanoland ethanal, but under cond it ions of ac id catalys is; (c) formation of 1 l-diethox yethan efrom I-ethoxyetha nol and ethanol with an ac id c atalyst; and (d) formation of diethylca rbo na te (CH,CH,O),C=O from ethanol an d ca rbo ny l di ch lo rid e.


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688 16 Carbonyl Compounds I. Aldehydes and Ketones. Addition Reactions of the Carbonyl GroupTable 16-4Addit ion Reactions of Aldehydes and Ketones

AdductReagent \(to C=O)(Nu-E) / Conditions Comments

NC-H INC-C-OH basic catalystsI

ether solvent,no catalystneeded

0 0 / strongly basicCH2-PR, CH2=C + R3P0 medium\0 0 ,O strongly basicCH2-SR, Ck y + R2S mediumC-I

I acidic or basicRO-H RO-C-OHI catalysts1 acidic catalystsRO-H RO-C-ORI

RNH, RN=C \(imine)

synthesis of cyanoalkenes,carboxylic acids, Section16-4A

synthesis of alcohols,Section 14-12A

synthesis of hydroxy-ketones, hydroxyaldehydes,and their dehydrationproducts (see Section17-3)synthesis of alkenes,Section 16-4Aoxacyclopropane synthesis,Section 16-4A

oxacyclopropanes,Section 16-4A

ketones,Section 16-4A

Section 15-4E

useful to protect carbonyland alcohol functions (seeSections 16-8 and 15-9)

purification, Section16-4B

acidic catalysts Section 16-4C, Table 16-5


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16-4A Addit ion of Carbon Nu cleophi lesTable 16-4 (continued)Add i t ion R eact ions of Aldeh ydes an d Ketones

AdductReagent \(to C=O)(Nu-E) / Conditions Comments

R2NH R,N-C= ac id ic catalys ts Section 16-4C(enamine)

ICI-H, RO H CI-C-OR ac id ic catalys ts Section 16-4D, synthesisI of a-h alo etherso l oH-AIH,, ~ i @ H-C-OAIH, + ~ i @ e th er s olu tio n S ec tio n 16-4E ,I synthesis of alcoholso l oH-BH,, Na@ H-C-OBH, + Na@ alco hols or aqueous Section 16-4E.1 solutions synthesis of alcoh ols

IH-CR,OH H-C-OH strong ly ba sic catalys ts Sec tion 16-4E,I or H-CR,-0-AI / synthesis of alcohols\

16-44 Addit ion of Carbon Nucleophi lesCyanohydrin FormationHydrogen cyanide adds to many aldehydes and ketones to give hydroxyni-triles ,usually called "cyanohydrins" :

11 base ICH3-C-CH3 + HCN C H 3 C - C H 3The products are useful in synthesis-for example, in the preparation ofcyanoalkenes and hydroxy acids:

2-hyd roxy-2-methyl-propanoic ac id(acetone cyanohydrin)


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690 16 Carbonyl Com pounds I. Aldehydes and Ketones. Add i t ion React ions of the Ca rbonyl GroupA n im portant feature of cyanohydrin formation is that it requires a basiccatalyst. In the absence of base, the reaction does not proceed, or is at bestvery slow. In principle, the basic catalyst may activate either the carbonylgroup or hydrogen cyanide. With hydroxide ion as the base, one reaction tobe expected is a reversible addition of hydroxide to the carbonyl group:

C H ,\SO&$@ CH:, O@\ /C = O +@OH/uC H , C H , O H1However, such addition is not likely to facilitate formation of cyanohydrinbecause it represents a competit ive saturation of the carbonyl double bond.Indeed, if the equilibrium constant for this addition were large, an excess ofhydroxide ion could inhibit cyanohydrin formation by tying up the ke tone a sthe adduct 1.Hydrogen cyanide itself has no unshared electron pair on carbon anddoes not form a carbon-carbon bond to a carbonyl carbon. How ever, a smallamount of a strong base can activate hydrogen cyanide by converting it tocyanide ion, which c an function a s a carbon nucleophile. A comp lete sequencefor c yanohydrin formation follows:

+ H C N + : C = N :/ \C H , C = NThe second step regenerates the cyanide ion. Each step of the reaction is re-versible but, with aldehydes and most nonhindered ketones, formation of thecyanohydrin is reasonably favorable. In practical syntheses of cyanohydrins,it is conv enient to ad d a strong acid to a mixture of sodium cyanide and thecarbonyl compou nd, so that hydrogen cyanide is generated in situ. Th e amo u ntof acid added should be insufficient to consum e all the cya nide ion, therefor esufficiently alkaline cond itions a re maintained for rapid addition.

Exercise 16-10 One possible way of carrying out the cyanohydrin react ion wouldbe to dispense with hydrogen cyanide and just use the carbonyl compound andsodium cyanide. Wou ld the equi l ibr ium constant for cyanohydrin formation be more


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16-4A Addi t ion of Carbon N ucleophi les 691favorable, or less favorable, with 2-propanone and sodium cyanide in water com paredto 2-propanon e and hydrogen cyanide in water? Give your reasoning.Exercise 16-11 What sh ould be the equation for the rate of formation of 2-propanonecyanoh ydrin by the mec hanism given above, (a) if the first step is slow and the secondfast? (b) If the sec ond step is slow a nd the first fast? (Review Sections 4-4C and 8-4A.)Exercise 16-12 Explain what factors would operate to make the equil ibrium con-stant for cyanohydrin formation 1000 t imes greater for cyclohexa none than for cyclo -pentanone. Why? What would you expect for cyclobutanone relative to cyclopenta-none? Why?

Addition of Organometall ic Reagents (See Section 14-12A.)Addition of Enolate Anions (See Section 17-3.)Addition of Ylide ReagentsThere are a number of rather interest ing substances for which we can write

0 @important dipolar valence-bond struc tures of the typ e- X .Th e importantIfacto r with these structures is that the negative e nd of the dipole is car bon witha n unsha red electron pair. T he posit ive e nd of the dipole can be several kindsof atom s or grou ps, the mo st usual being sulfur, phosph orus, o r nitrogen. Som eexamples (each written here as a single dipolar valence-bond structure) are:

cyc lopropy l idene- methyl idenetr iphenylphosphorane diazomethanediphenylsulfurane (a phosphorus yl ide) (a nitrogen yl ide)(a sulfur ylide)

The systematic naming of these substances is cumbersome, but theyhave come to be known a s ylides. T h e genesis of this name may seem obscure,but it is an attempt to reconcile the presence of a C-X cr bond, which is co-valent and nonpolar as in alkyl derivatives, as well as an ionic bond as inmeta l ha lides . Henc e , the combination ~ l - i d e . ~2Pronounced variously as illlid, yilllid, illlide, yilllide. The dipolar structures usuallywritten for ylides are an oversimplified representation of the bonding in these sub-stances, as you will see if you work Exercise 16-15.


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(692 16 Carbony l Compound s I. Aldehydes and Ketones. Addit ion React ions of the Carbonyl GroupA s w e m ight exp ect from the dipolar s tructure, yl ides can behave a scarbon nucleophiles to form carbon-carbon bonds by addit ion to the carbonylgroups of aldehydes and k etones:

However, the further course of reaction depends on the type of yl ide used.In the case of phosphorus ylides, the overall reaction amounts to a very use-fu l synthesis of alkenes by the transfer of oxygen to phosphorus an d carbon tocarbon, as sum ma rized in Eq uation 16- 1. Th is is called the Wittig reaction:

Reactions with sulfur ylides proceed differently. The products are oxacyclo-propanes (oxiranes)- ot alkenes. The addition step proceeds as with thephosphorus ylides, but the negatively charged oxygen of the dipolar adductthen displaces the sulfonium group as a neutral sulfide. This is an intramolecu-lar S,2 reaction similar to the formation of oxacyclopropanes from vicinalchloroalcohols (Section 15-1 1C):

OSR, 0 SR,As for the nitrogen ylides, a useful reagent of this type is diazomethane,CH,N,. Diazomethane can react with carbonyl compounds in different ways,depending on what happens to the initial adduct 2. Oxacyclopropanes areformed if the nitrogen is simply displaced (as N,) by oxygen (Path a , Equation16-2). Ketones of rearranged carbon framework result if nitrogen is displaced(as N,) by R:@which moves over to the CH, group (Path b, Equation 16-2):


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16-4A Addi t ion of Carbon Nucleophi lesDiazoketones, RCOCHN,, are formed if there is a good leaving group,such as halogen, on the carbonyl (Equation 16-3). Under these circumstancesthe reactant is an acid halide, not an aldehyde or ketone:

d azoketone

Exercise 16-13 a. Phosphorus yl ides can be prepared by heating tr iphenylphos-phine , (C6H5),P, with a prim ary alk yl ha lide , RCH2X, in a so lvent such as b enzene.The initial product then is mixed with an equivalent quantity of a very strong base,such as phenyl l i thium in ether. Write eq uations for the reactions and prob able mech-anisms involved, using ethyl bromide as the alkyl hal ide.b. Using the phosph orus yl ide prep ared ac cord ing to Part a, draw structures for theproducts you w ould expect i t to form w ith 2-pentanone.

