Tse-Lok Ho Brookhaven National Laboratory. Upton. New York, 11973
Analysis of Some Synthetic Reactions by the HSAB Principle
The specific it.^ and efficiencyof reactions often have been left unexplained. Addressing these deficiencies, we delineate an empirical ana1.yssi o f a selected number o f s.yntheti reactions based on the hard and soft acids and bases (HSAB) principle. Recent trends of oraanic chemistrv have been dominated largely by synthrsis, whose ctce lies in individual reactions. 'l'hc t;fficr:nc\~.swcificirv, and stereoelectronic cunrrol oieach process contribute heavily to the aesthetic as well as practical value of a synthetic exercise. While the basic, if not the detailed, mechanisms of most reaction types are either fairly well known or predictable by analogy, the specificity and efficiency of reactions have often been left unexplained. Addressing these deficiencies, I shall delineate an empirical analysis of a selected number of synthetic reactions based on the hard and soft acids a n d bases (HSAB) principle. The simplicity of such analysis will hopefully aid the student to focus more sharply on group reactivities and reactant compatibilities. It mieht also nrovide a basis on which new Drocesses are form z a t e d and put to test. The HSAB ~ r i n c i ~was l e ~roooundedbv Pearson (1.2) in 1963. The widk-ranging a p ~ l i c ~ h i l ito t y various branches of descriptive chemistry seems to be well established, and a monograph (3) dealing with organic panorama has been published. Thus, it is necessary only to reiterate here the principle which states that hard acids bind strongly to hard bases and soft acids bind strongly to soft bases; for other background materials, the reader is referred to the previous reviews (2,3). This article is not intended to be exhaustive, rather it represents a random sampling of some newer reactions which demonstrate the usefulness of the analysis. Furthermore, it should be emphasized that softness or hardness is not the only factor governing chemical events, although the most efficient processes are generally those having excellent matches in softness (hardness) among reactants. As application of the HSAB principle to reactions does not really require exact mechanistic knowledge, matters are greatly simplified. In the following discussion, the terms acid and electrophile, base and nucleophile, respectively, are interchangeable.
Chloromethyl ethers are hard acids. Consequently, exclusive O-alkylation (5) occurs when 0-dicarhonyl compounds are exposed to these reagents. Interestingly, ethyl sodioacetoacetate undergoes reaction a t carbon with the softer chloromethyl methyl sulfide ( 6 ) .
Acylation and silylation generally take place a t the oxygen base sites because acylating and silylatiug agents are hard acids. Variation in the alkylatingpatterns of imine anions (7)and a-cyano carbanions ( 8 ) follows the same trend. ""YMe NPh
RX RX RX
.,"
PhyCH.
'H
= EtI = Et,SO, = E~,O B
'
C
RCHTS Ma
EtNPh 0.1
1.2 F ~22 RR'CHCN
+
l'hYCH
: :
:
Et
NPh 1
1 1
+ MX
PIZ;in R C H = C = N S i R '
+ MI'I
2-Cyclohexentme iz an amhidenr elertrnphile puscesaing n hard c,~rlwnslsnd a vft ,i-csrhm center. \Vhile the kinetically controlled adducts with a-alkoxyacetic ester carbanions are the tertiary alcohols, Michael adducts with N-alkylthioacetate anions are formed (9). The hardening and softening effects of the a-alkoxy and N-alkylthio substituents, respectively, on the parent eCH&OOR are reflected in the regioselectivities.
Ambident Reactivities
The amhident reactivity of stabilized (&ketoesters, 8diketones) enolate anions is well documented. The dependence of the 0:C ratio in alkylation by electrophiles can he readily correlated with the hardness of the latter. As a rule, bieher . oronortions of O-alkvl . . .~ r o d u c t sresult when harder electrophiles are used. The trend is also observed in alkylation of s i m ~ l enolates. e as exemdified hv the amvlation of hutv-
The HSAB concept can be employed to explain why enamines undergo a-cyanation (10)with cyanogen chloride and a-bromination (11) with cyanogen bromide.
Note that the hardness of AmX decreases along the series AmC1> AmBr > AmI. Volume 55, Number 6. June 1978 / 355
According to polarieabiliry measuremrnu, the relative s d ness follw\s thr order Hrm> CiKe > CIm.Naturally the carbrm base ol the enamines sreks out the softer arid as it. reaction partner. Similar observations have been recorded for the cleavage of carbon-metal bonds in Grignard (12) and organotin compounds (13) with cyanogen halides.