Exercise 16-14 Show the structures of the reaction products to be expected in eachof the steps listed.

1, (c6H5)3p 2. C6H 5Li 3. cyclo he xa no nea. CICH20CH3 -enzene. 60 hr, 50" ' ether ether, -30, 15 hr1. (C6H,),P (e xc ess ) 2. C6H5Li 2 moles)b. BrCH2CH2CH2CH,Br >30 min., 250" ether3. C 6H5 CH 0 2 moles)

Exercise 16-15* a. Write valenc e-bond structures for diazomethane, CH 2N2, hataccord with the fact that the actual molecule is a gas at room temperature and hasa much smaller dipole moment (see Section 16-1B) than is sugges ted by the dipolar

0 0structure, CH2-N EN.b. 1,2-Diazacy clopropene, CH 2N2, s a stable isomer of diazomethane. Would youexpect this substance to a ct as an yl ide? Give your reasoning.

8 @c. Phosphorus and sulfur yl ides of the type -C-X-, but not the correspond ing

0 @ I Initro ge n ylide s, CH,-N(cH,),, are not to be reg ard ed as be ing stric tly di po la r, bu t


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694 16 Carbonyl Compounds I. Aldehydes and Ketones. Addit ion Reactions of the C arbonyl Grouprather to posse ss C-X bon ds with considerab le do uble-bond character, as expressedby the valence-bo nd structures

Use Figure 6-4 (Section 6-1) to explain why phosphorus and sulfur yl ides are morestable than corresponding nitrogen yl ides.Exercise 16-16* a. Show the intermediate substances and indic ate the prob ableme chanism s involved in the synthesis of the sulfur yl ide 3 by the fol lowing seque nce:

b. Draw structures for the products expected from the reaction of 3 with cyclopen-tanone.

16-4B Addit ion of Oxygen and Sulfur NucleophilesAlcohols, Thiols, WaterW e already hav e discussed additions of alcohols and , by analogy, thiols (RSW)to carbony l comp ounds (see Section 15-4E). W e will not repeat this discussionhere except to point out that addition of water to the carbonyl group of analdehyde is analogous to hemiacetal formation (Section 15-4E) and is catalyzedboth by acids and bases:

T he equilibrium fo r hyd rate formation dep end s both on steric and elec-trical factors. Methanal is 99.99 % hydrated in aqueous solution, ethanal is58 % hydrated, and 2-propanone is not hy drated significantly. T h e hydratesseldom can be isolated because they readily revert to the parent aldehyde.T he only stable crystalline hydrates know n are those having strongly electro-negative groups asso ciated with the carbonyl (see Section 15-7).


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16-4B Addit ion of Oxygen and Sulfur Nucleo phi les

Exercise 16-17 The equil ibrium constants for hydration are especially large formethanal, tr ichloroethanal, cyclopropanone, and compounds with the grouping-COCOCO-. Explain.

Hyd rogen Sulf ite (Bisulf ite) Add it ion to C arbonyl C ompound sSeveral carbony l additions have characteristics similar to those of cyanoh ydrinformation. A typical examp le is the add ition of sodium hydrogen sulfite, whichproceeds readily with good conversion in aqueous solution with most alde-hydes, methyl ketones, an d unhindered cyclic ketones to form a carbon-sulfurbon d. N o c atalyst is required beca use sulfite is an efficient nucleophilic age nt.T h e add ition step evidently involves the sulfite ion -no t hydrogen sulfite ion:

2-propanone hydrogen sulf i teaddi t ion product , l -methy l -I hydroxyethanesulfonate(isolated as sodium salt)

T h e addition products often ar e nicely crystalline solids that ar e insoluble inexc ess concen trated sodium hydrogen sulfite solution. W hether soluble or in-soluble, the addition products are useful for separating carbonyl compoundsfrom substances th at do no t react w ith sodium hydrogen sulfite.

Exercise 16-18 Sodium hydrogen sulfi te addition products are decomposed to theparent carbonyl compounds when treated with mild acid or mild alkal i . Write equa-tions for the reactions involved and explain why the substances are unstable both inacid and base. \Exercise 16-19 Explain how sodium hydrogen sulfi te might be used to separatecyclohexanone (bp 156") rom cyclohexanol (bp 161").


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696 16 Carbonyl Compounds I. Aldehydes and Ketones. Add it ion Reactions of the Carbonyl GroupPolymerization of AldehydesA reaction closely related to acetal formation is the polymerization of alde-hydes. Both linear and cyclic polymers are obtained. For example, methanalin w ater solution poly me rizes t o a solid long-chain polymer called paraformal-dehyde or "polyoxymethylene":n(CH2=O) + H,0 -+H-0-CH2+O-CH2f 0-CH2-0-Hn - 2paraformaldehydeTh is m aterial, w hen strongly heated, reverts to methan al; it therefore is a con-venient sou rce of gase ous m ethanal. W hen heated with dilute acid, paraformal-dehyde yields the solid trimer, 1,3,5-trioxacyclohexane (mp 61 ). T he cycl ictetramer is also known.

Long-chain methanal polymers have become very important as plastics inrecent years. The low cost of paraformaldehyde is highly favorable in thisconnection, but the instability of the material to elevated temperatures anddilute acids precludes its use in plastics. However, the "end-capping" of poly-oxymethylene chains through formation of esters or acetals produces a remark-able increase in stability, and such modified polymers have excellent propertiesas plastics. Delrin (DuPont) is a stabilized methanal polymer with exceptionalstrength and ease of molding.Ethanal (acetaldehyde) polymerizes under the influence of acids to the cyclictrimer, "paraldehyde," and a cyclic tetramer, "metaldehyde." Paraldehyde hasbeen used as a relatively nontoxic sleep-producing drug (hypnotic). Metalde-hyde is used as a poison for snails and slugs, "Snarol." Ketones do not appearto form stable polymers like those of aldehydes.

2,4,6-trimethyl-l,3,5-trioxacyclohexane 2,4,6,8-tetramethyl-1,3,5,7-tetraoxacyclooctane(paraldehyde) (metaldehyde)


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16-4C Nitrogen Nucleophiles 697

Exercise 16-20 Write a reasonable mechanism for the polymerization of methanalin water solution under the influence of a basic catalyst. Would you expect basecatalysis to produce any 1,3,5-trioxacyclohexane? Why?Exercise 16-21 How many different configurational isomers are there for paralde-hyde? Draw the conformation expected to be most stable for each. Review Section12-3DExercise 16-22* What kind of reagents migh t be used to convert paraform aldehyd einto a m ore thermally stable material? Give your reasoning.

16-4C Nitrogen NucleophilesReactions of RNH, Derivat ives with Carbonyl CompoundsA wide variety of substances with -NH, groups react with aldehydes and\ketones by an addition-elimination sequence to give C=N- compounds/and water. These reactions usually require acid catalysts:

Table 16-5 summarizes several important reactions of this type and the nomen-clature of the reactants and products.