Organometallic Reactions The svnthesis of benzene-dl from bromobenzene bv successive treatment with n-hutyllithium and deuterium oxide is imnractical. However. considerable imnrovement in vield can de accomplished b; adding n-BuLi directly to hromobenzene in an ether solution presaturated with D20 (14). Apparently the halogen-metal exchange proceeds much faster than deuterolysis (hydrolysis) of n-hutyllithium. The former reaction represents a favorable soft-soft interaction whereas
0
n-Ru-Li J
Hr-Ph
-
Phti
+ n-BuRr
@ ,
the latter is that of soft-hard type. Deuterolysis of the oreanometallic is inevitable under the circumstances, hut it takes plare only whm the exchnnge is rmnpl?ted. It should IS a harder base than he noted that thr enduing ~hens.lithi~lm n-butyllithium and therefore more susceptible to attack by hard acids. This kind of technique also allows the preparation of phenyltrimethylsilane by replacing DzO with trimethylsilyl chloride. Both "Dm" and "MesSim2'belong to the hard category. The halogen-metal exchange of a gem-dibromocyclopropanecarboxylic acid is 2.5 times faster than proton abstraction from the acid. This differential reactivity has been capitalized in a synthesis of henzocycloalkanones (15)by internal attack of a lithiated arene on a carboxylate group.
@ @ A variant consisting of sequential treatment of a-haloketones with pyridine and sodium dithionite (18)involves initially an essentially hard-hard interaction and a reduction (with a soft base) a t the soft site (C-4) of the pyridinium ring which is followed by fragmentation. a-Ketohalides are much harder than ordinary alkyl halides because the neighboring carbonyl group has a hardening effect.
ii a,a'-Dibromoketones react with diorganocuprates in a manner shown in the following equation (19).
After debromination by the soft orgauometallic reagent, cyclopropanone intermediates are formed by an internal displacement. Cyclopropanones, behaving somewhat like aSunsaturated ketones, are susceptible to attack by soft bases present in excess. The ensuing monoalkylated enolates may be quenched or alkylated further. An effective aldol condensation method involves the generation of aluminum enolates from a-bromocarbonyl compounds by treatment with a mixture of zinc dust and diethylaluminum chloride a t low temperature (20). Et,
01
/Et A1
OAIEt,
I'
n
\
n
It is noted that the classical Reformatskv reaction requires more strenuous conditions, where a hard arid irg.. All is ahsent for assisting the &I~ruminativeena,lization. Dehydration In a peptide synthesis based on redox condensation (21), disulfide-triphenylphosphine adducts are used to activate carboxylic acids for coupling with amines. The initial soft-soft interaction between PhsP and disulfide transforms the soft base [P(III)] into a hard acid
Debromination of ol-Bromoketones Several efficient methods for hydrodebromination of a hromoketones are available through recent development. While the use of sodium horohydride-heavy metal salt combination (16) can he portrayed by a push-pull mechanism in which all the interactions are soft, the procedure utilizing lithium iodide and boron trifluoride (17) involves soft-soft and hard-hard interactions a t two different reaction loci. The presence of two complementary reagents is essential for the desired reactions to occur.
356 1 Journal of Chemical Education
[-h or I
P(V)] which is reactive toward hard bases such as the carboxylate ion. On formation of phosphonium carboxylates the carhoxyl group is conferred a hard acid character suitable to react with amlnes. l'h P
+R
R
-
a
R'm,L'
PhyPSR R@ ;G-
The analysis reveals a powerful guideline for reaction design. In brief, reversal of the acidlbase nature and simultaneously the hardhoft characteristics of a compound tend to endow it with great reactivity toward an acidbase possessing opposite hardlsoft properties. Thus, the above example shows that the soft base triphenylphosphine, after modification, is capable of reacting with and converting the hard base carboxylate into an active hard acid.
Other svnthetic methods embodvina . . this stratem .. include the use of fhr azod~f~sniate esrrr-tril>hrnylpho~phinerouple in dehdration of fornmnide-. (221. alkslation of imines hy alcobois (23), and ether formation (24):~he interaction between PhaP and azodiformates produces dipolar species with both hard acid and hard base moieties. R
H-NR
ROH, etc.). Many reactive molecules have been generated via a desilylative elimination route.