The dependence of the rates of these reactions on acid concentration is re-vealing with respect to mechanism and illustrates several important pointsrelating to acid catalysis. Typically, relative to pH 7, the reaction rate goesthrough a max imum as pH decreases. Figure 16-4 shows schematically thetype of behavior observed. We can understand the maximum in rate by con-sidering the rates and equilibria involving RNH, and the carbonyl compoundas well as the rate of dehydration, Equations 16-4 through 16-6.

RNH , + H@ I--. RNHP (16-4)NHR


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698 16 Carbonyl Co mpo unds I. Aldehydes and Ketones. Addit ion Reactions of the C arbonyl GroupTable 16-5Products from Rea ctions of Carbo nyl Com poun ds with RNH, Derivative s

Reactant Typical producta Class of productH2N-R (R = al kyl, aryl, CH3CH=N-CH3amine or hydrogen) A

H2N-NH2hydrazine

H2N-NHR (R = alkyl, aryl) ~ N - N H - ( ' J - N O ~substituted hydrazine

0I IH,NNHCNH2semicarbazideHO-NH2hydroxylamine

imineb(Sch ff's base)

hyd razone

azine

aThe nom enclature of these substances is at be st difficu lt. The first-choice names use d here arethose recommended by J. H. Fletcher, 0. . Dermer, and R. B. Fox, Eds. "Nomenclature of OrganicCompounds," Advances in Chemistry Series, No. 126, American Chemical Society, Washington,D.C., 1974. These are far from comm on usage names as yet and, for conve rsational purpo ses, youwill f ind it best to say the name of the compou nd along w ith the class of produ ct formed, as inthe i tal ic ized names below.A. ethylidenem ethanam ine, 2-aza-2-butene, methylimine of ethanal;B. 1-methylethylidenediazane, 1-methylethy lidenehydrazine, 1,2-diaza-3-methyl-2-butene,

hydrazone of 2-propanone;C, bis(1-methylethylidene)diazine, bis(1-methylethyl idene)hydrazine, 2,5-dimethyl-3,4-diaza-2,4-hexadiene, azine of 2-propanone;

D. I-cyclobutyl idene-2-(2,4-dinitrophenyl)diazane cyclobutyl idene-2,4-dini trophenylhydrazine,2,4-dinitrophenylhydrazone of cyclobutanone;E. 2-phenylmethylidenediazanecarboxamide, semicarbazone of benzenecarbaldehyde ;F. methylideneazanol, oxime of methanal.bThese are either ketimine s or aldim ines , acc ordin g to whether the carbonyl com pou nd is aketone or an aldehyde. For R = H, the imine produ ct generally is unstable and polyme rizes.cUsually these derivatives are sol ids a nd are ex cellent for the isolation and characterization ofaldehydes and ketones.


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16-4C Nitrogen Nucleophi les

overal lreactionrate

Figure 16-4 Schematic variation of the rate of condensation of RNH,with a carbonyl com pou nd as a funct ion of pH

Clearly, if the unshared electron pair on the nitrogen of RNH, is combinedwith a proton, Equation 16-4, it cannot attack the carbonyl carbon to give theaminoalkanol as in Equation 16-5. So at high acid concentration (low pH) weexpect the rate and the equilibrium for the overall reaction to be unfavorable.In more dilute acid, the rate picks up because there is more free RNH, insolution. Dehydration of the arninoalkanol (Equation 16-6) is acid da lyzed ;this reaction normally is fast at pH values smaller than 3-4. Therefore, the slowstep at pH


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700 16 Carbonyl Com pound s I . Aldehydes and Ketones. Addit ion React ions of the C arbonyl GroupAdd i t ion of Am monia to AldehydesAm monia adds readily to many aldehydes. Fo r example,

I aminoethanol(aceta ldehyde amm onia)T h e aldehyde-amm onia add ucts usually ar e not very stable. T he y readilyundergo deh ydration a nd polymerization. 1-Aminoethanol, for exa mp le, givesa cyclic trimer of co mp osition C,H,,N3. 3H 2 0 ,mp 97", with structure 4:

Methanal and ammonia react by a different course with the formation of a sub-stance known as "hexamethylenetetramine":6CH2=0 + 4NH3- 6HI2N4 6H20

"hexamethylene-tetramine"The product is a high-melting solid (mp > 230" d.) and its structure has beenestablished by x-ray diffraction (Section 9-3). In fact, it was the first organicsubstance whose structure was determined in this way. The high melting pointis clearly associated with the considerable symmetry and rigidity of the cagestructure:

1,3,5,8-tetrazatricyc10[3.3.1.1 3,7] decane(hexamethylenetetramine)


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16-4C Ni t rogen Nucleophi iesThe corresponding all-carbon compound, adamantane (Section 12-8), also hasa high melting point (268"):

Treatment of hexamethylenetetramine with nitric acid gives the high ex-plosive "cyclonite," which often is designated as RDX and was widely used inWorld War 11: NO,I

cyc loni teThe methanal and ammonia that split off the cage structure during the reactionwith nitric acid need not be wasted. In the large-scale manufacture of cyclo-nite, a combination of nitric acid, ammonium nitrate, and ethanoic anhydrideis used, which results in full utilization of the methanal and ammonia:C6HI2N4+ 4HN034- 2NH4N03+ 6(CH3C0)20 -+ 2C3H6O6N6+ 12CH3COzH

Exercise 16-24 a. How many different posit ional and stereoisomers are possibleof a monomethyl-substituted hexamethylenetetramine?b. How m any stereoisomers are p os sib le for structure 4?c. Name compound 4 as an azacycloalkan e in acc ord with the systematic rules forcycl ic compounds (Sections 12-8 and 15-11A).Exercise 16-25 Suggest a method of synthesis of each of the fol lowing com pounds ,start ing with an appropriate aldehyde or ketone. Indicate which of the products youexpect to be m ixtures of con figurational isomers.


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702 16 Carbonyl Co mpoun ds I. Aldehydes and Ketones. Add ition R eactions of the Carbon yl GroupEnaminesSecondary amino compounds of the type R2N-H add to aldehyde and ketonecarbonyl groups in an acid-catalyzed reaction in much the same way as doR N H 2 com poun ds- with on e important difference. T h e product contains thestructural unit C= C-N rather than C-C =N ; and because there is acarbon-carbon double bond, such a substance is called an enamine (alkenei-rnine). An example is:

T h e co urse of this reaction can be und erstood if we notice that loss ofO H from the init ial product leads to a n immonium ion, 5, that cannot lose aproton and form a C = N bond:

Ho we ver, if there is a hydrogen on a carbon attached to the immoniumcarbon, it is possible for such a hydrogen to b e lost as a proton w ith concu rrentformation of the neutral enamine:

5 an enamineEnamine formation, l ike many other carbonyl addition reactions, is readilyreversible, and the carbonyl compound can be recovered by hydrolysis withaqueous acids. F o r this reason , to obtain a good conversion of carbonyl com-pound to enamine, i t usual ly is necessary to remove the w ater that is formedby distilling it away from the reaction mixture.Enam ines a re useful synthetic intermediates for th e formation of carbon-carbon bonds, as we will discuss in greater detail in Section 17-4B.


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16-4D Hydrogen-Hal ide Addi t ion to Carbonyl Groups and R eplacement of Carbonyl by Halog en 703Enam ines generally ar e unstable if there is a hydrogen o n nitrogen. The yrearrange to the corresponding imine. This behavior is analogous to the re-arrangement of alkenols to carbony l comp ounds (Section 10-5A):

Exercise 16-26 Write an equation to show the rearrangement of ethylidenemethan-amine to N -methylethenamine (CH,=CH-NHCH,). Use bond energies to calculatethe AH0 of the rearrangement. Assuming AS0 = 0, hich would be the more stableisomer? Would you expect that c orrections-for electron delocal ization may be neces-sary for either of these compounds? Give your reasoning.Exercise 16-27 How could you prepare the enamine 6 from suitable ketone andamine starting materials?

Spec ify the catalyst required and draw the structure of any by -products that you mayexpect to form in the reaction.