NHCOR'
Intramolecular transfer of a hard phosphonium group is illustrated in the thiirane formation from 8-hydroxysnlfenyl chlorides (2.5).
The biphilic reactions, whether they are concerted or stepwise, involve the change of softhard character of the attacking hase.
The oxaphilicity of silicon, consequential of its hardness, has been employed in a number of olefination methods. The siliron atom aervrs the same purpose as the P(V) renter of Wittig reagents, such that both subsequently depart with concomitant removal of an oxygen atom. The synthesis of ketene dit,hioacetals 1.74-36) is representative.
Isomerization of olefins via epoxides may be achieved by treatment of the latter species with triorganosilyl metal (37, 38) reagents. The macrolactonization of o-hydroxy acids developed by Corey and Nicolaou (26), and independently by Gerlacb and Thalmann (27), is a very valuable synthetic process. Although the occurrence of a soft-hard interaction intervenes in thioesterification, the unfavorable step may have been dictated hy the equally destabilizing charge separation. Conversion of carhoxylic phosphoric anhydrides to thioesters is an important. hiosynthetic operation.
This reaction has been exploited in the synthesis of complex natural nroducts (28) such as 7.earalenone. hrefeldin A, carpaine, recifeiolide. to the antihiotic methvmycin (29) In Masamune's aowoach .. activation of appropriate w-hydroxy thioesters with mercuric salts leads to useful vields of macrolides. The facile soft-soft interaction hetween Hg and S renders the thioester carbonyl very reactive toward hard hases such as hydroxy groups. The catalvsis of 2-hydroxypyridine in aminolysis (30) of esters reflects a multicenter reaction in which all relevant atoms participate in hard interactions. Qrganosillcon Compounds: Typical Hard Acids Owing to its greater hardness as compared to carbon, the silicon center shows high affinity for very bard bases (Fe,
All the side reactions are suppressed when acyloin condensation is carried out in the presence of MegSiCl(39). The rationale for this is that while the condensation is effected by a soft agent (Na metal) through electron transfer, the products are the hard enediolate and alkoxide ions, and the removal of these species (ex. with MegSiCI) is imperative in order to prevent Claisen and/or Dierkmann condensations from occurring. Trialkylsilyl and trialkylstannyl derivatives of secondary alcohols undergo oxidative fragmentation on contact with hydride abstractors (40,41). The most efficient reagents appear to incorporate hoth a soft. acid and a hard has? pair (ex. NOePFfie).
Recently a general method for ester hydrolysis under essentially neutral conditions has evolved from HSAR considerations (42). The reagent, trimethylsilyl iodide, contains a hard acid and a soft. hase center, which are complementary to carhoxylic esters. Volume 55. Number 6.June 1978 / 357
In the role of an acid, Se of organoselenides is the target of action by organolithiums. For example, tetrachloroselenophene fragments to dichlorohutadiyne (463, diselenoacetals (47) and selenothioacetals (48) lose seleno groups selectively. 'l'he equimthr mixture ot phenyltrim~thylsilaneand iodine i i rvrn mure rtfrrtiw i-$31. I t is i~t~ssihle that here a termolecular, HSAB-matched six-center transition state is involved.
Insertion of oreanosilvl derivatives MeeSiX hv carhonvl cornp'r~ind-.has hrrn intensively invritigated (44). Anionic s~eciesrar~ahlr otnddition rocarbunvl tC'Ne.. Y *P .I oreffectine lkand exihange on silicon (e.g. F e j a r i efficient catalysts. "
X = CN. N,, SR Y=F,CN
Addition of alkylthio- or arylthio-trimethylsilane to saturated ketones is strongly catalyzed by Lewis acids. This finding seems to negate the notion of initial attack of thiolate anions on C=O (a hard-soft interaction) leading to O-silylhemithioacetals and thioketals by a mixture of MesSiCI, RSH and pyridine. The reaction of organothiosilanes with ao-unsaturated carhonyl compounds may he conveniently initiated hy triphenylphosphine. As expected, Michael addition of the promoter to enones (enals) is the first step, and the adducts have heen isolated in the form of the phosphonium chlorides by deliberately using molar amounts of MenSiCl.
It is pertinent to mention that phosphines have been utilized as catalysts for Michael addition (45). Advantage was being taken in the facile generation of zwitterionic species and the ability of these to deprotonate Michael donors. While the soft phosphines cannot act as proton abstractor, the zwitterions are effective ones on account of the enolate character.