16-4D Hydrogen-Hal ide A dd t ion to C arbonyl Groupsand Replacement of Carbonyl b y HalogenAddition of hydrogen halides to carbonyl groups usually is so easily reversi-ble as to preclude isolation of the addition products:CH3 C\H,/CI

'C=O + HCI C/H H/ 'OH


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704 16 Carbonyl Compounds I. Aldehydes and Ketones. Addit io n R eactions of the Carbonyl G roupHowever, many aldehydes react with alcohols in the presence of an excess ofhydrogen chloride to give a-chloro ethers:CH3\ CH, O C H 3C=O + HCI + CH,OH \c' + H,O/H H/ \CI

1 chloro-1 methoxyethane(an a-chloro ether)In carrying out laboratory syntheses of a-chloro ethers, gaseous hydrogenchloride is passed into a mixture of the alcohol and aldehyde. Aqueous HCl isnot useful because the excess water gives an unfavorable equilibrium.a-Chloroethers are highly reactive compounds that very readily undergo S,2 as wellas SN and E 1 reactions. Two simple examples, methoxychloromethane(chloromethyl methyl ether) and chloromethoxychloromethane (bis-chloro-methyl ether), have been put under severe restrictions as the result of teststhat show they have strong chemical carcinogenic properties.

Exercise 16-28 Write equations to show how you would convert 2-butanone to2-methoxy-2-methylthiobutane by way of the corresponding a-chloro ether.

Exercise 16-29 Write a reasonable mechanism for the reaction of hydrogen chlo-ride and methanol with m ethanal to give me thoxychloromethane (m ethyl chloromethylether), Equation 16-7, that is consistent with the fact that the reaction occurs underconditions where neither dichloromethane nor chloromethane is formed.

Replacement of the carbonyl function by two chlorines occurs withphosphorus pentachloride in ether:

ether0 + PC15- + POC,,This reaction is useful in conjunction with E2 elimination to preparealkenyl halides, allenes, and alkynes. Cy cloalkenyl halides are easily pre-pared, but because of angle strain the cycloalkynes and cycloallenes withfewer than eight atoms in the ring cannot be isolated (see Section 12-7):

/ \ - - CH2)5 C-LI KOH(CH2), C=O E2 >


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16-4E Hydride as a Nucleop hi le. Reduction of Carbonyl Compounds

Rep lacem ent of a c arbony l group by gem -fluorines3 can be achieved w ithmolybdenum hexafluoride or sulfur tetrafluoride. Sulfur tetrafluoride con vertscarboxyl functions to trifluoromethyl groups:

Exercise 16-30 Cyclopentanone-1-14C treated su cce ssive ly with ph ospho rus penta-ch lo r i de and a l ka l i g i ves l - ~h lo rocyc lopen t ene -1 -~~C.his substance on treatmentwith' phenyllithium at 120" affords 14C -labeled 1-phen ylcyclopen tene, which on v ig-orous ox ida tion gives benzo ic ac id (C,H,CO,H) conta inin g in its ca rbo xy l ca rbo njust half of the total 14C of the 1-ph eny lcyc lope nten e. W rite equations for all the reac -t ions involved an d w rite a mec hanism for the ph enyll i thium substitution that accou ntsfor the 14C dis tribu tion .Exercise 16-31* Work out reasonable mechanisms for the reactions of phosphoruspentachloride and sulfur tetraf luoride with carbonyl groups. Both phosphorus andsulfur can accom mo date f ive (or more) bon ded atoms, and the structure of pho sphoruspentachloride in the solid state is [PC14@]PC16'].

16-4E Hy dride as a N ucleophi le. Reduct ion of CarbonylCompoundsMetal and Boron HydridesIn recen t years, inorganic hydrides such a s lithium aluminum hydride, LiAlH,,and sodium borohyd ride, NaB H,, have become extreme ly important as re-ducing agents of carbonyl compounds. These reagents have considerableutility, especially with sensitive and expensive carbonyl compounds. Thereduction of cyclobutanone to cyclobutanol is a good example, and you will3Gem is an abbreviation for geminal (twinned) and is a common conversational desig-nation for arrangements having two identical substituents on one carbon.


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706 16 Carbonyl Co mp ound s I. Aldehydes and Ketones. Add it ion R eactions of the Carbonyl Groupnotice that the net reaction is the addition of hydrogen across the carbonyl\double bond, C=O ' [HI , CH-OH,/ /

With the metal hydrides, the key step is transfer of a hydride ion to the car-bony1 carbon of the sub stanc e being reduce d.

The hydride transfer is analogous to the transfer of R:@ rom organometalliccom pound s to carbonyl group s (Section 14- 12A).Lithium aluminum hydride is best handled like a Grignard reagent,beci:use it is soluble in ether and is sensitive to both oxygen and moisture.(Lithium hydride is insoluble in organic solvents and is not an effective re-ducing agent for organic compounds.) All four hydrogens on aluminum canbe utilized:

Th e reaction products m ust be decomposed with water and acid a s with theGrignard complexes. A ny excess lithiurn aluminum hyd ride is decom pose d bywater and acid w ith evo lution of hydrogen:

Lithium aluminum hydride usually reduces carbonyl groups withoutaffecting carbo n-carb on dou ble bonds. I t is, in addition, a good reducingagent for carbonyl groups of carboxylic acids, esters, and other acid deriva-tives, as will be described in Ch apter 18.Sodium bo rohydride is a milder reducing agent than li thium aluminumhydride and will reduce aldehydes and ketones, but not acids or esters. It


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16-4E Hydride as a Nucleophile. Reduction of Carbonyl Compounds 707rea cts sufficiently slowly with w ate r in neutra l o r alkaline solution tha t reduc-tions w hich are reasonably rapid can be carried ou t in w ater solution withoutappreciable hydrolysis of the reagent:

Borane (as BH, in tetrahydrofuran or dimethyl sulfide) is an evenmilder reducing agent than B H 4@ or the c arbonyl group of aldehydes andketon es. Th is difference in reactivity can be used t o advantage whe n selectivereduction is necessary. F o r exam ple, borohydride reduces a ketone carbonylmore rapidly than a carbon-carbon double bond, whereas borane reduces thecarbon-carbon double bond more rapidly than carbonyl:

A useful com parison of the reactivities of borane s an d me tal hydrides towa rdvarious types of multiple bonds is given in Table 16-6.

Exercise 16-32 Show how you could prepare the fol lowing substances from theindicated starting materials:a. 4-methylcyclohexanone from 4-methylenecyclohexanoneb. 4-(hydroxymethyl)cyclohexanone from 4-oxocyclohexanecarboxylic acidc. 4-hydroxybutanoic a ci d from 4-oxobutanoic a ci dd. 2,2,2-trichloroethanol from 2,2,2-trichloroethanal

The Cannizzaro ReactionA characteristic reaction of aldehydes without a hydrogens is the self oxida-tion-reduction they undergo in the presence of strong base. With m ethanalas an example,

If the aldehyde has a hydrogens, other reac tions usually oc cur m ore rapidly.


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708 16 Carbonyl Co mpo unds I . Aldehy des and Ketones. Addi t ion React ions of the Carbonyl G roupTable 16-6Comparison of Products and Reactivities of Functional Groups for Reduction withBorane and Metal Hydridesaab

Reduct ion productCFunct ionalgr ou p LiAIH, NaBH, BH3

\ ICH-C-OH (4)I\ ICH-C-OH (4)I

"Numbers in parenthesis indicate order of reactivi ty in the vert ical column with (1) as the mostreactive. bNo prod uct is l iste d whe re rea ction norma lly is too slow to be of practic al value. "Afterhydrolysis. d X is halo gen or sulfonate, -0-SO2-Ar.

T he m echan ism of this reaction, usually called the Cannizzaro reaction:combines many fe atures of other processes studied in this chapter. T he firststep is reversible addition of hydroxide ion to the carbonyl group:

4Named after its discoverer, the same Cannizzaro who, in 1860, made an enormouscontribution to the problem of obtaining self-consistent atomic weights (Section 1-1).


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16-4E Hyd ride as a Nu cleoph ile. Reduction of Carbonyl Com pounds 709A hydrogen can be transferred as hydride ion to methanal from the hydroxy-alkoxide ion, thereby reducing the methanal to methanol:H c3 H-@. Go slowc /P- -A-O@+ H-CH H 'OH H OH\fast--+ CH30H + H-C \oc3Exercise 16-33 Assume that an equimolar mixture of methanal and 2,2-dimethyl-propanal (each undergoes the Cannizzaro reaction by itself) is heated with sodiumhydroxide solution. Write equations for the various possible combinations of Can-nizzaro reactions which may occur. Would you expect methanal used in excess toreduce, or oxidize, 2,2-dimethylpropan al? Give your reasoning?

Redu ction with Alum inum Al koxidesHydride transfer similar to that of the Cannizzaro reaction also may beachieved from a C-H grouping in an alkoxide ion corresponding to a primaryor secondary, but not a tertiary, alcohol. This is expected to be a reversiblereaction, because the products are another alkoxide and another carbonylcompound:

To utilize this equilibrium process as a practical reduction methodrequires rather special conditions. I t is preferable to use an aluminum alkoxide,

0 0A1(OR)3, rather than a sodium alkoxide, NaOR, to ensure that the reaction. -mixture is not too strongly basic. (Carbonyl compounds, particularly alde-hydes, are sensitive to strong bases.) The overall reaction may be written

for which the alkoxide is derived from 2-propanol. The advantage of this


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710 16 Carbonyl Compounds I. Aldeh ydes a nd Ketones. Add it ion R eactions of the Carbonyl Groupmethod is that the reaction can be driven essentially to completion by dis-tilling out the 2-propanone as it is formed. The reduction product subse-quently can be o btained by acid hydrolysis of the aluminum alkoxide:

Biological Reduct ionsThese have been discussed already in the context of the reverse reactions-oxidation of alcohols (Section 15-6C).

16-5 CATALYTIC HYDROGENATIONThe simplest large-scale procedure for reduction of aldehydes and ketonesto alcohols is by c atalytic hydrogenation:

H2, 1000 psiDo i, 50 >The advantage over most other kinds of reduction is that usually the productcan be obtained simply by filtration from the catalyst, then distillation. Thecommon catalysts are nickel, palladium, copper chromite, or platinum acti-vated with ferrous iron. Hydrogenation of aldehyde and ketone carbonylgroups is much slower than of carbon-carbon double bonds so m ore strenuousconditions are required. This is not surprising, because hydrogenation ofcarbonyl groups is calculated to be less exothermic than that of carbon-carbondouble bonds:

\ IC=O + H2 ---+ -C-OH AH 0 = - I 2 kcal/ II t follows that it is generally difficult to redu ce a ca rbonyl group in the p resen ceof a carbon-carbon double bond by hydrogenation without also saturatingthe double bond. Oth er reducing agents are more selective (Section 16-4E).


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16-6 Reduct ion of Carbonyl Compounds to Hydrocarbons16-6 REDUCTION OF CARBOWL COMPOUNDSTO HYDROCARBONS

\ \Th ere ar e several methods of transforming C = O to C H , . In some cases,/ /the following three-step sequence of conventional reactions may be useful:

This route requires a hydrogen a to the carbonyl function and may give re-arrangem ent in the dehydration s tep (Sections 8-9B and 15-5E). Alternatively,the hydroxyl can be converted to a better leaving group (halogen or sulfonateester), which then may be displaced by H :@ as LiAlH,; see Table 16-6):

More direct methods may be used, depending on the character of theR groups of the carbonyl comp ound. If the R groups a re stable to a variety ofreagents there is no problem, but with sensitive R groups not all methods areequally applicable. When the R groups a re stable to acid but unstable to base,the Clemmensen reduction with amalgamated zinc and hydrochloric acid isoften very useful.

The mechanism of the Clemmensen reduction is not well understood. It isclear that in mo st case s the alcohol is not an intermediate, because the Clem-mensen conditions do not suffice to reduce most alcohols to hydrocarbons.When the R groups of the carbonyl compound are stable to base butnot to acid, the Huang-Minlon modification of the Wolff-Kishner reductionusually gives good results. This procedure involves heating the carbonyl com-pound in a high-boiling polar solvent, such as 1,2-ethanediol, with hydrazineand potassium hydroxide and driving the reaction to completion by distillingout the w ater formed:

/C\H2 K O H , 150" /c\H2C H C = O + N H 2 - N H , C H , O H C H , O H ' C H , C H , + N 2 + HZ0\, / \ /CH2 CH,


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712 16 Carbonyl Com pou nds I. Ald ehy des an d Ketones. Addition R eactions of the Carbonyl GroupWhen the carbonyl compound is sensitive to both acids and bases, orfor oth er reasons gives poor yields in both the Clem me nsen and Wolff-Kishnerreductions, a recourse may be reduction of the corresponding thioacetal orthioketal with hydrogen-saturated Raney nickel (Section 11-2B):

Thioketals, unlike ordinary ke tals, are formed readily from ketones a nd thiols(RSH) in the presence of acid catalysts. Th e desulfurization p rocedure usuallygoes w ell, but th e prod uct is rathe r difficult to sepa rate by extraction from thelarge excess of Raney nickel required for optimum yields.

16-7 OXIDATION OF CARBONYL COMPOUNDSAldehy des are oxidized easily by mo ist silver oxide or by potassium permanga-nate solution to the corresponding acids. T he mechanism of the perma nganateoxidation has some resemblance to the chromic acid oxidation of alcohols(Section 15-6B):

HR-C /PLO], ,-,\\ \

Exercise 16-34 Ben zene carba ldehy de (benz aldeh yde , C,H,CHO) is ox idiz ed toben zene carbo xylic aci d (benz oic acid, C6H5C0,H) by ac id permangana te. The rateof the oxida tion is propo rtional to the co nce ntrations of H @, lde hyde , and MnO,Q. Therea ction is muc h slower with C,H,CDO than with C,H,CHO. When the reac tio n isca rried out in H:80 with C 6H 5C H 0and MnO,@, the product is C,H5C0,H. With C,H5-CHO, H,0, and Mni80,@, the C,H5C0,H contains 180 .Write a m ech anism for the reac-tion that is consistent with a ll the ab ove facts. (Notic e that the C,H5 gro up is not in-volved.) Give your reasoning.

M any aldehydes a re oxidized easily by atmosp heric oxygen in a radical-chain mechanism. Oxidation of benzenecarbaldehyde to benzenecarboxylicacid has been studied particularly well and involves formation of a peroxy


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16-7 Oxida tion of Carbonyl Compounds 713acid as an intermediate. Reaction is initiated by a radical R. which breaks therelatively weak aldehyde C-H bond (86 kcal).initiation

The benzenecarbonyl radical, C,H,CO, then propagates a chain reaction.propagation

peroxybenzenecarboxyl ic acidThe peroxy acid formed then reacts with benzenecarbaldehyde to give twomolecules of carboxylic acid:

The oxidation of benzenecarbaldehyde with peroxybenzenecarboxylicacid (Equation 16-8) is an example of a reaction of wide applicability in whichaldehydes are oxidized to carboxylic acids, and ketones are oxidized to esters.

R =H, alkyl, or aryl

The reaction, which is known as the Baeyer-Villiger oxidation, has syntheticutility, particularly for the oxidation of ketones to esters because ketones


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714 16 Carbonyl Co mpo unds I . Aldehydes and Ketones. Addi t ion React ions of the C arbonyl Groupnormally are difficult to oxidize without degrading the structure to smallerfragments. Tw o exam ples of the Baeyer-Villiger reaction follow:

The mechanism of the Baeyer-Villiger oxidation has been studied extensivelyand is of interest because it involves a rearrangement step in which a substit-uent group (R ) moves from carbon to oxygen. The reaction sequence is shownin Equations 16-9 through 16- 1 1

In the first step, Equation 16-9, the peroxy acid adds to the carbonyl group. Theadduct has several oxygen atoms on which protons can reside, and there willbe rapid shifts of protons between these oxygens. However, at some stage thestructure will be appropriate to allow elimination of a molecule of carboxylicacid, RICO,H, Equation 16-10. The resulting intermediate has an electron-deficient oxygen atom with only six valence electrons. As with carbocationsand borane complexes (Sections 8-9B, 15-5E, 1 1-6E, and 16-9 D, G), a neigh-boring R group can move over with its bonding electron-pair to the electron-deficient (oxygen) atom, Equation 16-11. You will notice that for aldehydes,the aldehyde hydrogen migrates in preference to the alkyl or aryl group. Inthe other examples given, a cycloalkyl migrates in preference to a methyl group,and aryl in preference to methyl.