The diffvrvnvc suftness mnkes is manifested in the behavior of thr selcnuacetals 0.;cmtrasted t o dithioilcetali which \indergo deprotonation only (cf. Corey-Seehach reaction (49)). a-Silylalkyl methyl selenides surrender the methylseleno group to n-hutyllithium. Interestingly, the phenyl selenides undergo phenyl butyl exchange (50) instead.
I believe that adducts with tetravalent selenium atoms are formed and decomposed via mode a or b (see arrows in figure) depending on R. If R is harder than R3"SiCHR', it takes precedence to capture Li which is a hard acid. f?
nRu
I
I
Pertinently, cleavage of the Se-C bond which has a higher hard-soft differential also stabilizes the whole system. Carboxylic esters are generally quite inert to Wittig reagents. By contrast, selenoesters are readily converted to en01 esters on exposure to metbylenetriphenylphosphorane(51). Since selenoesters are softer than normal esters, they are very susceptible to attack by soft bases such as the Wittig reagents. Extrapolating from the observations that ketone and thione groups often exhibit different regioaffinities for soft bases (e.g. RMgX, CHzNz), a mechanism involving selenophilic attack for the reaction under discussion merits serious consideration. This mechanism is sound in the HSAB context.
- ">ell,+
1 IWI I
m.m
f?o
Degradation of a-silyl selenides by hydrogen peroxide (52) involves Se in the role of a soft base and Si as a hard acid.
Selenium: Consequences of Being Son
Divalent selenium can act as either a soft acid or a soft base. 358 / Journal of Chemical Education
By virtue of their softness, selenides are readily oxidized to selenoxides hy hydrogen peroxide, ozone, and other reagents. However, the intrinsic soft nature of Se renders high valent selenium compounds rather unstable; thus, selenoxides decompose spontaneously a t room temperature or below. This property has heen exploited in olefin synthesis (53).
Comparison should he made with the corresponding sulfoxides which are thermolyzed at -100' higher. Among the many reactions whose main driving force is lowering the oxidation state of selenium, a method for regeneration of ketones from hydrazones, oximes, and semicarhazones by treatment with henzeneseleoinic anhydride may he mentioned (54).
Elemental selenium is a soft acid. It adds t o and therehy activates carhon monoxide. The transient adduct is reactive toward hard bases (55). se
+ r0
-
o 0 Se-C=o
-
& ?
be-COXR
RXH
H&-C1XRla
-COO[R),
+Se
I 00
+ H~
X=NH. 0
The scope of synthetic reactions involving sulfur compounds (56) is too wide to he discussed in this article. However, I wish to illustrate the relevance of HSAB in this area by analviine A method for se. . results from two recent DaDers. . . Iwtive cleavage of cinnamyl esters ( 5 7 )consists of methoxymercuration and subsequent rreatmpnt with KSCN.
h
~
e
The Markovnikov rule dictates the attachment of the mercurial residue to the carhon atom vicinal to the carboxyl function. This permits triggering an E2 reaction with a soft base such as the thiocyanate ion. The other observation is that 2-lithiodithianes add onto the carhonyl group of conjugated enones, whereas open-chain lithiodithioacetals tend to behave as Michael donors (58).