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16-8 Protect ion of Carbonyl Grou ps 715

Exercise 16-35 A radical-chain reaction similar to that described for the air oxida-tion of ben zaldeh yde occ urs in the peroxide-init iated ad dit io n of aldehy des to alkenes(see Table 10-3). Write a m echa nism for the p eroxide -induce d addit ion of ethanalto propene to give 2-pentanone.Exercise 16-36* Certain aldehydes decom pose to hydrocarbons and carbon monox-ide when heated in the p resen ce of peroxide s:

ROOR(CH,),CHCH,CHO - CH,),CHCH, + COWrite a reasonable ch ain mech anism for such react ions that is supported by c alcula -tions of the A H 0 values for the propagation steps. Use needed data from Table 4-3and Tab le 4-6. Your answer should reflect the fact that this reaction does not proceedwell with most aldehydes unless the reactants are heated (above about 120").

16-8 PROTECTION OF CARBONYL GROUPSThere are few reactions of aldehydes and ketones that do not in some wayaffect the carbonyl function. For this reason, it may be necessary to protectthe carbonyl function when it is desirable to avoid reaction at this function.For example, you may plan to synthesize 4-cyclohexylidene-2-butanone byway of a Wittig reaction (Section 16-4A), hich would involve the followingsequence:

This synthesis would fail in the second step because the phenyllithium wouldadd irreversibly to the carbonyl group. To avoid this, the carbonyl group wouldhave to be protected or blocked, and the most generally useful method of


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716 16 Carbonyl C om poun ds I . Aldeh ydes and Ketones. Addit ion React ions of the Carbonyl Groupblocking is to convert the carbonyl group to a ketal, usually a cyclic ketal:R\ HO-CH, H@

HO-AH2RWith the carbonyl group suitably protected, the proposed synthesis wouldhave a much better chance of success:

Notice that the carbonyl group is regenerated by acid hydrolysis in the last step.

16-9 PREPARATIVE METHODS FOR ALDEHYDESAND KETONESA number of useful reactions for the preparation of aldehydes and ketones,such as ozonization of alkenes and hydration of alkynes, have been con-sidered in previous chapters. These and other methods of preparation aresummarized in Tables 16-7 and 16-8 at the end of the chapter. Only a fewrather general methods that we have not discussed will be taken up here.


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16-9A Oxidat ion of 1,2-Diols and Alkenes16-9A Oxidat ion of 1,2-Diols a nd AlkenesAldehydes and ketones often can be prepared by oxidation of alkenes to 1,2-diols (Sections 11-7C and 11-7D), followed by oxidative cleavage of the1,2-diols with lead tetraethanoate or sodium periodate. For example,

H202,HC02H(or neutral KMnO) 'a:2OPb(02CCH3)4, + c H 2 ~(or NaIO,)

Cleavage of glycols with these reagents proceeds according to the followingstoichiometry :

Exercise 16-37 An elegant modif icat ion of the two-step procedure to prepare ke-tones from alkenes by hydroxylat ion a nd oxidat ive cleava ge of the diol formed usesa sm all amo unt of potassium perma nganate (or osm ium tetroxide, OsO,) as the cata-lyst and sodium per iodate as the ox idizing agent :

NalO,H0,C (050, or KMnO,) ' H O ~ C ~ O70%

Ex pla in how the reaction sequ ence could ope rate to enab le KMnO, (or OsO,) tofunction overall as a catalyst rather than as a reagent.Exercise 16-38 Write mechanisms for the oxidat ive cleavage of 1,2-diols by leadtetraethanoate and sodium periodate based on considerat ion of the mechanism ofchromic acid oxidat ion (Section 15-6B). 5


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718 16 Carbony l Compou nds I. Aldehydes and K etones. Add it ion R eactions of the Carbonyl Group16-9B Oxidation of Primary Alcohols and RelatedCompounds

In Chapter 15 primary alcohols, RCH,OH, were shown to be readily oxidizedto aldehydes, RCHO, and secondary alcohols, R,CHOH, to ketones, R,CO, byinorganic reagents such as CrO, and KMnO,. However, it is a problem to avoidoveroxidation with primary alcohols because of the ease with which aldehydesare oxidized to acids, RCHO --+RC02H. A milder oxidant is methylsulfinyl-methane [dimethyl sulfoxide, (CH,),S=O], and this reagent can be used toprepare aldehydes from alcohols by way of an intermediate such as the ester orhalide in which the OH group is converted to a better leaving group:

RCH20H (CF3C02)20 1 1> RCH20CCF3 (CH3),S=0base > RCHO (16-14)(not isolated)

(not isolated)(CH,),S=O

base > RCHO

Whichever method is employed, the key step is the formation of an alkoxy-sulfonium salt, 7, by a displacement reaction involving dimethyl sulfoxide as anoxygen nucleophile. (Notice that the S=O bond, like the C=O bond, is

0 0strongly polarized as S -0 .)

In the examples listed in Equations 16- 12 through 16- 15, the X group is Br,-0 I-OSO,R', -O,CCF,, and C6Hl,NHC=NC,H,,, respectively. In the next

step a sulfur ylide, 8, is formed from the reaction of a base with 7, but the ylide


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16-9C Reduction of Carbox yl ic Acids to Aldehydes 769evidently is unstable and fragments by an internal E2 reaction to form analdehyde :

C H C q 3 /CH3S

I0 -base: H @+ base -----------, 0 - +IR-C-H 0I I IIH H R/c, H7 8

16-9C Reduc t ion of Carboxylic A cid s to AldehydesConversion of a carboxylic acid to an aldehyd e by direct reduction is not easyto achieve, because acids generally a re difficult to red uce , whereas aldehydesare easily reduced. T hu s the problem is to keep the reaction from going too far.T h e mo st useful procedures involve conversion of the acid to a deriva-tive that either is mo re easily reduced than an aldehyde , or else is reduced toa substance from which the aldehyde can be generated. The so-called Rosen-mund reduction involves th e first of the se sche m es; in this procedu re, the acidis converted to a n acyl chloride, which is reduce d with hydrogen ove r a palla-dium catalyst to the aldehyde in yields up to 90%. The rate of reduction ofthe aldehyde to the co rresponding alcohol is kept a t a low level by poisoningthe catalyst with sulfur:

M etal hydrides, su ch as lithium aluminum hyd ride, also can be used toreduce derivatives of carboxylic acids (such a s amides and nitriles se e Ta ble16-6) to aldehydes. An example follows:

cyclopropanecarboni t r i le cyclopropanecarboxaldehyde

T he redu ction ste p usually is successful only if inverse addition is used, tha t is,adding a solution of lithium aluminum hydride to a solution of the nitrile inether, preferably at low temperatures. If the nitrile is added to the hydride,the reduction product is a primary amine, RCH,NH, (see Section 18-7C).


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720 16 Carbonyl Compounds I. Aldeh ydes and Ketones. Add i t ion Rea ct ions of the Ca rbonyl Group

Exercise 16-39 Explain how resonance can be used to accou nt for the fact that theAH0 for reduction of CH3C0,H to C H 3 C H 0 s about 18 kcal mole-' more positive thancalculated from bon d energies, whereas AH0 for the corresponding reduction ofCH3COCI to CH,CHO is about as expected from bond energies. Would you expectAH0 for reduction of CH3CONH, to b e as expected from the pertinent bo nd energies?Why?

16-9D Rearrangements of 1,2-DiolsMany carbonyl compounds can be synthesized by acid-catalyzed rearrange-m ents of 1,2-diols (a type of reac tion o ften called the "pinacol-pinacolone"rearrangement).

R = alkyl, aryl, or hyd rog en

T h e general characteristics of the reaction ar e similar to those of carbocationrearrangements (Section 8-9B). The acid assists the reaction by protonatingone of the -OH groups to make it a better leaving group. The carbocationthat results then can undergo rearrangement by shift of the neighboring Rgroup with its pair of bonding electrons to give a new, thermodynamicallymore stable species with a carbon-oxygen double bond (see Section 16-7).The prototype of this rearrangement is the conversion of pinacol topinacolone as follows:

2,3-dimethyl-2,3- butane diol(pinacol)

CH3I -H@ CH,3,3-dimethyl-2-butanone CH,,-C-C-CH, Y I(pinacolone) C H , - C C - C H ,I1 I0 CH3 I1 I@OH CH,


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16-9E Rearrangements of Hydroperoxides 721

Exercise 16-40 Write a sequence of reactions whereby 2-methylpropene may beconverted to 2-m ethylpropanal by way of a pina col-typ e rearrangem ent. Wo uld youexpec t any conco mitant formation of 2-butanone? Exp lain.Exercise 16-41 Predict the prod ucts to be expected from acid-catalyzed rearrange-ments of 1,2-propanediol and 2-methyl-2,3-butanediol.Exercise 16-42 Treatment of tetramethyloxacyclopropane, (CH,),C-~(cH,), , withac id produces pinacolone. Explain. '4Exercise 16-43 How could one dehydrate 2,3-dimethyl-2,3-butanediol to 2,3-di-methyl-l,3-butadiene without forming excessive amounts of 3,3-dimethyl-2-butanonein the pro cess?Exercise 16-44 Strong a cid converts 1 I diph eny l-l,2-e than edio l f irst to diphenyl-ethanal and then m ore slowly to 1,2-diphenylethanone (b enz yl phenyl ketone). Exp lainhow and why kinetic and equil ibrium control may be expected in this case to givedifferent products.

16-9E Rearrangements of HydroperoxidesAn important method of preparing carbonyl (and hydroxy) compounds, es-pecially on an industrial scale, is through rearrangements of alkyl hydro-peroxides:

I H@ \R-C-0-0-H - -OH + C= o R = alkyl, aryl, or hydrogen/The peroxides can be made in some cases by direct air oxidation ofhydrocarbons,

and in others by sulfuric acid-induced addition of hydrogen peroxide (asH-02H) to double bonds:


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722 16 Carbonyl Compounds I. Aldehydes and Ketones. Addition Reactions of the Carbonyl Group(Notice that hydrogen peroxide in methanoic acid behaves differently towardalkenes in producing addition of HO-OH, Section 11-7D.) The direct airoxidation of hydrocarbons is mechanistically similar to that of benzenecarb-aldehyde (Section 16-7).

The rearrangements of hydroperoxides are acid-catalyzed and are analogousto carbocation rearrangements except that positive oxygen (with only sixvalence electrons) instead of positive carbon is involved in the intermediatestage:

benzenol 2-propanone(phenol) (acetone)

In principle, either phenyl or methyl could migrate to the positive oxygen,but only phenyl migration occurs in this case. The rearrangement reaction isclosely related to the Baeyer-Villiger reaction (Section 16-7).

Exercise 16-45 Write equations for the acid-catalyzed rearrangement of 1,3,3-tr imethyl butyl hydrop eroxide a nd pre dict the favored p roduct therefrom.

16-9F Aldehy des by Hydroformy at ion of Al kenesThis reaction is important for a number of reasons. It is an industrial syn-thesis of aldehydes from alkenes by the addition of carbon monoxide andhydrogen in the presence of a cobalt catalyst. A prime example is the synthesis


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16-9F Aldehydes by Hydroformylat ion of Alkenes 723of butanal from propene, in which 2-methylpropanal also is formed:

Co2(Co)8 > CH3CH,CH2CH0+ CH3CHCH,H3CH=CH2 +CO + H2 1700, 25 0 atm butanal(75%) ICHOAs you can see, the reaction formally amounts to the addition of methanalas H-CWO to the alkene double bond. Because one additional carbon atomis introduced as a "formyl" CHO group, the reaction often is called hydro-formylation, although the older name, 0x0 reaction, is widely used.

Hydroformylation to produce aldehydes is the first step in an importantindustrial route to alcohols. The intermediate aldehydes are reduced to al-cohols by catalytic hydrogenation. Large quantities of C,-C, alcohols areprepared by this sequence:

CH, CH33-methyl butanal (90%)

The history of the 0x0 reaction is also noteworthy. I t was developed originallyin Germany in the years following World War I. At that time, the Germanchemical industry was faced with inadequate supplies of petroleum. ManyGerman chemists therefore turned to research on ways by which hydrocarbonscould be synthesized from smaller building blocks, particularly carbon monox-ide and hydrogen derived from coal. The success achieved was remarkableand led to alkane and alkene syntheses known as the Fischer-Tropsch process:

cobaltcatalystnCO + (2n+ l)H,- C,,H,,,+ ,+nH,OThis reaction in turn led to the discovery that aldehydes were formed by thefurther addition of carbon monoxide and hydrogen to alkenes, and was furtherdeveloped as the 0x0 process for production of alcohols. The combinationCO + H2 often is called "synthesis gas." I t is prepared by the reduction ofwater under pressure and at elevated temperatures by carbon (usually coke),methane, or higher-molecular-weight hydrocarbons:

When carbon monoxide is produced from hydrocarbons, the process amountsto the reverse of the Fischer-Tropsch synthesis.The mechanism of hydroformylation is in many respects related to the mech-anism of homogeneous hydrogenation and is discussed further in Chapter 3 1.


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724 16 Carbonyl Compounds I. Aldehydes and Ketones. Add it ion Reactions of the Carbonyl Group

Exercise 16-46 Propose a possible synthesis of each of the fol lowing compoundsfrom the indicated reagents and condit ions where specif ied. Assume that any addi-tional needed reagents are available. Reactions from other parts of Section 16-9 maybe used.a. cyclohexanecarbaldehyde from cyclohexane by way of a hydroformylat ionreactionb. cyclopentylmethanol from cyclopentene

d. heptanal from 1-heptene and (CH,),S=O

e. f rom fJ'J (two ways)CH2 \

f . 'CH5 from (C6H5),C=0 and cyclope ntane by way of a W ittigreact ion (Section 16-4A)

16-9G Carb onylation of Al kyl boran esThe aldehyde synthesis by hydroformylation of alkenes described in thepreceding section can be achieved indirectly using boron hydrides. An over-simplified expression of this reaction is

The overall reaction is quite complex but involves a rearrangement similarto that described for the hydroboration-oxidation of alkenes (Section 11-6E).The first step is hydroboration of the alkene to a trialkylborane. When thetrialkylborane is exposed to carbon monoxide, it reacts (carbonylates) to forma tetracovalent boron, 9:


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16-9G Carbonylation of A lkyl boranes 725The complex 9 is unstable and rearranges by transfer of an alkyl group fromboron to the electron-deficient carbonyl carbon to give 10:

Now, if a metal-hydride reducing agent, such as LiAlH,, is present, the car-bony1 group of 10 is reduced and 11 is formed:

The reduction product, 11, can be converted to an aldehyde by oxidation withaqueous hydrogen peroxide, provided the p H is carefully controlled. (Remem-ber, aldehydes are unstable in strong base.)

You may have noticed that only one of the three alkyl groups of a trialkyl-borane is converted to an aldehyde by the carbonylation-reduction-oxidationsequence. To ensure that carbonylation takes the desired course withoutwasting the starting alkene, hydroboration is achieved conveniently with ahindered borane, such as "9-BBN," 12. With 12, only the least-hindered alkylgroup rearranges in the carbonylation step:

Carbonylation of alkylboranes also can produce ketones. The conditions aresimilar to those in the aldehyde synthesis except that the hydride reducing


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726 16 Carbonyl Compounds I. Aldehydes and Ketones. Addition Reactions of the Carbonyl Groupagent is omitted. By omitting the reducing agent, a second boron-to-carbonrearrangement can occur. Oxidation then produces a ketone:

Rco O @ rearr IR:%B----+ ,B-C=O R,B-C=O

I earr\ rearrRB-CR, slow O=B-CR,13

I

Rearrangement will continue a third time (ultimately to produce a tertiaryalcohol) unless movement of the alkyl group remaining on boron in 13 isprevented by steric hindrance.