Why are the lithiodithianes more reluctant to rehybridize? The reason might he steric. Widening of the intracyclic hond angle of C-2 is required for attaining the sp2 configuration, and in so doing strain is introduced (angle strain and 1,3diaxial interaction due to a reflex effect) which may not he compensated by energy gain through p,-d, overlap. It should he noted that if the lithiodithiane carries a 2suhstituent capable of conjugation (e.g. COOMe, CN) 1,4addition to enones is observed. reflectine that rehvhridization has taken place. Complex Metal Hydride Reductions
The reduction of ap-unsaturated ketones with complex metal hydrides has been examined from the HSAB viewpoint (59). From an analysis hased on the reasonable assumptions that in the conjugate enone system C-4 is softer than C-2 icarbonvl carhon) and that the more covalent M-H hond corresponds to the softer hydride, a unified picture emerges. The replacement of some of the hydride ions by hard alkoxy groups suppresses the softer conjugate addition to the enones. The proportion of 1,2- versus l,4-reduction of cyclopentenone varies from 1486 using LiAlH4 to a dramatic 90:9.5 using lithium trimethoxyaluminum hydride. The uo-unsaturated esters are reduced to allylic alcohols by LiAIHa in the presence of ethanol. The ethoxvaluminum hvdride is the active reducer. Analogously, the reduction of cholestenone with NaBH4 and NaBH(0Meh produces 1,2- and 1,4-reduction products in the ratios of 7426 and 98:2, respectively. The opposite effect is exerted by alkyl suhstituents. Potassium tri-sec-hutylhorohydride effects 1,4-reduction of cyclohexenones exclusively. Since boron is closer in electronegativity to hydrogen than aluminum, the B-H hond is more covalent than the A1-H hond. It follows that the horohydrides are softer than the corresponding aluminum hydrides. As a result, horohydrides are quite inert to protic solvents (hard He sources), and they tend to give more conjugate reduction products. The softer counterion Nae also favors 1,4-reduction (cf. NaBH4 versus LiBH4). The alkali metal ions, in fact, play a significant role in modifying the substrate frontier orbital energy levels through their interaction with the carhonyl oxygen. The extent of this modification is dependent on the hardness of the cation. The addition of an amine to the metal hydrides limits the transfer of one hydride ion to the substrates. As the formation of alkoxyhorohydride is also inhibited, 1,4-reduction is favored. The conjugate reduction of enones is easier than that for enal, because aldehyde carhonyl is softer than the ketone counterpart. Alkyl suhstituents in the u and ppositions of the enones interfere with conjugate reduction. However, treatment of a-alkylthiocyclohexeuones with NaBH4 successfully gives saturated alcohols (60). I t has been proposed that intramolecular He delivery from a S-coordinated horohydride is involved. A marked increase in the 1,keduction (61) of enones by LiAIH(SRh is observed (see table). Symbiotic softening of the reagents by the thio suhstituents is responsible for the reversal of the alkoxy effects. Percentage of 1,4-Reductions LiAlH,
Explanation of this dichotomy has been lacking. However, if we consider that C-2 of 2-lithiodithianes is essentially spahybridized, like that of most other saturated alkyllithiums, then its attack at the carhonyl of an enone system is well precedented. On the other hand, the lithiodithioacetals are expected to assume a sp2-hybridized state which is favored by orbital overlap with the neighboring sulfur atoms and the decreased steric repulsion among the three suhstituents. The resulting anionic centers are softer (electron pair on p orbital) and 1,4-addition becomes the preferred course of reaction.
LiAIHl
LiAlH.
LIAIH,
+ 3MeOH + 3f-BuOH + 3MeSH + 3t-BUSH
Enone
LiAlH4
Cyclohexenone Cyclopent-
22
5
86
9.5
78
56
95
100
95
100
enone
Volume 55. Number 6.June 1978 1 359
.4lun1inum hydrides in which the metal atoms do not bear form31 negative charge are harder; therefore aluminum hydride and diisobutylaluminum hydride (62) attack selectivrlv a t . the enone carhonyl. I +Addition across the enone system is the major reaction ccorse for organotin hydrides which are quite soft (63). Sulfnnes are very difficult to reduce. They are converted t~ sulfides in low yields by lithium aluminum hydride. While ;;dium dirthylnluminum hydride is ineffective, diisobutylaI u ~ r i i l ~ uhvdride m (64) improves the efficiency greatly. The fullowing equation summarizes the HSAB relationship. 3
0
(23) Mitsunohu, 0.. Wads, M.. and Sann,T., J . Amar. Chem. Soc., 94,679 (1972). (24) Msnhnr. M S . , Hoffman, W. H.,Lnl, B.,and R0ae.A. K.. J. Chem .&c. Perkin mm.. 1.461 (1915). (25) Raldruln,d.E..mdHeason,D.P.,Chsm. Commun., 667i19161. (26) C o w . E. L a n d Nicolnou,K. C.. J. Amrr Chsm Snc. 96.6614 11974) 129) Marnmune. S.,Yarnarnoto, H.. Karnstn, S.. and Fukuraua. A,, J. Amer. Chem Soc., 91,3518 11975). 130) Openshau, H.T..snd Whittaker,N.. J . Chpm Soe.. C.89 (1969).
@
kiterafura Cited
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I?>!
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360 / Journal of Chemical Education
1521 Swhdrv. K ,and S~%d~deu. H. S.. Trlrohrdron 1 . r ~ 1223 . 11976). (6:ll Sharplpas, K. B.. Cnrdon. K. M., 1.awr. R. F., Patrirk, U. W.. Singer. S.P.. andYuun~, M. W..rh