Exercise 16-47" a. Show the steps and reaction condit ions by which 2-methyl-1,3-butadiene c an be conv erted to 3-m ethylcy clope ntano ne by an al kyl borane, RBH,,when R is a large alkyl group.b. Suggest a route to each of the following compounds from the indicated startingmaterials: ( I ) 2-methyl-4-heptanone from propene and 2-methylpropene, and (2)octanedial from 1,5-hexad ene.

Additional Reading

H. C. Brown, "Organoborane-C arbon Mo noxid e Reactions. A New Versatile App roac hto the Synthesis of C arbo n Structures," Accounts of Ch em ica l Research 2, 65 (1969).A. Maercker, "The Wittig Reaction," Organic Reactions 14, 270 (1965).G. W ittig, "From Diyls over Ylides to My Idyll," Accounts of Che mic al Research 7,6 (1974).C. H. Hassa ll, "The Baeyer-Vil l iger Oxidation of Aldehydes and Ketones," OrganicReactions 9, 73 (1957).E. Vedejs, "Clemmensen Reduction of Ketones in Anhydrous Organic Solvents,"Organic Reactions 22, 401 (1975).


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Table 16-7 ii?General Methods for the Preparation of Aldehydesa E

r?,0

Reaction Comment =I(D1. o31. oxidation o f alkenes with ozone, RCH=CH, RCHO + H,C=O2. Hz, Pd >

1. 03,CH3C02C2H5,20' hexaned al2. Hz, Pdcyclohexene

NalO,2 oxidative cleavage of 19-diols, RCHCH, or Pb(OCOC~,)4 RCHO + H2C=0I IHO OHC6H5CH,CHCH, Pb(0C0CH3)4 > C,H5CH2CH0 + H,C=OI IHO OH

3-phenylpropane-1,2-diol phenylethanal3. oxidation of primary alcohols, RCH,OH '01 > RCHO

a. chromic acid:

I-propanol propanalb. aluminum alkoxides (Oppenauer oxidation):

See Section 11-7A; of limitedpreparative use; mainly used tolocate position of double bondsin structure determinations.

The 1,2-diols may be generatedfrom alkenes in situ (see discussionin Section 16-9A and Method 2b,Table 16-8).

See Section 15-6B; useful for thepreparation of volatile aldehydesbecause with these, further oxida-tion usually can be prevented bydistilling the p roduct out of thereaction mixture.See Section 16-4E; often useful forlow-boiling aldehydes that can bedistilled out of mixture as formed,thereby preventing condensationreactions; aluminum isopropoxide ortert-butoxide commonly are used ascatalysts; carbon-carbon doublebonds are not attacked.


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728 16 Carbonyl Compounds I. Aldehydes and Ketones. Addit ion Reactions of the Carbonyl Group

1- r2u2zEE,$ $ 2 uQ ( d g.:a, -k & Z C0 28-- + z $a, .-a , G - l U OQ s g "O ( d & $ ?.:gzgg2552 a 0E G Oa, E,gxi 'Fg. t l= :G


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6. addition o f Grignard reagents to I , ? , 1-triethoxymethane (ethyl orthoformate)CH,(CH,),MgBr + HC(OC,H,), - H,(CH,),CH(OC2H5), + C2H50MgBr

pentylmagnesium 1 I-diethoxyhexanebromideCH3(CH2),CH(0C2H,)2 HC1~ CH,(CH,),CHO

hexanal7. addition of organometallic compounds to N,N-dimethylmethanamide

OLi 0

The addition product is an acetal,which can be hydrolyzed in diluteacid to the aldehyde.

The tertiary amine, R,CHN(CH,),,often is a major product withRMgX and HCON(CH,),. See Section14-12C.

I-cycloheptenecarbaldehyde8. hydration of alkynes A commercial synthesis of ethanal;

~ ~ 2 0 ,@ see Section 10-5A.HC=CH + H20 > [H,C=CHOH] - H,CHOethyne ethanal

9. hydrolysis of aldehyde derivatives-includes hydrogen sulfite additioncompounds, acetals, oximes, Schiff's bases, hydrazones, andsemicarbazones10. addition o f carbon monoxide and hydrogen to alkenes

cyclopentene cyclopentanecarbaldehyde (65%)11. hydroboration of alkenes and carbonylation of alkylboranes

0CH2=CHCH2CN IICo [0 1 HCCH2CH,CH2CN2BH R,BCH,CH,CH,CN --,--+

More useful for the purificationthan for preparation of aldehydes.

See Section 16-9F.

See Section 16-9G; R,BH = "9-BBN"

'-4

7 NaPreparations of aromatic aldehydes are described in Chapters 22 and 6. CD


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16 Carbo nyl Comp ound s I. Aldehy des an d Ketones. Add it ion Reactions of the Carbony l Group


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Table of General M etho ds for the Preparation of Ketones


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16 Carbonyl Compounds I. Aldehydes and Ketones. Addit ion Reactions of the Carbonyl Group


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Supplementary ExercisesSupplementary Exercises

16-48 Write equations for the synthesis of the following substances based on theindicated start ing materials. Give the reaction condit ions as accurately as possible.a. 2-methyl propa nal from 3-methyl butanolb. I -cyc lobuty lethanone from cyclobutanecarboxylic ac idc. pentanedial from cyclopentanoned. cyclobutane from methylenecyclobutanee. 2,2,2-trichloroethyl trichloroethanoate from 2,2,2-trichloroethanalf. cyclopentene-1 carboxyl ic acid from cyclopentanone16-49 Write reasonable mechanisms for each of the following reactions. Supportyour formulations with detailed analogies insofar as possible.

0 0II IIa. H-C-C-H + NaOH HOCH2C02Na

(Notice that this is a base-catalyz ed reaction.)

d. Hexam ethylenetetramine from methanal and am monia. (C onside r the possibil i tyof CH2=N H as an interme diate for the stepw ise formation of N,N1 ,N"-tris(hydroxy-me thyl) - I 3,5-triazacyclohexane as an intermediate fol lowed by acid- ind uce d con-densation of the latter with ammonia.)16-50 I t is important to be able to decide whether a plausible-looking reactionactually wil l proceed as written. The following equations represent "possible" syn-thetic reactions. Con sider eac h carefully and de ci de whether it wil l proce ed as written.Show your reasoning. If you think another reaction would occur, write an equationfor it.

excessCH OHa. CH3CH(OC2H5),+ 2NaOCH32 H3CH(OCH3),+ 2NaOC2H550"H 0b. (CH,),CCOCH,CH, + KMnO, (CH,),COH + CH3CH2C02KKOH


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734 16 Carbonyl Compound s I . Aldehydes and Ketones. Addit ion Reactions of the Carbonyl G roupCH OHe. O=CH-C0,H + NaBH,A =CH-CH,OH

f. CH,=O + (CH,),C=O + NaOH- C0,Na + (CH,),CHOH16-51 Write a me cha nism for the oxidation of sodium methanoate (formate) to carb ondiox ide by potassium pe rman ganate which is consistent with the fol lowing facts:(a ) v = k[HCO,@][MnO,@](b ) the CO, has no 180n it if oxidized with Mni804@(c ) DCO,@ is oxidi ze d at one seventh th e rate of HCO,@Compare your m echanism w ith that generally ac cep ted for the Cannizzaro reaction.16-52 2-Propanone reacts with trichloromethane in the presence of potassiumhydroxide to give 1 I I-tr ichloro-2-m ethyl-2-propanol. What is l ikely to b e the mech-anism of this reaction? What further evidence could be gained to establish themechanism? (If you do not see a possible answer, refer to Section 14-7B for helpfulinformation.)16-53 The s tructure of the sex attractant. of the silkworm, "bom byk ol," is given inSection 5-6 as structure 30. The compound has been synthesized by the route givenbelow . Write the structures of ea ch of the synthetic intermed iates A-F.

Na C= CH 1. CH,MgCI PBr,CH,CH,CH,Br- 2 HCHO > B - C

(C H ) P 1 . base (C2H50N a)C E H2, Pd2. O=CH(CH2),C02C2H5 ' (Llndlar)LiAIH,F ------+ "bombykol"

Bpo c Chapter 16

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